CHAPTER 3

The Venom System and Envenomation

he most widely recognized feature Campo 1956). But it was not until the 1880s
T of the Helodermatidae family is that its
members are venomous. Misunderstanding
that the anatomy of the venom gland was inves-
tigated (Fischer 1882), and experiments were
and confusion about this trait have accompa- conducted to show that its salivary secretions
nied Heloderma since before the genus was were, in fact, toxic to other animals (Mitchell
described by Hernández in 1577. As discussed and Reichert 1883). Instead of resolving uncer-
in chapter 1, the specific epithet, suspectum, was tainty about the venomous nature of Heloderma,
chosen for the Gila Monster because E. D. Cope however, this work served to initiate a contro-
suspected it was venomous (Cope 1869), but it versy that lasted for several decades. Subse-
was not until well into the twentieth century quent experiments (Yarrow 1888) failed to show
that scientists agreed that, indeed, this was toxic effects of Heloderma venom, probably be-
true. Debate continues over whether the venom cause inappropriate methods were used to col-
is used for prey acquisition or defense, and, lect the venom. Additional investigators exam-
more recently, promise has arisen over its po- ined the histology of the venom gland (Holm
tential applications in modern medicine and 1897) and showed, with controls, that carefully
pharmacology. extracted venom injected into small vertebrates
In this chapter, I outline the structure and had lethal effects (Santesson 1897; Van Den-
function of the venom delivery system of helo- burgh 1898; Van Denburgh and Wight 1900).
dermatid lizards. I provide a historical overview, Nevertheless, skepticism remained. Snow
synthesize recent developments in venom bio- (1906), having suffered a bite without experi-
chemistry, and consider the function of the encing serious pain or swelling, again raised
venom system in its ecological context. I con- the question of whether Heloderma was ven-
clude the chapter with an overview of enveno- omous. In 1907, Goodfellow made the follow-
mation history and the treatment of bites. ing statement: “. . . exhaustive studies were
made by some of the attaches of the Smithson-
ian Institution, among whom was Dr. R. E.
HISTORICAL OVERVIEW
Shufeldt, concerning the nature of the animal,
Several authors in the latter half of the nine- and conclusions reached which the writer had
teenth century commented on the “vile nature” previously attained—that the reptile was non-
of Heloderma and recognized that its unique venomous; and it may be accepted as conclu-
grooved dentition might be associated with a sively demonstrated that the bite of the “monster”
venomous bite (see Bogert and Martín del is innocuous per se. In 1913, an authoritative,

41
244-page book summarizing detailed studies of venom toward the venom-conducting teeth, and
the venom of Heloderma was published by the capillary action carries the venom from grooved
Carnegie Institution of Washington (Loeb et al. teeth into the wound.
1913). This book contained detailed studies by 11 The structure of the venom gland was first
contributors on numerous aspects of the venom, described by Fischer (1882), but the most com-
including its biochemistry and effects on various plete descriptions to date remain the work of
physiological systems in a number of organ- Fox (1913) and Phisalix (1912, 1917). More re-
isms. By the 1920s, this book, and additional cent reviews (e.g., Bogert and Martín del Campo
studies on the venom gland, venom effects, and 1956; Tinkham 1971b; Russell and Bogert 1981),
venom characteristics by Phisalix (1911, 1912, as well as what I provide below, are largely sum-
1917, 1922), finally convinced the scientific com- maries of this earlier work.
munity that helodermatid lizards were indeed The venom glands of helodermatid lizards
venomous, and the debate was settled over the are visible externally as conspicuous swellings
“suspected” venomous nature of Heloderma. below the lower lips (fig. 9, plate 20). Each
gland is surrounded by a fibrous capsule from
which septa extend to divide the gland into
VENOM DELIVERY SYSTEM
three or four distinct lobes (fig. 9). Each lobe of
Heloderma delivers venom through an efficient the venom gland is a structurally independent
system consisting of paired venom glands that organ that forms a sac with a swollen glandular
empty through ducts at the base of venom- region at its base and a narrowed excretory duct
conducting teeth. Venom is produced and near the upper end, which empties at the base
housed in multilobed venom glands (fig. 9), of the teeth in the lower jaw (fig. 10). Each lobe
which, unlike those of venomous snakes, are lo- of the venom gland is subdivided (by septa) into
cated in the lower jaw and drain through ducts several lobules, which are further subdivided
associated with each of the lobes. In contrast, into smaller lobules. These subdivisions con-
the venom glands of snakes are situated behind tinue to occur, resulting in tiny chambers, or
the eye, above the upper jaw, and drain through alveoli, each separated from one another by a
a single duct that leads to an opening at the base delicate septum. The cavities within the alveoli
of the associated fang (Greene 1997). The are continuous with the lobules, which are, in
venom glands of Heloderma are not surrounded turn, continuous with one another, forming a
by compressor musculature as in most ven- network of intralobular tubules. It is within
omous snakes. Instead, tension within the these structures, apparently, that venom is pro-
glands produced by jaw movements propels duced by columnar, granule-secreting cells that

(a) (b)

FIGURE 9. The venom glands of helodermatid lizards are located in the lower jaw. Each gland comprises three or four distinct
lobes as shown in these 2 views of a Gila Monster’s right lower mandible with the skin removed (drawings by Randy Babb).

42 t h e v e n o m s y s t e m a n d e n v e n o m a t i o n
 LABIAL GROOVE alveoli, apparently also serves as a storage reser-
VENOM DUCT voir for venom.
TOOTH
Helodermatids are not specialized for inject-
ing large quantities of venom during brief con-
EPIDERMIS
TONGUE tact, as are many venomous snakes, but the
venom delivery system is structured to quickly
and effectively transfer venom into a bite. Dur-
ing biting, tension produced in the gland by jaw
DENTAL CUP movements propels venom through the venom
ducts into a region between the fourth and sev-
JAW BONE enth pair of dentaries (counting from the front),
VENOM GLAND where the teeth show their greatest specializa-
tion for piercing and venom delivery. A series of
small folds and grooves in the membranous tis-
sue within this region serves as a temporary
reservoir for the venom and may facilitate the
flow of venom from duct to tooth. When the
lizard bites, venom flows from these reservoirs
FIGURE 10. This cross section through the anterior portion through the grooved teeth into the wound.
of the right mandible shows relationships of the primary Each specialized tooth has two grooves, with
structures of the venom delivery system of helodermatid
lizards. Each lobe of the venom gland forms a sac with a
a shallower (sometimes absent) groove toward
narrowed excretory duct near its upper end. The duct emp- the rear (fig. 11) . Each groove is flanked by a cut-
ties at the base of venom-conducting teeth in the lower jaw. ting flange, which makes the tooth better
adapted for piercing flesh than a merely conical
line the intralobular tubules. As these cells dis- tooth. Not all the teeth are similar in structure
charge their contents, the secreted granules or size. The largest, most deeply grooved teeth
flow from the tubules into a central collecting are the dentaries (in the lower jaw), which can
lumen, which connects to the excretory duct. be up to 6 mm long in H. horridum and 5 mm
The lumen, along with associated tubules and long in H. suspectum (fig. 11). The maxillary

FIGURE 11. Skull of Heloderma suspectum showing arrangement of venom-conducting teeth (top). The largest, most deeply
grooved teeth are the dentaries (in the lower jaw), which can be up to 5 mm long in H. suspectum (drawings by Randy Babb).

