molecules

Review
Citrus Waste as Source of Bioactive Compounds: Extraction and
Utilization in Health and Food Industry
Zahra Maqbool 1 , Waseem Khalid 1, * , Hafiz Taimoor Atiq 2 , Hyrije Koraqi 3 , Zaryab Javaid 4 , Sadeq K. Alhag 5 ,
Laila A. Al-Shuraym 6 , D. M. D. Bader 7 , Mohammed Almarzuq 8 , Mohamed Afifi 9,10,11 and Ammar AL-Farga 9

1 Department of Food Science, Faculty of Life Sciences, Government College University,

Faisalabad 38000, Pakistan
2 Department of Food Science and Technology, Muhammad Nawaz Sharif University of Agriculture,
Multan 23546, Pakistan
3 Faculty of Food Science and Biotechnology, UBT-Higher Education Institution, Rexhep Krasniqi No. 56,
10000 Pristina, Kosovo
4 Department of Pharmacy, University of Central Punjab, Lahore 54590, Pakistan
5 Biology Department, College of Science and Arts, King Khalid University, Muhayl Asser 61913, Saudi Arabia
6 Biology Department, Faculty of Science, Princess Nourah Bint Abdulrahman University,
Riyadh 11671, Saudi Arabia
7 Chemistry Department, College of Science, King Khalid University, P.O. Box 9004, Abha 61413, Saudi Arabia
8 Unit of Scientific Research, Applied College, Qassim University, Buraidah 52571, Saudi Arabia
9 Biochemistry Department, Faculty of Sciences, University of Jeddah, Jeddah 21959, Saudi Arabia
10 Department of Biochemistry, Faculty of Veterinary Medicine, Zagazig University, Zagazig 44519, Egypt
11 Najla Bint Saud Al Saud Center for Distinguished Research in Biotechnology, Jeddah 21577, Saudi Arabia
* Correspondence: [email protected]

Abstract: The current research was conducted to extract the bioactive compounds from citrus waste
and assess their role in the development of functional foods to treat different disorders. The scientific
Citation: Maqbool, Z.; Khalid, W.; name of citrus is Citrus L. and it belongs to the Rutaceae family. It is one of the most important fruit
Atiq, H.T.; Koraqi, H.; Javaid, Z.; crops that is grown throughout the world. During processing, a large amount of waste is produced
Alhag, S.K.; Al-Shuraym, L.A.; Bader, from citrus fruits in the form of peel, seeds, and pomace. Every year, the citrus processing industry
D.M.D.; Almarzuq, M.; Afifi, M.; et al. creates a large amount of waste. The citrus waste is composed of highly bioactive substances and
Citrus Waste as Source of Bioactive phytochemicals, including essential oils (EOs), ascorbic acid, sugars, carotenoids, flavonoids, dietary
Compounds: Extraction and fiber, polyphenols, and a range of trace elements. These valuable compounds are used to develop
Utilization in Health and Food
functional foods, including baked products, beverages, meat products, and dairy products. Moreover,
Industry. Molecules 2023, 28, 1636.
these functional foods play an important role in treating various disorders, including anti-aging,
https://doi.org/10.3390/
anti-mutagenic, antidiabetic, anti-carcinogenic, anti-allergenic, anti-oxidative, anti-inflammatory, neu-
molecules28041636
roprotective, and cardiovascular-protective activity. EOs are complex and contain several naturally
Academic Editors: Vito Michele occurring bioactive compounds that are frequently used as the best substitutes in the food industry.
Paradiso, Ângela Fernandes and Citrus essential oils have many uses in the packaging and food safety industries. They can also be
Marta Igual Ramo
used as an alternative preservative to extend the shelf lives of different food products.
Received: 3 January 2023
Revised: 21 January 2023 Keywords: citrus waste; potential health benefits; bioactive compounds; EOs
Accepted: 1 February 2023
Published: 8 February 2023

1. Introduction
Citrus is one of the most important fruit crops in the world. The scientific name of
Copyright: © 2023 by the authors.
citrus is Citrus L. and it is a member of the Rutaceae family. It is grown extensively in areas
Licensee MDPI, Basel, Switzerland.
that are classified as tropical or subtropical, as well as many other areas, which together
This article is an open access article
distributed under the terms and
produce more than 100 million tons annually [1]. Customers display a significant preference
conditions of the Creative Commons
for citrus fruits because of their attractive colors, flavorful aromas, and pleasant flavors.
Attribution (CC BY) license (https:// Worldwide, citrus fruits are most commonly cultivated crops. Citrus fruits are an important
creativecommons.org/licenses/by/ staple food in the diets of people all over the world [2]. These fruits are crucial throughout
4.0/).

