XENOBIOTICS AND ITS
METABOLISM
Group 7
Nagpiing, Jean
Noche, Reginald Bruce
Orellana, Joi Marie
Panis, Moises Laureano
Pareja, John Paul
Peralta, Kathy
1F
DEFINITION
Xenobiotics
chemical which is found in an organism but
which is not normally produced or expected to
be present in it
Greek words (xenos) = foreigner, stranger
and (bios, vios) = life.
PRINCIPAL CLASSES
• Drugs
antibiotics,
analgesics like
acetaminophen,
cardiac drugs
PRINCIPAL CLASSES
• Carcinogens
Food Dyes, Preservatives,
Nitrosamines, Alcohol, Artificial
Sweeteners
PRINCIPAL CLASSES
• Environmental
Pollutants and
Chemicals
>200,00
manufactured
environmental
chemical/pollutants
in existence
SIGNIFICANCE
• Studying these Xenobiotics are significant in man
because these Xenobiotics can enter the body and
may have different effects on human systems.
Xenobiotics can be a toxic metabolite which can
lead to toxicity.
• It can be an active metabolite that can alter or
enhance activity or it can also lead to toxicity. It can
be an inactive metabolite that leads to loss of
activity and it can be a reversible metabolite that
results to prolonged activity.
XENOBIOTIC ABSORPTION
oral INTESTINES
topical SKIN
XENOBIOTICS IV BLOOD
IM, SC,ID MEMBRANES
inhalation LUNGS
EXCRETION
XENOBIOTICS METABOLISM
• Mechanism of elimination of foreign and
undesirable compounds from the body
• Metabolized by biotransformation or
detoxification reaction
• Site of metabolism = Liver
XENOBIOTICS METABOLISM
Phase 1
2 PHASES
Phase 2
Phase I
• variety of enzymes act
to introduce reactive
and polar groups into
xenobiotics’ substrates
– “functionalization”
• Catalyzed by members
of a class of enzymes
referred to as mono
oxygenases or
cytochrome 450
Phase 1
Hydroxylation
- major reaction involved in phase 1
RH + O2 + NADPH + H R-OH +H20 + NADP
Lipophillic toxicant Hydrophillic molecule
Cytochrome P450
Phase 1
Cytochrome P450
- Located in the Smooth Endoplasmic Reticulum or
in the Mitochondria
- monooxygenase
- one atom of oxygen enters R-OH and one atom
enters H20
RH + O2 + NADPH + H R-OH +H20 + NADP
R-OH +H20 + NADP
Excretable Form
Other Enzymes
• Amine oxydase
• Amidases
• Alcohol
Dehydrogenase
• Epoxide Hydratase
• Esterases
Phase 2
• Phase I derivatives are
made more polar (Water
soluble) through
Conjugation Reaction
• Includes 5 important
reaction
Glucorinadation
Sulfation
Conjugation with
Glutathione
Acetylation
Methylation
PHASE 2 REACTIONS
1. Glucoronidation
Conjugation with Glucoronic Acid
Glucoronyl donor: UDP-Glucoronic acid
Catalyst: Glucoronyl Transferase ( ER and
cytosol )
Aniline, phenols, 2- acetyl Aminoflourine,
benzoic Acid, many steroids
Glucoronidation
• Glucoronidation of xenobiotics
PHASE 2 REACTIONS
2. Sulfation
Conjugation with sulfate
PAPS Adenosine 3 - Phosphate -5
phosphosulfate (Active sulfate)—sulfate donor
Alcohols, Aralymine, and Phenols
PHASE 2 REACTIONS
3. Methylation
Transferof the methyl group to the
Xenobiotic
Methyl Group Donor: S- Adenosyl
Methionnine
Catalyst: Methyl Transferase
PHASE 2 REACTIONS
4. Acetylation
Transfer of the Acetyl Group to the Xenobiotics
Acetyl Group Donor: Acetyl CoA (Active Acetate)
Catalyst: Acetyl Transferase
Subject to Acetylation: ISONIAZID
X + AcetylCoA Acetyl-X + CoA
POLAR
PHASE 2 REACTIONS
5. Glutathione Conjugation
Most potentially toxic electrophillic xenobiotics
(carcinogens) are conjugated to Glutathione
Conjugates are excreted in the bile and converted into
cysteine and mercapturic conjugates in the intestines
and kidneys
Catalyst: Glutathione S-transferase
R + GSH R – S- G
xenobiotic mercapturic acid
PHASE 2 REACTIONS
• Glutathione
Tripeptide consisting of glutamic acid,
cysteine and glycine
Decomposition of potentially toxic
hydrogen peroxide in the reaction
catalyzed by glutathione peroxidase
Cytochrome p450
• responsible for the hydroxylation on phase 1 of
xenobiotic metabolism.
• can bre reffered as “monooxygenase”
• most versatile “catalyst”
• Can render substrates which are generally and
initially lipophilic to more hydrophilic by hydroxylation.
• Enzymes that use iron to oxidize things, often as part
of the body's strategy to dispose of potentially harmful
substances by making them more water-soluble.
• Exhibits a distinct peak at 450nm when chemically
reduced and exposed to carbon monoxide.
• Hydroxylation – chief reaction involved in phase 1.
Characteristics
i. Large number of isoforms about (150)
ii. Hemoprotein like hemoglobin
[Link] distributed across species
iv. Microsomal found in the smooth
endoplasmic reticulum, mostly in the
liver
v. NADPH, not NADH is involved in the
reaction mechanism of cytochrome
p450
vi. Lipids are important component of
cytochrome p450
Factors affecting Xenobiotics
Metabolism
Genetic factors, age and sex
Factors affecting Xenobiotics
Metabolism
• due to difference in the activities of
different enzymes.
– Metabolism slowly in neonates and
elderly.
– Diet and intake of different nutrients
Factors affecting Xenobiotics
Metabolism
Intake of various
xenobiotics
(Phenobarbital) –
can cause enzyme
induction.
Factors affecting Xenobiotics
Metabolism
Pathological state.
– Disease involving gut and liver.
- Metabolites of certain xeonobiotics can
either stimulate or inhibit.
THANK YOU!
References:
• [Link]
etabolism-2825134
• Murray L.K. et al: Harper’s
[Link] Hill; 2006
• [Link]
• [Link]
[Link]
• [Link]
nal_of_nutrition_and_wellness/volume_7_num
ber_1_21/article_printable/absorption_and_me
tabolism_of_xenobiotics_an_overview.html