the venom system and envenomation 43

teeth (in the upper jaw) are shorter and less vomiting accompanied by discharge of urine
strongly grooved. Some teeth (especially the and feces, and copious flow of saliva and tears.
premaxillaries toward the front of the mouth) Death from large doses of Heloderma venom
are hardly grooved at all, but they can still effec- has been attributed primarily to respiratory
tively deposit venom into an adversary (Tinkham disturbances (Cooke and Loeb 1913). Post-
1956; Strimple et al. 1997). mortem examinations reveal congestion and
Jaw movements other than those associated edema in the lungs, a marked congestion of
with biting may also produce sufficient tension the serous layer of the stomach and intestines,
within the glands to bathe all the teeth in and hemorrhage in the kidneys and liver
venom. An agitated lizard will often display a (Cooke and Loeb 1913; Ariano Sánchez 2003).
defensive posture of opening its jaws wide (ex- Sublethal doses in mice and rats produce pro-
posing the purplish-white interior of its mouth) trusion of the eyes and periorbital bleeding
then closing and reopening the jaws as a threat (Cooke and Loeb 1913; Ariano Sánchez 2003),
continues. This behavior may serve to bathe the and in rabbits they lead to an increase in the
maxillary teeth, dentaries, and premaxillaries in number of white blood cells (Meyers and Tuttle
venom preparatory to envenomation. 1913). In humans, the effects of bites are asso-
The quantity of venom deposited into the vic- ciated with excruciating pain that may extend
tim may vary with many factors, including size of well beyond the area bitten and persist up to
the lizard, degree of agitation, and length of time 24 hours. Other common effects of Heloderma
it remains attached. In captive Gila Monsters, bites on humans include local edema (swelling),
quantities ranging from 0.5 to 2.0 ml in a single weakness, sweating, and a rapid fall in blood
milking have been extracted by a variety of meth- pressure (see below). A summary of the effects
ods (Loeb et al. 1913; Arrington 1930; Brown and of Heloderma venom on mammals is given in
Lowe 1955; Alagón et al. 1982; fig. 12). table 4.
The lethal dose (LD50) of Heloderma venom
varies among studies and venom lots (Russell
EFFECTS OF THE VENOM
and Bogert 1981). Such values are influenced by
The most complete investigation of the effects the relative amounts of venom and saliva col-
of Heloderma venom remains the work of Loeb lected in each sample and are, therefore, diffi-
et al. (1913) who tested hundreds of species, in- cult to evaluate. The venom is most toxic when
cluding invertebrates. Invertebrates are essen- administered intravenously in mice, with LD50
tially immune to the effects of Heloderma values varying from 0.4 to 2.7 mg/kg for H.
venom. Effects on vertebrates are more severe suspectum (table 5). With an i.v. LD50 of 1.4 to 2.7
and varied. Ectotherms appear markedly less mg/kg, the venom of H. horridum appears to
susceptible to the effects of the venom than do have toxicity similar to that of H. suspectum.
endotherms (Cooke and Loeb 1913). Notably, The LD for H. horridum charlesbogerti venom is
Gila Monsters appear to be immune to the ef- 1.0 mg/kg when injected intramuscularly in
fects of their own venom (Cooke and Loeb 1913; rats (Ariano Sánchez 2003). When injected into
Brown and Lowe 1954). mammals, the venom of Heloderma appears
In mammals, major effects include a rapid to be about as toxic as that of the Western
reduction in carotid blood flow followed by a Diamondback Rattlesnake, Crotalus atrox (Russell
marked fall in blood pressure, respiratory ir- and Bogert 1981).
regularities, tachycardia and other cardiac
anomalies, as well as hypothermia, edema and
CHEMICAL MAKEUP OF THE VENOM
internal hemorrhage in the gastrointestinal
tract, lungs, eyes, liver, and kidneys (table 4). As knowledge of the toxic effects produced by
Common symptoms in dogs and cats include Heloderma venom increased, so did interest in

44 the venom system and envenomation

 TABLE 4
Effects of Venom of Helodermatid Lizards in Nonhuman Mammals

effects references

Respiration
Initial increase in rate, “forced” respirations Cooke and Loeb 1913
followed by decrease and eventual standstill
Ventilatory irregularities: gasping, rapid, shallow Patterson 1967a
breaths, apnea
Cardiovascular System
Marked and rapid fall in blood pressure Mitchell and Reichert 1883
Initial tachycardia Van Denburgh and Wight 1900
Cardiac irregularities Fleisher 1913
Impaired cardiac function/cardiac failure Patterson 1967a
Reduction in carotid blood flow and arterial Russell and Bogert 1981
blood oxygenation
Cyanosis
Hemorrhage
GI tract Cooke and Loeb 1913
Intestines, kidneys, lungs Patterson 1967a
Eyes St ýblová and Kornalik 1967
Liver Ariano Sánchez 2003
Blood
Leucocytosis Meyers and Tuttle 1913
No effect on blood coagulation time Cooke and Loeb 1913
Prolonged prothrombin time (anticoagulation) Patterson and Lee 1969
Smooth Muscle
Stimulating effect in ileum, colon, uterus Patterson 1967b
Edema (note also with human envenomation)
Intestines, stomach, lungs Cooke and Loeb 1913
Other Effects
Paralysis of limbs, partial paralysis of body Patterson 1967a
Protrusion of eyes (exophthalmia) Cooke and Loeb 1913
Lacrimation
Abdominal rigidity
Convulsions
Vomiting

NOTE: Based on in vivo studies in cats, dogs, guinea pigs, mice, and rats.

the chemical constituents causing these symp- the venom of H. horridum in 1960 (Zara-
toms. The first studies on the chemical nature fonetis and Kalas 1960). Mebs and Raudonat
of Heloderma venom (Santesson 1897) identi- (1966) identified a very active hyaluronidase (a
fied two “toxic principles,” referred to as nu- spreading factor; see below), phospholipase A,
clein and albuminose, but it was not until 1913 and a kinin-releasing enzyme with small pro-
that the first toxin, a lipase, was isolated (Als- teolytic activity in both H. horridum and H. sus-
berg 1913). The 1960s saw renewed interest in pectum venom. In 1967, Tu and Murdoch
the chemistry of Heloderma venom. Serotonin showed that H. suspectum venom was largely a
and amine oxidase activity were identified in mixture of proteins, some of which hydrolyze

the venom system and envenomation 45

 TABLE 5
LD50 of Heloderma Venom in Mice and Rats

avenue species ld50 (mg/kg) species

Johnson et al. 1966 Intraperitoneal mice 3.0 suspectum

Mebs and Raudonat 1966 Subcutaneous mice 0.82 suspectum
Stahnke 1966 Intraperitoneal rats 10.3 suspectum
Stahnke 1966 Intraperitoneal mice 3.0 suspectum
Patterson 1967a Intracardiac rats 1.35 suspectum
Stýblová and Kornalik 1967 Intravenous mice 0.4 suspectum
Stýblová and Kornalik 1967 Subcutaneous mice 4.0 suspectum
Tu and Murdock 1967 Subcutaneous mice 2.0 suspectum
Stahnke et al. 1970 Subcutaneous rats 14.0–16.8 suspectum
Hendon and Tu 1981 Intravenous mice 2.7 suspectum
Russell and Bogert 1981 Intravenous mice 0.52 suspectum
Mebs and Raudonat 1966 Subcutaneous mice 1.4 horridum
Hendon and Tu 1981 Intravenous mice 2.7 horridum
Alagón et al. 1982 Intraperitoneal mice 2.0 horridum
Ariano-Sánchez 2003 Subcutaneous rats 1.0 horridum
charlesbogerti

certain peptides. Patterson and Lee (1969) venoms of Gila Monsters and Beaded Lizards:
later showed coagulation was affected if helospectin I and II (Parker et al. 1984), helo-
venom was incubated with blood plasma for dermin (Hoshino et al. 1984), exendin-3 (found
longer periods. Subsequent work isolated he- in H. horridum; Eng et al. 1990), and exendin-4
morrhagic toxins in the venom (Nikai et al. (found in H. suspectum; Eng et al. 1992). These
1988; see below). In the late 1960s, Mebs iso- peptides mimic several human neurosecretory
lated kallikrein from the venom of H. suspec- hormones that relax smooth muscle and medi-
tum (Mebs 1968, 1969). Murphy et al. (1976) ate energy metabolism. The major compounds
demonstrated enzyme activities in the venom so far identified in the venom of helodermatid
of H. horridum. In the 1980s, additional pro- lizards as well as their chemical nature and
teins—gilatoxin (Hendon and Tu 1981), hor- physiological effects are discussed below and
ridum toxin (an arginine ester hydrolase; summarized in table 6.
Alagón et al. 1982; Nikai et al. 1988), heloder-
matine (a kallikrein-like hypotensive enzyme; HYALURONIDASE
Alagón et al. 1986), an additional phospholi- Hyaluronidase is a hydrolase enzyme that
pase (A2; Gomez et al. 1989), and helother- cleaves internal glycosidic bonds of hyaluronic
mine (Mochca-Morales et al. 1990)—were dis- acid, a mucopolysaccharide that is an important
covered and added to the known arsenal of component of connective tissue. Because this
Heloderma venom components. action facilitates venom diffusion into the tissue
With the discovery in the 1980s that Helo- (Tu and Hendon 1983), hyaluronidase has been
derma venom contained strongly bioactive termed spreading factor. Hyaluronidase is also
agents, with hormonelike actions similar to va- common in snake venoms where it also acts as
soactive intestinal peptides (VIP), interest and a spreading factor (Meier and Stocker 1995).
research in these intriguing molecules acceler- Venom of both Heloderma species shows partic-
ated dramatically (Raufman 1996). Five bioac- ularly high hyaluronidase activity, which is be-
tive peptides have been isolated so far from the lieved to explain the potent edema effects of