Molecules 2023, 28, 1636. https://doi.org/10.3390/molecules28041636 https://www.mdpi.com/journal/molecules

Molecules 2023, 28, 1636 2 of 20

the world both nutritionally and commercially [3]. Citrus species could be a source of valu-
able oils that could be used in food and for other industrial purposes [4]. Around the world,
citrus fruits are considered nutrient-dense, energy-dense, and health-promoting fruits.
Several of these fruits (lemon, grapefruit, sweet orange, citron, clementine, and pomelo)
have also been used as traditional medicinal herbs in Asian countries to treat a variety of
illnesses. Several studies showed that citrus fruits contained secondary metabolites as well
as bioactive compounds that can be used as either chemotherapeutics or supplements [5,6].
The secondary metabolites found in citrus fruits are important to human health due to their
functional properties. There are different secondary metabolites present in citrus waste,
including coumarins, alkaloids, carotenoids, limonoids, phenolic acids, flavonoids, and
essential oils (EOs) [7]. The utilization of plant residues can reduce the risk of metabolic
syndrome-related ailments such as neurodegenerative diseases, diabetes, cardiovascular
disease, and cancer. Citrus L. is a basic fruit crop that contains high levels of flavonoids,
carotenoids, limonoids, terpenes, and other bioactive components [8]. Citrus fruits are
abundant in vitamins C, A, and E, minerals, coumarins, flavonoids, limonoids, pectins,
carotenoids, and other beneficial phytochemicals. The phytochemicals are consumed in the
form of fresh fruits or products and exert positive effects on people’s health, including anti-
mutagenicity, antioxidant, anti-carcinogenic, anti-inflammatory, and anti-aging effects [9].
Additionally, these phytochemicals promote cardiovascular health and nervous system
function [7]. Citrus fruit phytochemicals may have antioxidant properties via raising liver
protective enzyme activity, blocking lipids to prevent deoxyribonucleic acid (DNA) dam-
age, and bolstering the immune system [10]. Citrus fruits are prized for their nutritional
content and for providing some of the world’s most popular flavors. Growing citrus fruits
(tangerines, lemons, oranges, grapefruits, and limes) is one of the most common means
of producing fruit across the globe. Due to expanding customer demands, their output is
increasing year after year [11]. Every year, the citrus processing industry produces a large
amount of fruit waste, with citrus peel waste accounting for over half of the wet fruit mass.
The waste from citrus has fundamental economic value because it contains a great deal of
EOs, ascorbic acid, sugars, carotenoids, flavonoids, dietary fiber, polyphenols, and trace
elements. This waste also includes a high concentration of sugars that can be fermented to
produce bioethanol. These components are useful in the production of medicines, cosmetics,
and food supplements [12].

2. Different Sources of Citrus Waste

Oranges, lemons, grapefruits, mandarins, and limes are the citrus fruits that are most
commonly grown around the world. Due to escalating consumer demands, production
grows yearly. Annually, the industries that process citrus produce large amounts of waste,
with citrus peel waste alone representing nearly 50% of the wet fruit mass [13]. Food waste
is composed of ingredients that are useful for human utilization, but these are degraded,
polluted, and discarded. Food waste is an increasing issue that affects all facets of waste
management. In order to develop long-term solutions, all actors involved in the food supply
chain, including the industry, agriculture, merchants, collection to disposal processes, and
consumers, must participate [14]. The processing of citrus fruit generates a range of waste,
including liquid, solid, and distillery effluents. Rags, peels, sludge, seeds, and residue
constitute solid waste. However, there are different types of liquid waste too, including
cannery effluents, can cooler overflows, fruit washing wastewaters, sectioning table and
peeling wastewaters, and floor flushing water [15]. Citrus is primarily used in the food
manufacturing process to create fresh juice or drinks with citrus flavors, resulting in a
significant amount of citrus waste each year in the form of peels, pulp, and seeds. However,
the seeds, pulp, and peels of many fruits and vegetables may contain a significant number
of bioactive compounds [16]. A previous study was conducted on the recovery of vitamin C,
phenolic compounds, and antioxidant activity from citrus (lemon, orange, and grapefruit)
fruit waste. Each citrus fruit’s peel, whole fruit, and pulp with seeds were converted into
ethanol extracts. Results showed that peels had higher levels of phenolic compounds,
Molecules 2023, 28, 1636 3 of 20