46 the venom system and envenomation

 TABLE 6
Major Constituents of Heloderma Venom and Their Actions

description/action physiological effects

Hyaluronidase Hydrolase enzyme; cleaves hyaluronic acid Acts as a “spreading factor” by facilitating diffusion of venom through
connective tissues surrounding bite site
Serotonin Neurotransmitter hormone Mediates inflammation, vasodilation, smooth muscle activity, and
other effects
Phospholipase A2 Hydrolase enzyme; catalyze hydrolysis Presynaptic membrane toxins in snakes; effects of Heloderma
of phospholipid glycerol backbone phospholipase A2s are unknown
Nerve Growth Factor Induce nerve growth; degranulate mast cells Effects unknown
Helothermine 25-kDa peptide with similarity to family of Causes lethargy, partial paralysis of rear limbs, intestinal distension,
mammalian cysteine-rich secretory proteins and hypothermia in rats
Gilatoxin 33-kDa serine protease glycoprotein Kallikrein-like lethal toxin; causes lowered blood pressure and
contraction of isolated uterus smooth muscle in rats
Horridum toxin 31-kDa glycoprotein similar to gilatoxin Kallikrein-like lethal toxin; causes hypotension, hemorrhage in
internal organs, hemorrhage and bulging of the eyes
Helodermatine 63-kDa serine protease glycoprotein Kallikrein-like enzyme; causes a dose-dependent decrease in arterial
blood pressure in rats
Unnamed lethal toxin 28-kDa peptide Kallikrein-like lethal toxin that suppresses contraction of isolated
diaphragm muscle in mice
Helospectin I & II 37- to 38-amino-acid peptides from exocrine Stimulate amylase release from the pancreas; show physiological
(exendin-1) gland having endocrine function effects similar to VIP (vasoactive intestinal peptide); have been
localized in various human tissues
Helodermin (exendin-2) Basic 35-amino-acid peptide with stable Causes hypotension in dogs and rats; shows physiological effects
secondary structure similar to VIP
Exendin-3 39-amino-acid (4.2-kDa) peptide from Interacts with newly described exendin receptor and mammalian VIP
H. horridum venom receptors; induces amylase release from the pancreas
Exendin-4 (exenatide) 39-amino-acid peptide from H. suspectum venom Induces insulin release through activation of glucagon-like peptide-1
(GLP-1) receptor
Gilatide Fragment of exendin-4 peptide Acts on GLP-1 receptor; improves memory in rodents

NOTE: See text for more complete descriptions and references.

Heloderma bites (Mebs and Raudonat 1966; venoms, especially in their N-terminal amino
Russell and Bogert 1981). acid sequences and molecular weight (Tu 1991;
Vandermeers et al. 1991). Interestingly, they are
SEROTONIN most similar to PLA2 from bee venom. The major
Serotonin, derived from the amino acid trypto- variant of PLA2 in Gila Monsters (Pa5) shows a C-
phan, produces potent local physiological ef- terminal extension seen only in Heloderma and
fects and also functions as a neurotransmitter. bee (Apis mellifera) venoms (Gomez et al. 1989).
Serotonin mediates local processes such as in-
flammation, vasodilation, and smooth muscle NERVE GROWTH FACTOR
activity and causes aggregation of platelets Nerve growth factors are found in a number of
(Greger 1996). It is found in a variety of toxins viperid and elapid snake venoms. They nor-
from animals such as spiders, toads, and wasps. mally induce the growth of nerve tissues, but
The specific in vivo effects from the serotonin they may also contribute to the toxic action of
found in Heloderma venom are not known, al- venoms by degranulating mast cells, which con-
though it likely participates in the inflammation tributes to inflammation (Meier and Stocker
response. 1995). A nerve growth factor was discovered in
the venom of H. horridum in 1968 (Levi-
PHOSPHOLIPASE A2 Montalcini and Angeletti 1968), but its role re-
Phospholipase A2 enzymes are classified as hy- mains unexplored.
drolases that act on ester bonds in fat molecules
(phospholipids). These common constituents HELOTHERMINE
of viperid and elapid snake venoms are toxic to This toxin from H. horridum venom is a 25.5
presynaptic membranes, disrupting the release kDa protein with an N-terminal amino acid se-
of neurotransmitters at nerve synapses and neu- quence initially thought to be unique (Mochca-
romuscular junctions and inhibiting platelets Morales et al. 1990). Further characterization of
(among other actions; Rosenberg 1988; Meier helothermine showed it to have structural ho-
and Stocker 1995). This behavior can cause mology with a family of cysteine-rich secretory
paralysis and loss of muscle control and func- proteins found in mammalian male genital
tion, among other signs. We do not know tracts and in salivary glands, as well as in some
whether phospholipase A2 from Heloderma is other animal toxins (Morrissette et al. 1995;
responsible for such actions in humans and R. L. Brown et al. 1999). When injected into
other mammals because the specific in vivo ef- mice, helothermine causes lethargy, partial
fects of this enzyme have not been investigated. paralysis of rear limbs, intestinal distension,
However, phospholipase A2 enzymes from H. and lowering of body temperature; hence, as its
horridum have been shown to inhibit platelet name suggests, it is a potentially hypothermic
aggregation in human blood plasma (Huang toxin (Mochca-Morales et al. 1990). Although
and Chiang 1994). deadly to mice, its LD50 has not been reported
Five variants of phospholipase A2 (or PLA2) (Mochca-Morales et al. 1990). Helothermine
have been identified and characterized in the blocks certain ion channels in cell membranes
venom of H. suspectum (Sosa et al. 1986; (e.g., calcium channels in cardiac muscle, skele-
Gomez et al. 1989; Vandermeers et al. 1991). tal muscle, and cerebellar granules; Morrissette
All of these stimulate the release of amylase et al. 1995; Nobile et al. 1994, 1996). This prop-
from secretory cells (acini) in rat pancreatic tis- erty gives it promise as a pharmacological tool
sue, and they hydrolyze phosphatidylcholines for studies on the structure and function of ion
(lecithins), which are important in cell structure channels in muscle and brain tissue. Unlike
and metabolism. Gila Monster PLA2s are appar- other toxins found in the venoms of heloder-
ently quite different from those found in snake matid lizards (discussed below), helothermine

48 t h e v e n o m s y s t e m a n d e n v e n o m a t i o n
shows no enzymatic effects. Helothermine is a kininogen and angiotensin, which are involved
member of the helveprins (20–25 kDa pro- in mediating blood pressure. Gilatoxin appears
teins), which are found in many reptile venoms to be found only in helodermatid lizards and
(S. P. Mackessy, pers. comm.). has an LD50 of 2.6–2.9
g/g. Interestingly, it
becomes more toxic when administered to mice
THE KALLIKREIN-LIKE TOXINS in combination with other venom fractions
These are the toxins most responsible for the (Tu 1991), suggesting that the toxin acts synergis-
excruciating pain that results from the bites of tically with additional venom components.
Gila Monsters and Beaded Lizards. Four differ-
ent proteins that possess kallikrein-like toxins HORRIDUM TOXIN
have been identified in the venom of heloder- Horridum toxin, from the venom of H. hor-
matid lizards (table 6). Kallikreins are hy- ridum, is the only hemorrhagic toxin so far
potensive hormones that exert powerful local isolated from helodermatid lizards. Another
physiological effects. They cleave kinogens glycoprotein, horridum toxin is a distinct form
that, in turn, release bradykinins—local hor- of gilatoxin, but with a similar structure (Nikai
mones that mediate the inflammation/pain et al. 1988; Datta and Tu 1997; Tu 2000). It
response. Bradykinins produce pain by stimu- also shows kallikrein-like activity, releasing
lating both sensory C-fibers and spinal ganglia, bradykinin upon hydrolysis of kinogen (Datta
and they reduce blood sugar by shifting D-glu- and Tu 1997). Similar to gilatoxin, it has
cose from plasma to muscle (Greger 1996). strong hypotensive effects when injected into
Bradykinins also cause vasodilation of periph- rats. It is more toxic than gilatoxin, showing
eral arterioles and increased vascular perme- an LD50 of 0.38
g/g (Nikai et al. 1988). In ad-
ability, which results in edema (swelling dition to the inflammatory effects produced by
caused by leaking of plasma fluid into tissues). bradykinin, horridum toxin causes hemor-
Bradykinins also stimulate secretion of adren- rhage in internal organs and especially in the
aline, which can cause an increase in heart eye, leading to exophthalmia (protrusion of
rate, among other effects. Plasma concentra- the eyeballs), an effect that has not been ob-
tions of bradykinins are usually very low served from other venoms (Datta and Tu
(4 pmol/L) so local increases in these sub- 1997). The actual exophthalmic effect, how-
stances can have dramatic effects (Greger ever, occurs only when the kallikrein activity is
1996). Kallikreins in venoms of viperids may contaminated with a similar-sized metallopro-
contribute to the immobilization of prey ani- tease (S. P. Mackessy, pers. comm.). Although
mals (Meier and Stocker 1995). horridum toxin has been isolated only from
As with helothermine, above, the first three H. horridum, exophthalmia has also been ob-
kallikrein-like proteins have been shown to be served in rats and mice injected with venom
lethal toxins. from H. suspectum (Cooke and Loeb 1913; Pat-
terson 1967a; St ýblová and Kornalik 1967),
GILATOXIN suggesting a similar toxin may also be present
Gilatoxin, a glycoprotein, was the first lethal in the venom of the Gila Monster. Horridum
toxin isolated from the venom of helodermatid toxin has been shown to degrade fibrinogen to
lizards (Hendon and Tu 1981). Later research fibrin, an important step in the blood coagula-
found that gilatoxin is one of several toxins in tion process that is normally performed by the
Heloderma venom that shows kallikrein-like ac- enzyme thrombin. Clots do not form from
tivity (Utaisincharoen et al. 1993). Present in horridum toxin poisoning, however, suggest-
both species, it comprises about 3%–5% of the ing that it does not act like thrombin, as do
venom volume. Gilatoxin is a serine protease many snake venoms that show kallikrein-like
that acts on a number of substrates including activity.

the venom system and envenomation 49

UNNAMED LETHAL TOXIN (vasoactive intestinal peptide), a hormone se-
Another very toxic “lethal toxin” was isolated creted by nerves found throughout the gastroin-
from the venom of H. horridum by Komori et al. testinal tract. A neurotransmitter hormone, va-
(1988). This toxin has a molecular weight of 28 soactive intestinal peptide is a powerful relaxant
kDa and an LD50 of 0.135
g/g when injected in- of smooth muscle (hence its name) and medi-
travenously in mice. This appears to be the ates the secretion of water and electrolytes by
most toxic substance isolated so far from the the small and large intestines. (Interestingly,
venom of Heloderma. The toxin suppresses con- VIP-secreting tumors give rise to “pancreatic
traction of the diaphragm muscle in mice, but cholera” with symptoms similar to those shown
shows no hemolytic or hemorrhagic activity. by a severe bite case—see below.) The actions
Proteolytic, phospholipase A2, or arginine ester and structure of VIP are also similar to secretin,
enzymatic activity are all absent in this appar- another messenger peptide involved in stimu-
ently novel toxin (Kamori et al. 1988). lating pancreatic secretions. In the early 1990s,
two additional biologically active peptides, ex-
HELODERMATINE endin-3 and exendin-4, were discovered in the
Not considered a lethal factor, helodermatine is venom of helodermatid lizards (Eng et al. 1990,
an arginine esterase purified from H. horridum 1992). Exendins are so named because they are
venom. It was the first enzyme with kallikrein- peptides from exocrine glands (of Heloderma)
like activity to be isolated and characterized having endocrine actions (Eng et al. 1990). The
from Heloderma venom (Alagón et al. 1986). helospectins became known as exendin-1 and
Helodermatine is another serine protease glyco- helodermin as exendin-2.
protein, as are gilatoxin and horridum toxin, Exendins (including helospectins and helo-
but, at 66 kDa, it is about twice their molecular dermin) exert their biological effects by interact-
mass. When injected into anesthetized rabbits, ing with specific receptors found on cell mem-
it causes a rapid dose-dependent decrease in ar- branes in various tissues of mammals. The
terial blood pressure, an effect likely attributed receptors known to be involved include VIP and
to its active kallikrein nature. Its N-terminal secretin receptors, exendin receptors (newly
amino acid sequence is similar to kallikrein discovered because of work with Heloderma
from pig pancreas and to kallikrein-like en- venom), and GLP-1 receptors (involved in in-
zymes from venom of the rattlesnakes Crotalus sulin release and glucose metabolism). The ef-
atrox and C. adamanteus. fects of these bioactive peptides are numerous
and diverse, but they generally involve decrease
THE BIOACTIVE PEPTIDES of blood flow via effects on smooth muscle, and
In the early 1980s, investigators searching for activation of adenyl cyclase. Adenyl cyclase, an
biologically active chemicals in animal venoms enzyme released when a mammal requires
made a very important discovery. They found energy, catalyzes a reaction that results in the
that the venom of helodermatid lizards elicited formation of cAMP, which, in turn, activates
a spectacular secretory response from pancre- numerous enzymes including those that me-
atic acini (secretory cells that make a useful tabolize carbohydrates for energy production.
model system for testing the biological activity An excellent review of bioactive peptides from
of chemical substances; Raufman 1996). This Heloderma is given in Raufman (1996). The na-
discovery led to an intense effort to find the ture and action of these interesting peptides are
compounds responsible for this response, discussed below.
which culminated in 1984 with the description
of helospectin I and II (Parker et al. 1984) and THE HELOSPECTINS
helodermin (Hoshino et al. 1984). These pep- Helospectin I and II are very similar peptides
tides are similar in structure and action to VIP (38 and 37 amino acids, respectively) that

50 the venom system and envenomation

stimulate amylase release from the pancreas. configuration it maintains in water, which may
Helospectin I differs from helospectin II in that account for its prolonged physiological action
it has an additional serine residue at its C ter- (Blankenfeldt et al. 1996). Helodermin shows
minus. It is believed that, because of their 85% identity with helospectin I and II, which
similar actions, helospectins and VIP act on a probably explains the similarity in their biologi-
common membrane receptor in mammals cal activity (Raufman 1996) and also suggests a
(Grundemar and Hogestatt 1990). Six forms of common evolutionary origin for these venom
helospectin have recently been identified from peptides. Helodermin binds to receptors in a
H. horridum venom that show minor differ- number of human tissues in the gastrointesti-
ences in the side groups attached to their Ser32 nal tract, lungs, and even on human breast can-
residues (Vandermeers-Piret et al. 2000). Inter- cer cells (Raufman 1996). It has also been
estingly, helospectins (and helodermin) have shown to inhibit growth and multiplication of
been immunohistochemically localized, usually lung cancer cells (Maruno and Said 1993).
associated with nerve endings, in a variety of Helodermin may also inhibit the activity of
human tissues ranging from the upper respira- phospholipase A2, suggesting that it could serve
tory tract to the genitalia (Graf et al. 1995; a protective function to attenuate phospholipase
Hauser-Kronberger et al. 1996, 1999). In these activation within the venom glands (Raufman
tissues, they appear in association with VIP re- 1996). Helodermin is found only in the venom
ceptors and (as with VIP and secretin) may play of H. suspectum.
a role in regulating secretory activities and local
blood flow. The location of these lizard venom EXENDIN-3 AND EXENDIN-4
peptide sequences within the tissues of mam- The most important peptides in Heloderma
mals leads to some intriguing ecological and evo- venom, in terms of pharmacological applica-
lutionary questions (see below). The helospectins tions, are exendin-3 and exendin-4. Exendin-3, a
are present in venoms of both H. horridum and 39-amino-acid peptide, occurs in the venom of
H. suspectum, but they are more abundant in H. horridum. It shows similarity with other hor-
H. horridum venom. mones involved in digestion: glucagon (48%)
and human glucagon-like peptide-1 (GLP-1;
HELODERMIN 50%). In its 12 amino acid residues, it has strong
Helodermin, a basic 35-amino-acid peptide dis- homology with secretin (91%), but only 41%
covered in Gila Monster venom, was the first se- with secretin overall, and only 29% similarity to
cretin/VIP-related peptide found in an animal VIP. It shows limited structural similarity with
other than a mammal or bird (Hoshino et al. helospectin and helodermin (32% and 26%, re-
1984; Vandermeers et al. 1984). In dogs, it spectively; Eng et al. 1990).
causes prolonged, systemic hypotension (Rob- Exendin-4, found only in Gila Monster
berecht et al. 1988); in rats, it produces a dose- venom, differs from exendin-3 by two amino
dependent hypotension, apparently via K acids, suggesting minor evolutionary changes
channels that exist on arterial smooth muscle from an ancestral peptide (Raufman 1996). Ex-
cells (Horikawa et al. 1998). The discovery of endin-4 shows great structural homology (53%)
helodermin also included the discovery of an- to human glucagon-like peptide-1, a hormone
other bioactive peptide, pancreatic secretory fac- released from the gut in response to a meal
tor, that later turned out to be a member of the (Goke et al. 1993; Raufman 1996; Drucker
phospholipase A2 family (Dehaye et al. 1984; 2001). GLP-1 stimulates insulin release and
Vandermeers et al. 1984). In comparison with moderates blood glucose levels, traits that have
other members of the secretin/VIP family of attracted interest in its potential for treating
peptides, helodermin has an unusually stable Type II (noninsulin dependent) diabetes (Goke
secondary structure, partly owing to a secondary et al. 1993; Doyle and Egan 2001). In the blood,