vitamin C, flavonoids, and antioxidant activity than their internal, wasted parts (seeds and
pulp) in each citrus variety [17]. The extracts (peel, pulp, and seeds) of Citrus reticulata
(Phlegraean mandarin), Citrus japonica (Kumquat), and Citrus clementina were compared
and characterized in terms of photosynthetic pigment content, total polyphenol amount,
antioxidant activity, and vitamin C [18]. The generation of waste from citrus processing is
shown in Figure 1.

Figure 1. Generation of waste in juice processing.

2.1. Citrus Peel

In the quest to reduce global food losses and waste, citrus peel waste (CPW) in
particular has emerged as a sustainable and promising option for biorefinery without
competing with human foods and animal feeds. According to recent studies, CPW is
widely produced and has the industrial potential to be biologically converted into fuels and
chemicals [19]. The extraction of essential oils (limonene) and pectin for use as cosmetic
and food additive ingredients is the most widely known method for using CPW [20].
Fruit waste is produced in large quantities by agricultural processes all over the world.
Frequently, this waste is simply discarded into landfills or the ocean. Fruit waste contains a
variety of sugars, such as fructose, sucrose, and glucose, which can be fermented to produce
bioethanol. Some fruit wastes, such as citrus peel waste (CPW), contain substances that can
stop fermentation, which is necessary for efficient bioethanol production. A novel method
for converting CPW from a single source (mandarin, orange, lemon, grapefruit, or lime)
or CPW combined with other fruit waste (apple pomace, banana peel, or pear waste) into
bioethanol has been developed [21].

2.2. Citrus Seeds

After the seeds are gathered, cleaned, dried, and ground, it is necessary to optimize a
number of downstream processes in order to extract phytoconstituents from them. Solvents,
time, temperature, pressure, and particle size are some of the steps involved in downstream
processes. Various extraction techniques are used for citrus seeds, including supercritical
CO2 extraction, solvent extraction, cold pressing, and ultrasound-assisted extraction [22].
Molecules 2023, 28, 1636 4 of 20

Citrus seeds are typically discarded as waste because they are thought to be useless.
According to Ammerman and Arrington [23], the average percentage of seeds in dried
citrus pulp is 4.8%. These discarded seeds can be used profitably as a protein supplement for
livestock, because they are high in protein. Furthermore, citrus seeds have high potential for
use as biodiesel due to their 30% oil content (by weight). According to a rough analysis of
flour produced from unhulled and dehulled citrus seeds, it contained 28.5% carbohydrates,
52% fat, 3.1% crude protein, 5.5% crude fiber, and 2.5% ash (dry basis). Rashid et al. [24]
produced methyl esters that complied with both the ASTM D6751 and EN 14214 biodiesel
standards by trans-esterifying citrus seed oil with methanol under the catalysis of sodium
methoxide.

2.3. Citrus Pomace

Citrus pomace is the leftover residue from the processing of citrus fruit to create juice
or other products. When citrus fruits are processed into industrial citrus juice, nearly half
of their volume is wasted, and the enormous amount of citrus pomace causes serious
ecological problems [25]. In the case of not using adequate citrus, the pomace generated
by the agro-fruit industry has a negative impact on the environment and will result in
significant financial losses. Fruit pomaces are rich in a variety of beneficial bioactive
substances, including dietary fiber, carbohydrates, phenolic compounds, polysaccharides,
phytochemicals, natural antioxidants, and a number of other nutrients that are beneficial
for health [26]. In a previous study, the effect of various solvents was examined in relation
to the recovery of vitamin C, flavonoids, phenolic compounds, and extractable solids
(ES) from lemon pomace waste. The results showed the effects of various solvents, such
as water, methanol, ethanol, and acetone. The total phenolic compounds, vitamin C,
total flavonoids, and antioxidant activity of lemon pomace were measured by using a
combination of solvents [27]. Moisture (10%), fat (0.4–1.6%), sugars (30–40%), pectin
(14–25%), micronutrients (0.5%), and hemicellulose and cellulose (13–17%) constitute the
bulk of dried citrus pomace [28].