the venom system and envenomation 51

GLP-1 has a short half-life and must, therefore, literature for exendins will turn up hundreds of
be administered frequently to maintain ade- papers published since their discovery in 1990.
quate insulin levels. Exendin-4, on the other Adult-onset (Type II) diabetes accounts for most
hand, activates the same receptor as GLP-1 but of the 17 million cases of diabetes in the United
turns out to be more effective at inducing in- States. Prospects for exendin-4, or its trade
sulin release. Moreover, exendin-4 has a much name exenatide (AC 2993), currently in phase 3
longer biological action than GLP-1 (Young et al. development for use in treating human dia-
1999a; Doyle and Egan 2001). Amylin Pharma- betes, are so bright that Eli Lilly & Company
ceuticals, Inc., has developed a synthetic ex- closed a $325 million deal in September 2002
endin-4 (AC 2993) that lowers plasma glucose with Amylin Pharmaceuticals for rights to de-
to within the normal range, without inducing velop and market a synthetic version of this
hypoglycemia, in people with Type II diabetes compound (fig. 12).
(Kolterman et al. 1999, 2003). In healthy volun-
teers, exendin-4 also reduces plasma glucose by GILATIDE
delaying gastric emptying and by reducing calo- This novel nine-amino-acid peptide, discov-
rie intake (Edwards et al. 2001). ered in 2001, is really a fragment of the larger
These traits have propelled exendin-4 to the exendin-4 molecule (Haile et al. 2001, 2002).
forefront of pharmacological research on the The extent to which it occurs independently in
treatment of diabetes. A search of the medical the venom of helodermatid lizards is not yet

FIGURE 12. The venom of helodermatid lizards also contains several bioactive peptides that have brought the shy, venomous
lizards into pharmacology journals and headlines in medicine. The best-known lizard peptide, exendin-4, mediates insulin
release and glucose uptake from the blood after a meal. A synthetic version of exendin-4 (exenatide) is a leading candidate
for treating adult-onset (Type II) diabetes, which accounts for most of the 17 million cases of diabetes in the United States.
Prospects for this drug are so bright that Eli Lilly & Company recently closed a $325 million deal with Amylin Pharmaceuti-
cals for rights to develop and market this compound (photo by Tom Wiewandt).

52 the venom system and envenomation

known. Gilatide has been shown to strongly venom system of Heloderma is used primarily
enhance memory in mice, based on standard for defense, or to subdue and aid in digesting
cognition tests. This effect appears to be medi- prey, as is the case for most venomous snakes.
ated through GLP-1 receptors, a pathway previ- In snakes, venom serves an important feeding
ously unknown to be involved in learning and role, primarily in subduing or immobilizing
memory (Haile et al. 2002). Anonyx, a New prey that are large, dangerous, or otherwise dif-
York–based pharmaceutical company, is in- ficult to handle (Greene 1997). Most vipers im-
vestigating the potential for using gilatide to mobilize their prey by rapidly injecting large
help people suffering from memory disorders quantities of toxins that induce hypotension,
such as those associated with Alzheimer’s dis- clotting, and the enzymatic breakdown of tis-
ease and attention deficit/hyperactivity disorder sues, especially the lining of blood vessels
(ADHD). Should gilatide indeed turn out to be (Meier and Stocker 1995; Greene 1997). Many
an active, independent component of heloder- elapid snakes (e.g., cobras and mambas) inject
matid lizard venom, what could be a more effec- smaller quantities of neurotoxins that immobi-
tive formula for a defensive venom than to mix lize prey by blocking impulses at the neuro-
components producing great pain with one that muscular junction, paralyzing muscles of respi-
also enhances one’s memory of the experience? ration and leading to respiratory failure (Greene
A summary of the major constituents of 1997). Many snake venoms have both tissue-
Heloderma venom is provided in table 6. destructive and neurotoxic properties. A sec-
Many of these peptides have valuable research ondary feeding role of snake venoms may be to
and pharmacological applications. Venom con- aid in digesting prey, although few studies have
stituents have enabled discovery of new mem- directly demonstrated this effect (Thomas and
brane receptors in mammals, have enlightened Pough 1979). Predigestion may be particularly
physiologists as to how these receptors func- important for viperids that inhabit cooler tem-
tion, and hold promise for treating diseases perate latitudes and feed on relatively large prey
such as cancer and diabetes. The venom of helo- (Thomas and Pough 1979; Mackessy 1988;
dermatid lizards may be unique among reptile Greene 1997). In contrast to most venomous
venoms in showing such a high number of snakes, effects of envenomation by Heloderma
bioactive peptides (Bertanccini 1976; Raufman tend to be more localized and, as summarized
1996). Why do several venom constituents above, show relatively little tissue destruction.
closely resemble human neurosecretory hor- Thus the utility of snake venoms for de-
mones? Why does the venom exhibit a redun- fense, although often profound, is secondary to
dancy of peptides producing strong kallikrein- their feeding role (Greene 1997). For heloder-
like activity? What is the ecological function of matid lizards, on the other hand, an elaborate
this complex slurry of peptides, and how do the venom system seems unnecessary for subduing
various venom components act to achieve their prey. Beaded Lizards and Gila Monsters are spe-
ecological role, if any? The answers to these cialized nest predators that feed almost entirely
questions are best considered in an ecological on eggs or juvenile birds and mammals (see
and evolutionary context. chap. 7). Venom is not needed to subdue de-
fenseless young or eggs in vertebrate nests.
Helodermatid lizards do not feed on rapidly
ECOLOGICAL/EVOLUTIONARY ROLE
moving prey, and, although meals may be large,
OF HELODERMATID VENOMS
individual prey tend to be smaller than 10% of
Although the biochemistry of Heloderma venom their adult body mass. The venom system of
shows great promise in pharmacology, its eco- Heloderma precludes rapid injecting of venom
logical role has received less attention. A peren- during brief contact, a trait that is important for
nial source of confusion has been whether the subduing large prey that are dangerous and

the venom system and envenomation 53

difficult to handle. Moreover, the venom of travel considerable distances during infrequent
helodermatid lizards does not appear to have aboveground forays (Beck 1990; Beck and Lowe
sufficient tissue-destroying properties to be ef- 1991). These large, slow-moving lizards cannot
fective in helping to predigest prey (see above). quickly sprint away from a potential threat, as
Nor do limited field observations suggest the can most other lizards. Their peak speed of 1.7
use of venom to subdue prey. Wild Gila Mon- km/hour on a treadmill (Beck et al. 1995) con-
sters feeding on juvenile cottontails (relatively trasts strikingly with some inguanine lizards of
large prey at approximately 45 g each) delicately similar size, which can attain speeds of over 25
swallow the nestlings without the characteristic km/hour (Garland 1984). These traits make
chewing or pumping motions shown when en- surface-active Heloderma particularly vulnerable
venomating an adversary (Beck 1990; chap. 7). to predators. Predation is obviously an impor-
In captivity, however, I have observed Gila Mon- tant factor, and Heloderma occasionally suc-
sters and Beaded Lizards that were feeding on cumb to predators (see chap. 6).
dead mice “chewing” their prey before swallow- Gila Monsters and Beaded Lizards generally
ing them. Although these observations do not avoid encounters with predators by relying on
rule out a feeding function, they suggest that their secretive habits and cryptic patterns.
the venom of helodermatid lizards does not While radiotracking surface-active Beaded
serve a major role in subduing prey. In some Lizards in Jalisco, I often observed that, when
cases, however, especially for juveniles, it could lizards noticed my presence from a distance,
aid in immobilizing prey. they would stop moving and press their body to
A digestive role of the venom might be ruled the ground. As I approached more closely,
out entirely were it not for exendin-4, which Beaded Lizards (and Gila Monsters) attempted
comprises up to 5% of the dry weight of Gila to escape but could be easily overtaken and
Monster venom (J. Eng, pers. comm.) and has captured if they could not quickly flee into a
been shown to increase 30-fold in the blood of burrow. Thus, when confronted with an adver-
Gila Monsters immediately after a meal (Young sary during an aboveground foray, the inability
et al. 1999b). This result leaves open the in- of Heloderma to swiftly escape necessitates an
triguing possibility that exendin-4 could regu- effective defense.
late glucose uptake in the gut of helodermatid How effective is the bite of Heloderma at re-
lizards. Could the venom glands, which are pelling potential predators? As an adversary is
modified salivary glands, serve as a source of seized by the jaws of a heloderm, a complex
hormones exerting endocrine control of carbo- mixture of venom proteins and peptides also
hydrate metabolism in Gila Monsters and seizes physiological control of the intruder.
Beaded Lizards? We do not yet know what phys- Kallikrein-releasing toxins cause immediate
iological role, if any, exendin serves in Heloderma. bradykinin release accompanied by severe pain,
It remains to be discovered, or discounted, inflammation, weakness, and a rapid drop in
whether exendin might aid in lizard digestion blood pressure. Hyaluronidase enzymes facili-
just as it may help humans cope with diabetes. tate the spread of venom components through
So, whereas it seems obvious that helodermatid connective tissues surrounding the bite site.
lizards need not use venom to subdue their Horridum toxin may begin causing internal
prey, a role of the venom system in processing hemorrhaging; helothermine may begin acting
prey remains a possibility that needs to be fur- to lower body temperature and induce lethargy.
ther explored (chap. 10). Meanwhile, the heloderm holds on with
For defense, on the other hand, the venom bulldog tenacity and continues to chew addi-
system is crucial. Gila Monsters and Mexican tional venom into the wound. At this point, all
Beaded Lizards spend the vast majority of their of an intruder’s attention must be focused on
time hidden in shelters, yet they occasionally removing the venomous lizard from the bitten

54 the venom system and envenomation

area. And herein lies another of the paradoxes and potentially dangerous prey (S.M. Smith
of helodermatid lizards. The same behavior 1977; Lindstrom 2001). To the Heloderma, as long
that so effectively delivers venom to its ene- as the risk of death does not exceed the benefits
mies (and makes them wish they had avoided received from reduced predation owing to recog-
contact to begin with) puts the lizard at risk of nition by predators, its defensive strategy would
injury as an adversary attempts to remedy its be successful. Because this genus has survived
painful situation. for at least 23 million years, it appears such a
How can this apparent paradox be resolved? strategy has, indeed, been effective.
Is the effectiveness of Heloderma’s venomous Whether or not the venom system seems ef-
bite really undermined by its tenacious behav- ficient to us, Heloderma appears to have used it
ior? There are very few recorded accounts of di- effectively for a long time. Natural selection does
rect encounters between Heloderma and their not produce adaptations that are perfect by any
natural predators (Sullivan et al. 2002; chap. 6). means, and half-baked solutions are often all
Of 12 cases of Gila Monster bites on dogs re- that is possible given evolutionary constraints
ported in Tucson, Arizona, during 2001–02, (Gould 1980). Natural selection is limited by the
two resulted in death of the Gila Monster (un- raw material it has to work with, in this case the
published records, Arizona Poison Control Cen- morphological constraints imposed by the lizard
ter). In most cases, each dog shook off the Gila body plan. Helodermatid lizards do not have ag-
Monster without seriously injuring it. From re- ile, elongate bodies that enable them to coil and
viewing numerous case histories of Heloderma rapidly strike at a foe (that adaptive zone is the
bites on humans (see below), I found only one domain of the snakes), so a highly specialized
instance in which the lizard was seriously in- venom apparatus designed for efficient injection
jured while being extracted. In most cases, the of venom through hollow fangs does not make
lizard was forcefully pulled or pried off, and a sense for Heloderma, given the niche it fills and
few teeth broken, while attention was focused the evolutionary constraints imposed by its gen-
on the bite injury (and not on the lizard). It is eralized lizard morphology.
plausible that, when bitten by a Heloderma, Lizards (including Heloderma) bite as a final
many natural predators would likewise extract means of defense, and when they do they tend
the lizard without killing it. Occasionally, Helo- to hang on. Interestingly, Alligator lizards of the
derma may also be killed while being removed genus Elgaria (family Anguidae, sister group to
from an adversary. However, it seems unlikely the Helodermatidae) bite in a manner similar to
that, if it survived being bitten, an adversary helodermatid lizards. Southern Alligator lizards
would eat the Heloderma (some of the bioactive (Elgaria multicarinata) readily bite when han-
peptides present in the venom may even sup- dled, hang on tenaciously when biting, and ex-
press appetite; Szayna et al. 2000; Edwards et ert greater bite pressure (similar to the chewing
al. 2001). It is equally unlikely that an adversary actions shown by Heloderma) as attempts are
would risk future encounters after a bite from made to extract them from a bitten extremity
one of these dangerous lizards (a fragment of (personal observation). For a bite to be effective,
the exendin peptide even helps improve memory; a lizard may have no choice but to hang on. If
Haile et al. 2002). A predator, therefore, gains the lizard releases its hold before an adversary
nothing by attacking a Heloderma, but it does risk has been effectively stunned, surprised, or im-
injury, incapacitation, or death. Regardless of mobilized (in the case of Heloderma), it would
whether the Heloderma were killed, individuals be vulnerable to subsequent capture and poten-
bitten by Gila Monsters or Beaded Lizards would tial consumption. In this context, it makes
very likely show lower survivorship and reduced sense why Heloderma behave as they do when
reproductive success. Over evolutionary time, they bite and why they do not possess a more
predators learn to recognize and avoid noxious “efficient” venom system. What helodermatids