3. Extraction of Bioactive Compounds from Citrus Waste

Culturing citrus fruits requires extensive processing. However, after processing, a num-
ber of by-products and wastes are produced that are rich sources of bioactive components,
such as pectin, essential oils (EOs), and water-insoluble and -soluble antioxidants. The
major phytochemicals of Citrus L. waste are shown in Figure 2. While some of these wastes
are now valorized in various ways, such as non-toxic and effective methods, different
techniques used for successful extraction might fundamentally improve their valorization
and produce greater revenues and high-quality bioactives [29].
The by-products of citrus and their waste include significant amounts of substances
of high value, and they can be utilized for a variety of technological and health-related
purposes, as mentioned in Table 1. Citrus by-products contain bioactive compounds with bi-
ological activity, including carotenoids, polyphenols, and essential oils (EOs). Carotenoids
and polyphenols have numerous health benefits that are related to their antioxidant activ-
ity [30]. Citrus fruits are frequently processed into turbid juices, and the residue part is
considered waste, including juice vesicles, membranes, peels, and seeds. These account
for 45 to 60% of the weight discarded [31]. Due to the abundance of polyphenols, EOs,
flavonoids, dietary fiber, sugars, ascorbic acid, and carotenoids in orange peel, it can be
utilized as a source of economically useful, elevated components, in areas such as solid
biofuel, bioabsorbents, animal feed, fertilizer, EOs, pectin, ethanol, methane, industrial
enzymes, and single-cell protein [32–35].
Molecules 2023, 28, 1636 5 of 20

Figure 2. Major phytochemicals of Citrus L. waste.

Table 1. Compositions and potential food applications of citrus fruits.

Citrus Source Part Composition Food Application References

Antioxidants, vitamin Carbonated drinks, alcoholic
Citron Peel, pulp [36]
C, phenols, flavanols beverages, jams, syrup
Vitamin C, pectin, Edible coatings, use as film
Lemon Peel [37,38]
phenols, carotenoids matrixes
Enhance vegetable oil oxidative
Narirutin, naringin,
Sweet orange Peel stability, candied orange peel, [39,40]
quinic acid, sakuranetin
salad dressings, desserts
Naringin, naringenin, Jam making, sauces, dessert
Grapefruit Peel [32,41]
flavonoids, phenols recipes, flavoring of beverages

3.1. Pectin
Ngouémazong et al. [42] described pectin as an emulsifier, texturizer, thickener, and
stabilizer in food. It is utilized in a variety of applications, including fillings for confec-
tionery and dietary fiber supplements [43]. It is derived commercially from the peels of
orange, lime, lemon, and grapefruit as a white to pale brown powder [44]. The extraction
of pectin is among the most efficient and cost-effective methods [45]. In a factory setting,
citrus peels and rinds are heated to approximately 100 ◦ C and subjected to acidic conditions
to extract pectin [46]. Alternative extraction methods for pectin extraction have recently
been developed, including ultrasonic extraction (USE) [47], microwave-assisted extraction
(MAE) [48], and enzymatic extraction [49]. The hydrolysis of lignocellulosic materials has
been greatly aided by the application of subcritical water extraction [50], in addition to
processing any remaining orange peel for its pectin [51]. In addition to its technological ca-
pabilities in a variety of commodities, pectin can play a role as a dietary fiber and bioactive
compound and act as an anti-cancer agent [52] (Figure 3).
Molecules 2023, 28, 1636 6 of 20

Figure 3. Extraction of pectin from Citrus L. waste.

3.2. Dietary Fiber

Citrus fruits contain both soluble and insoluble fiber that may be separated. Soluble
dietary fiber is largely made up of mucus, gum, and pectin; in contrast, hemicellulose,
cellulose, and lignin make up the bulk of insoluble dietary fiber [53]. Approximately
50–60% of its dry weight can be attributed to cellulose and hemicellulose, which make it
a prime source for both substances. Citrus fiber is a biologically active component (BAC)
that contains polyphenol-like components and plays a role as a lipid oxidation inhibitor in
meat products, prolonging the stability of the meat and enhancing the overall oxidative
stability [54]. Because of their high water and oil absorption rates, the pulp, seeds, and
even the peel of oranges have been utilized as a fat substitute in ice cream [55]. Citrus
peel is subjected to dietary fiber extraction using subcritical water. Pectin, hemicellulose,
and cellulose, together with other dietary fiber sources, were successfully extracted from
orange peel through the utilization of a hydrothermal treatment that was carried out at
temperatures ranging from 160 to 320 degrees Celsius in a moderate flow extractor. This
is an important sequential process for the recovery of useful compounds from citrus fruit
waste in a manner that is non-toxic to the environment [56].

3.3. Essential Oils (EOs)

Plants create essential oils, which are volatile aromatic compounds and are referred to
as EOs. These chemicals have been employed as flavoring agents in food, medicine, and
cosmetics since ancient times [57]. Citrus species have garnered a great deal of attention
due to their abundance of EOs. EOs are highly adaptable and may be used to impart
flavor to a large number of products, including beverages, cosmetics, soaps, and household
goods [58]. EOs have antibacterial, antifungal, and insecticidal properties, as well as
antifungal, antibacterial, and insecticidal activity [59]. Citrus essential oils were extracted
from five citrus species by using hydrodistillation. GC–MS analysis showed different
phytochemicals in all five citrus oils, including alkaloids, tannins, sterols, terpenoids,
saponins, and limonene [60]. A previous study investigated the antioxidant properties,
antimicrobial activity, and chemical composition of the essential oil isolated from the
aerial parts of Citrus aurantifolia L. The essential oil was extracted using hydrodistillation.
Gas chromatography–mass spectrometry (GC–MS) was used to identify and quantify the
chemical constituents of the oil. Thirty-three chemical compounds were identified, in
which d-limonene was the major constituent. The minor constituents were 3,7-dimethyl-
Molecules 2023, 28, 1636 7 of 20

2,6-octadien-1-ol, geraniol, E-citral, Z-citral, and β-ocimene [61]. The GC–MS analysis of
Citrus aurantium L. (CAEO) identified at least ten compounds, with 2-β pinene, δ-3 carene,
and D-limonene as the major compounds [62]. The current study was conducted on Citrus
medica limonum, in which leaves’ essential oil was extracted by hydrodistillation and the
chemical constituents were analyzed by gas chromatography–mass spectroscopy (GC–MS)
and Fourier transform infrared (FTIR) spectroscopy. Eleven components were identified in
the leaf oil by GC–MS, in which the major constituents were citronellal, limonene, (E)-citral,
1,6-octadien-3-ol, and 3,7-dimethyl [63].

3.4. Carotenoids
Carotenoids are also known as carotenes, which are lipid-soluble hydrocarbons, while
xanthophylls are their oxygenated derivatives. Carotenes are found in most red and yel-
low fruits, green leaves, and many roots [64]. Carotenoids are plentiful in citrus fruits.
Carotenoids (zeaxanthin, lutein, and lycopene), cryptoxanthin, and pro-vitamin are found
in the highest concentrations in fruits and vegetables. Carotenoids play an important role
in human health. They act as antioxidants and aid in the growth and health of bones.
They also exert a positive influence on the immune system, increase cell-to-cell commu-
nication, improve eye health, and reduce cancer risks. A previous study demonstrated
that carotenoids have many health advantages. The capability of carotenoids to generate
vitamin A makes them the only well-established healthier alternative to carotenoids in
humans [65]. Citrus fruits are a significant source of dietary nutrients due to their high
levels of carotenoids. The two primary forms of carotenoids are hydrocarbon carotenoids
and oxygenated carotenoids [66]. Methanol and diethyl ether were shown to be excellent
solvents to extract carotenoids from sour oranges [67].