the venom system and envenomation 55

lack in their “crude” delivery system, however, In contemporary helodermatid lizards, the
they compensate for in a sophisticated array of venom system functions as an effective defense
venom constituents and bite tenacity. No doubt, mechanism, while some of the bioactive pep-
the venom chemistry of Heloderma is efficient tides in the venom could play a role in diges-
for defensive purposes. tion. The venom proteins and peptides appear
One might more appropriately ask: Why are to act primarily on initiating a powerful inflam-
there not more lizards that use a venom system matory/pain response, relaxing smooth muscle
for defense? The answer might be that most (which results in vasodilation and hypotension),
lizards can run away more effectively than they and influencing energy metabolism. Taken to-
can bite. However, there are rare cases where gether, the venom constituents clearly act phys-
bites of varanid lizards may produce symptoms iologically to immobilize or incapacitate the bite
of toxicity (Ballard and Antonio 2001). In at victim. Some of these components not only pro-
least three cases, reptile keepers bitten by foundly affect the physiology of potential mam-
Varanus griseus, the Desert Monitor, showed malian adversaries, but they are, in a sense, part
symptoms ranging from dysphagia (difficulty of their physiology. These venom components
swallowing), tightness of the chest muscles, are analogues of important mammalian hor-
and dyspnea (labored respiration) to dizziness, mones, including serotonin, secretin, VIP, and
facial pain, and muscle soreness (Ballard and GLP-1. The kallikrein enzymes are common
Antonio 2001). Desert monitor lizards have participants in the inflammatory response in
shown chewing motions during bites that may mammals. As noted above, many of the bioac-
continue for over one minute. Whether these tive peptides (helospectin and helodermin, in
signs/symptoms are truly reactions to toxic pep- particular) have been located, using immuno-
tides or proteins in the venom of Varanus needs histochemical techniques, in several mam-
to be thoroughly investigated. malian tissues including the brain, pancreas,
Of the few other vertebrates known to use a blood, colon, lung, stomach, breast, heart, intes-
venom system exclusively for defense, the Platy- tine, uterus, liver, urogenital system, and others
pus (Ornithorhynchus anatinus) and Stonefish (Raufman 1996). In these tissues, they appear
(Synanceja horrida) are noteworthy. Peptides in association with membrane receptors that
and other components in Platypus venom relax play a role in regulating secretory activities and
smooth muscle in rats, promote edema and in- local blood flow. When they were first discov-
flammation, and produce extreme pain (Fenner ered, it was thought that some of the bioactive
et al. 1992; De Plater et al. 1998). Stonefish peptides in Heloderma venom represented ho-
venom produces intense pain and induces hy- mologues of mammalian hormones yet to be
potension via relaxing smooth muscle in the discovered (Parker et al. 1984). This appears not
walls of blood vessels (Low et al. 1993). These to be the case; for example, helodermin and
venoms act to repel and potentially immobi- exendin-4 from Heloderma are not the evolution-
lize potential predators with symptoms (severe ary precursors to mammalian VIP and GLP-1.
pain, inflammation, and hypotension) similar They are distinct peptides encoded by different
to those produced by bites of Heloderma. Spit- genes and, therefore, appear to have evolved in-
ting cobras seem to have evolved the ultimate dependently of the mammalian peptides they
venom delivery system for defense. Venom is resemble (Chen and Drucker 1997; Pohl and
ejected from the fangs as a jet that becomes a Wank 1998). To find so many Heloderma venom
fine spray (Bogert 1993). A tiny speck of African peptide sequences within the tissues of mam-
Spitting Cobra, Naja nigricollis, venom landing mals suggests an intricate example of biochemi-
in the eye produces a pain, in the words of a cal mimicry. The venomous bite of helodermatid
photographer affected by the venom, greater lizards has apparently evolved to incapacitate and
than any ever experienced (Bogert 1993). deter an enemy with a diversity of toxins that

56 t h e v e n o m s y s t e m a n d e n v e n o m a t i o n
manipulate its physiology in a variety of ways. An and Bogert and Martín del Campo (1956) em-
intriguing possibility also exists that exendin, phasized that details regarding deaths from
and perhaps other bioactive peptides in the Heloderma bites were often sketchy, contradic-
venom of Gila Monsters and Beaded Lizards, tory, and invalidated, and that alcohol was in-
may act to regulate the lizards’ own digestive volved in most cases. Russell and Bogert (1981)
physiology (Young et al. 1999b). What has pre- discussed the outcomes of another 16 cases, as
viously been called a “primitive,” “crude,” or well other published records available to them
“inefficient” venom system appears, in fact, (Shannon 1953; Bogert and Martín del Campo
highly refined and effective. 1956; Grant and Henderson 1957; Albritton et
Since the early 1980s, when many of the con- al. 1970; Stahnke et al. 1970). None of the 16
stituents of Heloderma venom were discovered, cases mentioned by Russell and Bogert resulted
little attention has been directed at whole-venom in death. Since the dubious case in 1930 of an
physiological effects. When taken as a whole, intoxicated pool-hall operator in Casa Grande,
many of the venom components may show syn- Arizona (chap. 1), there have been no authenti-
ergistic consequences that are not apparent cated reports of a death from the bite of Helo-
when examined alone. For example, gilatoxin derma suspectum. In fact, I have not even been
shows greater toxicity when combined with able to find any published validated cases of truly
other venom components than when acting “legitimate” bites (i.e., victims being accidentally
alone (Tu 1991). It is likely that other venom con- bitten by wild Gila Monsters that were not poked,
stituents, especially the kinin-releasing peptides picked up, handled, or otherwise harassed).
and the bioactive peptides, may interact in simi- Hearsay and fertile imaginations have, there-
lar ways. Investigations into how the venom fore, produced far more information about the
components may interact with one another in bite of Heloderma than have scientific records
mammalian tissues would be another fruitful and reports. Of the many bite cases reported in
arena for future research (chap. 10). A picture of newspapers, correspondences, and the popular
whole-venom effects partially emerges by exam- literature since 1950, I could find only 17 that
ining the effects of Heloderma envenomation in were based on firsthand information and pub-
humans, which we consider next. lished in peer-reviewed biological or medical
journals (tables 7 and 8). Even in these cases, one
description of a myocardial infarction following
HUMAN ENVENOMATION BY
the bite of a Gila Monster (case no. 11, tables 7
HELODERMA: OVERVIEW OF BITE
and 8) was published twice, by different authors
CASE HISTORIES
in 1988 and 1989 (Bou-Abboud and Kardassakis
A rich, entertaining, and commonly erroneous 1988; Preston 1989). A summary of these bites
literature is associated with bite case histories of and their signs and symptoms are given in tables
Heloderma (see chap. 1). Vivid tales abound re- 7 and 8. Since 1950, bites by Heloderma have be-
counting suffering, terror, and death. I have come less newsworthy, so only the most serious
found more exaggerated and erroneous infor- or noteworthy cases get reported in scientific
mation associated with this Heloderma topic journals. Since 1981, I could find only 10 such
than with all others combined. Woodson (1947) cases. Tables 7 and 8 do not include cases re-
provided one of the first summaries of the bite ported in the news media (unless they are also
of Heloderma, reporting that 29 of 136 cases published in a peer-reviewed journal), or those
ended in death. Bogert and Martín del Campo contained in unpublished hospital records, re-
(1956) summarized 34 cases between the gional reports, etc. Tables 7 and 8 should be in-
1880s and 1956, mostly from newspaper clip- terpreted carefully, therefore, because, although
pings and correspondence, eight of which al- they contain some of the best-documented cases,
legedly resulted in death. Both Woodson (1947) they are not necessarily the most representative.

the venom system and envenomation 57

 TABLE 7
Heloderma Bite Cases Published in Peer-Reviewed Journals since 1950

case no. cause bite location references

(all from careless handling)

1 Pet Finger Shannon 1953

2 Pet Finger Shannon 1953
3 Demonstration Finger Tinkham 1956
4 Demonstration Thumb Grant and Henderson 1957
5 Demonstration Finger Albritton et al. 1970
6 Demonstration Finger Stahnke et al. 1970
7 Pet Hand Roller 1977
8 Pet Abdomen Heitschel 1986
9 Wild capture Forearm Piacentine et al. 1986
10 Pet Hand Streiffer 1986
11 Wild capture Forearm Bou-Abboud and Kardassakis
1988 and Preston 1989
12 Recent capture Calf Caravati and Hartsell 1994
13 Wild capture? Thumb Caravati and Hartsell 1994
14 Pet Shoulder Caravati and Hartsell 1994
15 Wild capture Triceps Caravati and Hartsell 1994
16 Pet Finger Strimple et al. 1997
17 Pet Hand Cantrell 2003