3.5. Polyphenols
The waste of citrus fruits can be used after management in the proper way. The peels
offer a superior source of naturally occurring flavonoids and polyphenolics [68]. There
are six distinct types of flavonoids found in peels concerning their chemical structures,
including flavones, flavanols, flavanones, anthocyanidins, isoflavones, and flavonols [69].
Flavonoids are phenolic compounds with biological characteristics such as antiallergenic,
anti-inflammatory, antiviral, and vasodilation [70]. Flavonoids can protect cells from
injury by directly scavenging free radicals and preventing their harmful effects [71]. To
obtain polyphenols from the peels of a variety of citrus fruits, a strategy was employed
that combined solid and liquid extraction and was founded on an ethanolic solution in
water. This method proved to be quick, sustainable, and likely economical, with minimal
equipment requirements and ease of operation [72].

4. Application of Citrus Waste in the Food Industry

Different studies showed that citrus peels contain essential oils that can be used for
multiple purposes in food preservation, food safety, and nutraceutical industries. Various
research has produced essential oil (EOs)-based thin films, microencapsulation utilizing
nanoemulsion coatings, biodegradable polymers, spray applications, and the antibacterial
action mechanism of the active chemicals present in EOs [73]. Cosmetics, medicines, food
formulations, and packaging are a few of the industries that use citrus essential oils (CEOs).
CEOs have extensive uses in the areas of food safety, packaging, and storage [74]. Figure 4
describes the potential applications of Citrus L.
Molecules 2023, 28, 1636 8 of 20

Figure 4. Potential applications of Citrus L.

4.1. Essential Oil-Containing Polysaccharide-Based Edible Films and Coatings

Food industries face a major challenge in the form of waste, which has to be managed
and utilized for multiple purposes. Most of the food industries and food scientists use
these food wastes as coating materials to protect food products from various environmental
factors. Therefore, food coatings and films have gained wide interest due to their excellent
palatability and biodegradability, and their ability to maintain food freshness during
storage. In the last decade, polysaccharides have been investigated as a viable material for
edible films. Applications related to microbiological food safety demonstrated that these
polymeric materials have enormous untapped potential. In a study, essential oils (EOs)
were mixed with polysaccharide matrices to further enhance the functional qualities of
edible films [75]. In another research work by Perdones et al. [76], cold-stored strawberry
was coated with chitosan and lemon essential oil and stored in at 5 ◦ C. Chitosan coatings
showed no significant effect on the acidity, pH, and soluble solid content of strawberries
throughout the storage period. In the food processing industry, the EOs of citrus lemon
peel can be used as a natural antibacterial and antioxidant agent. Lemon peel EOs have
antibacterial effectiveness against several food-borne diseases [77].

4.2. Application of Fiber Concentrate in Bakery Products

Romero-Lopez et al. [78] conducted a study on the addition of citrus fiber to muffins.
A dietary fiber-rich orange bagasse product (DFROBP) boosted the fiber content of the
experimental muffins by 40 and 63% relative to a control muffin. By partially substituting
wheat flour with DFROBP, it was possible to create baked goods with high levels of total
dietary fiber and a high indigestible fraction, dietary traits that may be advantageous for
people with varying nutritional requirements [79].
Molecules 2023, 28, 1636 9 of 20

4.3. Application of Citrus Pectin in Dairy Drinks

Citrus pectin, a polysaccharide found in plant cell walls, is primarily used in the food
processing industry as a stabilizer, thickener, and gelling agent. Pectin can be extracted
from the peels of various fruits and their waste; it is used in food industries and is extracted
from citrus peels and apple pomace. Pectin is commonly used as a stabilizer agent in
acidified milk beverages and yogurts. Acidified milk drinks are very popular due to their
natural taste and high nutritional value. Many research works have shown that protein
flocculation and whey separation in acidified milk beverages are due to the absence of a
stabilizer agent. Furthermore, citrus pectin can be added as a protective colloid to stop this
behavior and stabilize milk drinks [80].

4.4. Utilization of Citrus Waste in the Beverage Industry

Utilizing citrus waste in the food sector is vital due to its bio-functional properties
and its potential as a useful approach to improving food quality and customer health. It
contributes to the creation of nutrient-rich foods and beverages of superior quality. Citrus
waste contains a high level of vitamin C, and it can be used to produce juices and other
nutrient-rich beverages [81]. Citrus waste also contains essential oils (EOs). These EOs can
be used in a variety of beverages, food additives, and pharmaceutical, food, and cosmetic
products, because they can provide flavor and impart a sweet aroma (fragrance). Due
to the abundance of phenols and carotenoids in citrus manufacturing by-products, these
materials can be put to good use as biofertilizers to increase the freshness and longevity of
food and drink [82].

4.5. Applications of Essential Oils (EOs) for Food Safety

For a very long time, EOs have been used in food processing and preservation in-
dustries for multiple purposes. Recently, researchers and scientists have focused on an-
tibacterial packaging for food products, edible thin films, effective antibacterial films,
nanoemulsions for the preservation of fruits and vegetables, soda/citrus concentrate com-
ponents, flavoring agents in carbonated colas, soft drinks, and the preservation of meat,
fish, and shellfish [73]. EOs are more complex than other types of oils because they contain
a variety of naturally occurring bioactive chemicals that are frequently utilized in the food
industry as superior substitutes. The antioxidant, antibacterial, and antifungal properties
of EOs have been investigated in many research works. EOs obtained from tea tree oil, cin-
namon oil, sesame oil, clove oil, lemon oil, chia oil, and thyme oil are only a few examples
of oils that have significantly increased antioxidant and antibacterial activity, along with
increased cereal storage life and enhanced food security [83]. The key EO groups, such as
terpenes and aromatic volatile compounds, contribute to food safety without compromising
quality. Because of their varied actions, including antibacterial and antioxidant capabilities,
EOs could replace some chemical preservatives, extending the freshness of foods including
cereals and vegetables [74].

5. Herb–Drug Interaction of Citrus L.

Herb–drug interactions (HDIs), a growing concern in the clinical use of conven-
tional drugs, have become more prevalent as traditional herbal medicines are used more
frequently. Complex HDIs are linked to complex chemical compositions and multiple
potential bioactivities [84,85]. HDIs can be divided into pharmacokinetic interactions and
pharmacodynamic interactions based on various interaction pathways, with the former
being the focus of earlier studies that focused on drug transport and metabolism. On the
one hand, HDIs may affect drug levels and/or activity, which may result in therapeutic
failure or unfavorable reactions; on the other hand, some HDIs may have positive clinical
effects, such as increased efficacy and decreased side effects [86]. Plant preparations are
used as medicines by numerous people all over the world. There is rising interest in and
use of phytomedicines, even in industrialized regions such as Europe, where most patients
can access conventional therapies. Plant preparations are combined with conventional
Molecules 2023, 28, 1636 10 of 20

medications, in addition to being used as an alternative form of therapy [85]. The complex
mixtures of bioactive compounds in plants indicate potential for interactions, so these
combinations merit careful consideration [87]. Nearly 25% of American adults state that
they take a prescription drug and a dietary supplement at the same time. The most well-
known example may be St. John’s wort’s induction of CYP enzymes and pGP, but there
are many other factors to take into account [78,88]. Health professionals and researchers
working on drug discovery need to be more aware of HDI. The potential for HDIs should
always be evaluated in the non-clinical safety assessment stage of the drug development
process, given the rise in plant-sourced pharmacological actives [89]. The phytochemicals
of Citrus L. also act as agonists or antagonists with various nuclear receptors, such as
PXR, CAR, and AhR, and regulate their downstream genes, such as CYP3A4, CYP2C9,
and P-gp transporters, and they may induce herb–drug interactions. This is an important
and emerging field of phytomedicine. The herb–drug interaction of grapefruit is widely
known with anti-cancer and anti-infective agents, antilipemic agents, cardiovascular agents,
CNS agents, gastrointestinal agents, and immunosuppressants, etc. [90]. The goal of the
prior study was to evaluate Citrus aurantium L.’s drug–drug interactions (Rutaceae). The
herb fructus aurantii (FA), which has been shown to have a number of pharmacological
properties, is frequently used in clinics as a digestive and expectorant agent. Rat CYP1A2,
CYP3A4, and mRNA expression were all significantly upregulated in comparison to the
control group, while CYP2E1 protein expression was significantly downregulated and the
corresponding mRNA expression and enzyme activity remained unchanged. In HepG2
cells, CYP1A2 and CYP3A4 mRNA expression was statistically up-regulated in comparison
to the control group, but CYP2E1 mRNA expression was neither significantly induced
nor inhibited [91]. The current study, which was motivated by the “grapefruit (GF) juice
effect”, was carried out to examine the herb–drug interactions (HDIs) of citrus herbs (CHs).
The 159 compounds in CHs and a total of 249 components in GF showed excellent po-
tential as active ingredients based on network analysis. In addition, 360 genes related
to GF, 422 to CH, and 111 to drug transport and metabolism were gathered, and 25 and
26 overlapping genes were found. Higher levels of naringenin, isopimpinellin, apigenin,
sinensetin, and isoimperatorin were found in compound–target networks, and the find-
ings of protein–protein interactions suggested that CYP3A4 and UGT1A1 served as the
hub proteins. Through a variety of drug transporters and drug-metabolizing enzymes,
conventional medications such as erlotinib, nilotinib, tamoxifen, theophylline, venlafaxine,
and verapamil were linked to GF and CHs. Surprisingly, GF and CHs shared 48 potential
active substances, with naringenin, tangeretin, nobiletin, and apigenin having the strongest
interactions with targets [92]. This study’s goal was to assess the HDI potential of plants
that are frequently used as components in BDS and other herbal products. The findings
suggest that long-term or excessive use of herbal preparations containing these plants may
increase the risk of CYP- and P-gp-mediated HDIs, which could result in unpleasant side
effects from the altered pharmacokinetics of concurrently taken medications [93].