Nevertheless, an analysis of the cases sum- Bleeding at the site of the bite may be profuse,
marized in tables 7 and 8 is instructive. Most not from anticoagulant effects of the venom,
bites were to a finger or hand and came from but from the lacerating effect of the teeth and
pet Gila Monsters. These bites are more likely to tenacity of the bite (fig. 13). Pain, often severe,
produce intense pain and local edema but are usually begins within minutes, and may last
less likely to produce more serious symptoms several hours. The pain has been described as a
such as severe hypotension, cardiac and blood steady burning, like a spine imbedded in the
abnormalities, or shock. All bites resulted from flesh. Pain may spread well beyond the site of
careless handling, some of which occurred dur- the bite; a person bitten on the arm may feel
ing public demonstrations or classroom lec- pain from the shoulder to the hand. Edema
tures. Alcohol was involved in some of the most (swelling) can occur within minutes and extend
serious cases (Heitschel 1986; Piacentine et al. well beyond the region of the bite (fig. 13).
1986; Caravati and Hartsell 1994). A second set of relatively common symp-
Based on an examination of case histories by toms includes hypotension, sweating, an in-
Bogert and Martín del Campo (1956), Russell creased heart rate, and vomiting. Blood chem-
and Bogert (1981), recent bite case reports istry changes, including elevated leukocyte
(tables 7 and 8), and my knowledge of approxi- count, reduced potassium levels, and reduced
mately 30 unreported or untreated bites over re- platelets, are occasionally shown in moderately
cent years, the most common signs and symp- severe cases (tables 7 and 8). There is limited ev-
toms of Heloderma envenomation in humans idence that previous exposure to Heloderma bites
are similar to those observed in other mammals may sensitize some individuals and result in an
(table 4). They include pain, local edema, and a allergic reaction to the venom (Cantrell 2003).
feeling of weakness, faintness, or nausea. More severe cases seem to result from bites

58 the venom system and envenomation

 TABLE 8
Bite Signs/Symptoms and Their Frequency

cases reporting
percent (%) of cases (FROM TABLE 7)

Pain 82 1–3, 5–8, 10–13, 15–17

Local edema/swelling 82 1–7, 9–11, 13, 15–17
Weakness, faintness, dizziness 65 1, 3, 4, 6, 8, 11–13, 15–17
Nausea 65 2, 3, 5–8, 10, 12, 14, 16–17
Hypotension 47 6, 8–14
Diaphoresis (sweating) 47 4, 8–11, 13, 16–17
Tachycardia (elevated heart rate) 35 5, 8, 11, 12, 14, 15
Vomiting 35 3, 5, 10, 12, 14, 17
Leucocytosis (elevated WBC count) 29 6, 8, 11, 12, 17
Hypesthesia (hypersensitivity around bite) 24 1, 2, 12, 16
Reduced blood potassium levels 18 8, 9, 11
Reduced platelets 18 8, 11, 17
Cyanosis (bluish discoloration around bite) 13 3, 8
Cardiac abnormalities 12 7, 11
Swollen or painful lymph glands 12 10, 11
Lethargy 12 8, 14
Anaphylaxis 6–12 9, possibly 17
Diarrhea 6 8
Tinnitis (ringing in ears) 6 2
Exophthalmia or periorbital hemorrhage 6 8
Hypothermia 6 12
Miosis (contraction of pupil) 6 14

located closer to the core of the victim’s body, 36 hours (Heitschel 1986). This case (the only
such as the abdomen, shoulder, calf, or forearm female in the sample) is noteworthy because the
(tables 7 and 8). The most severe cases result in victim’s symptoms are similar to pancreatic
extreme hypotension, which may be accompa- cholera, a condition produced by VIP-secreting
nied by life-threatening anaphylaxis (Piacentine tumors and also known as WDHA (watery diar-
et al. 1986), coagulopathy and acute myocardial rhea, hypokalemia, acidosis) syndrome (Conni-
infarction (Bou-Abboud and Kardassakis 1988), grave and Young 1996). Such symptoms may be
or profuse diarrhea and lethargy (Heitschel an example of the action of VIP-like bioactive
1986). These cases likely illustrate the powerful peptides in Heloderma venom.
physiological effects of the kallikrein-like and
bioactive peptides found in Heloderma venom.
TREATMENT OF BITES
In the most serious case, a young woman
had hidden a Gila Monster under her sweater Bites by Heloderma may be increasing because,
and walked into a tavern, whereupon the lizard as captive-breeding techniques have improved,
bit her on the abdomen. Her screams alerted bar more people are keeping these lizards in pri-
patrons of her condition, and her boyfriend re- vate collections (chap. 8). The docile nature of
moved the lizard by severing its head. When she Heloderma kept in captivity often lulls their
arrived at the hospital, the woman was nearly handlers into a dangerous habit of compla-
incapacitated, showing severe pain, vomiting, cency. The vast majority of bites by heloder-
and diarrhea. She remained in intensive care for matid lizards occur on the fingers or hands.

the venom system and envenomation 59

FIGURE 13. Bite to the index finger
from a Heloderma suspectum. The
laceration occurred as the Gila
Monster was extracted from the
finger. Considerable edema that
commonly occurs from Gila Mon-
ster bites had already subsided when
this photograph was taken two days
later (photo by M.L. Gilbert).

Most of these pass on uneventfully and go un- required, teeth are usually pulled out and a
reported (Miller 1995). Although a Heloderma laceration results (fig. 13). I do not recom-
bite is very unlikely to be lethal to a healthy mend trying to remove the lizard by applying
adult, it should nevertheless be considered a se- a flame to its chin or by using dangerous
rious medical emergency. A common miscon- solvents such as gasoline (which have been
ception is that only the dentaries in the lower advocated in the past). These measures only
jaw (and to a lesser extent the maxillaries in the add to the possibility that additional
upper jaw) can deliver sufficient venom to injury and pain will result.
cause serious effects. This is not the case; sig- 2. Immediately remove any rings, bracelets, or
nificant symptoms can occur by a seemingly other jewelry (including piercings). These
minor “slashing” bite from even the premaxil- articles may cause complications as edema
lary teeth toward the front of the mouth (Tin- (swelling) develops.
kham 1956; Strimple et al. 1997).
3. The bitten part should be immobilized; a
When a person is bitten by a Heloderma, the
light cloth bandage and mild pressure may
following first aid measures are recommended:
be applied to control any bleeding.

1. Remove the lizard as quickly as possible. 4. The victim should be transported (by an-
The longer the lizard bites, the more venom other person) to medical care as quickly as
it is able to deposit into the wound and the possible and reassured that they will not die.
more likely the bite is to produce serious 5. DO NOT apply stun guns, heat, or ice to
symptoms. In mild bites, where only a fold the wound. DO NOT use tourniquets or
of skin is bitten, it may be possible to simply constriction bands of any kind nor make
hold the lizard behind the jaws and carefully incisions to suck out venom.
pull it away; in cases where the jaws are
more firmly attached, it may be necessary to Once the victim has arrived at the hospital,
pour water on the lizard or to pry it off with vital signs should be monitored immediately.
pliers or some other device. A thin, flat lever One of the biggest dangers is shock/hypoten-
inserted between the lower jaw and the flesh sive crisis brought about by a rapid fall in
and turned 90 degrees may work to quickly blood pressure. This can be treated in the vic-
release the jaws. When Heloderma are force- tim by infusing electrolyte solutions and ad-
fully removed from the bite site, as is often ministering antishock drugs. Pain normally

60 the venom system and envenomation

peaks within 1 to 2 hours, but may linger for Kardassakis 1988) have been observed. Anti-
days (Caravati and Hartsell 1994). It can be histamines or corticosteroids are usually un-
difficult to relieve; analgesics and morphine necessary because allergic reactions are rare,
have been used effectively (Strimple et al. although one case of anaphylaxis has been re-
1997). Edema normally peaks within 2 to 4 ported (Piacentine et al. 1986). The wound
hours and resolves itself without special meas- should be carefully inspected for any broken
ures within 72 hours. Because it is largely sub- teeth and thoroughly cleaned with antiseptic.
cutaneous, edema has not been reported to Soft-tissue radiography is not sufficient to lo-
cause compartment syndrome or neurological cate broken teeth (Caravati and Hartsell
problems. Depending on the severity of the 1994). Antibiotics are routinely given, al-
bite, laboratory blood tests should be per- though tissue necrosis and infections are very
formed to assess the possibility of electrolyte rare. Tetanus immunization should be up-
imbalance, leukocytosis, and coagulopathy, dated if necessary. Most victims of Heloderma
which have been reported previously (see ta- envenomation are released from the hospital
bles 7 and 8). An electrocardiograph should be within 24 hours and recover completely
used to evaluate any heart anomalies; myo- within 2 weeks. More severe cases may re-
cardial conduction disturbance (Roller 1977) quire hospitalization up to 48 hours (e.g.,
and myocardial infarction (Bou-Abboud and Heitschel 1986).

the venom system and envenomation 61