6. Health Benefits of Bioactive Substances Derived from Citrus Waste

Several secondary metabolites (coumarins, flavonoids, carotenoids, limonoids, pheno-
lic acids, essential oils (EOs), and alkaloids) are found in citrus fruits, as shown in Figure 5.
Citrus secondary metabolites have a biological effect on human health, including neuro-
protective, anti-inflammatory, anti-oxidative, anti-cancer, and cardiovascular-protective
effects [94]. The health benefits of the bioactive compounds in citrus are mentioned in
Table 2.
Molecules 2023, 28, 1636 11 of 20

Figure 5. Bioactive compounds in citrus waste and their health benefits.

Table 2. Health benefits of bioactive compounds in citrus.

Bioactive/Functional
Citrus Source Scientific Name Diseases References
Compounds
Eriocitrin, hesperidin, Antioxidant action, reduce risk of
Lemon Citrus limon 6,8-di-c-glu-apigenin, cardiovascular complications, [95]
quercetin, hesperetin antimicrobial effects
Anti-catarrha, anti-hypertensive,
Phenolics, flavonones,
Citron Citrus medica antibacterial, antifungal, [96]
vitamin C, pectin
anti-cancerous
Naringin, naringenin,
Pomelo Citrus maxima Antihyperlipidemic properties [97]
phenols
Prevent arteriosclerosis, reduce risk
Hesperidin, sinensitin, of kidney stones, reduce cholesterol
Sweet orange Citrus sinensis [98]
liminoids, polyphenols levels, improve stomach ulcer
anti-inflammatory effect
Luteolin, tangerine, Improve immunity, prevent kidney
Lime Citrus lotifolia [99,100]
hesperidin stones, promote healthy skin
Antioxidant, anti-inflammatory, and
Naringin, narirutin, anti-tumor activity; reduces the risk
Grapefruit Citrus paradisi [101,102]
neoponcirin, quercetin of atherosclerosis; increases bone
cell activity
Polyphenols, essential Antioxidant activity, liver protection,
Kumquat Citrus japonica [103,104]
oils (EOs), vitamin C anti-cancer activity

6.1. Functional Benefits in the Control of Diabetes

In a research work, a novel preventive beverage/functional food was developed using
a variety of citrus fruits with high antioxidant activity and polyphenolic content. The
results revealed that the citrus extracts had the potential to treat diabetes, cardiovascular
disease, and cancer, as they contained nutraceuticals and bioactive compounds [105]. Citrus
flavonoids have the ability to boost insulin release and reactivity, improve glucose tolerance
and peripheral glucose uptake, modulate enzyme activity, reduce the levels of insulin
resistance and hepatic glucose, and suppress inflammation [71].
Molecules 2023, 28, 1636 12 of 20

6.2. Anti-Cancer Properties

Cancer is a leading cause of sudden death around the world. In recent decades,
the interest of scientists and researchers has increased in the development of functional
food products with excellent anti-cancer properties. Some functional food products have
several limits in terms of applicability and effectiveness, and they are frequently linked
with significant adverse consequences, which can lower the overall quality of life for
patients [106]. In the field of functional foods, the recent discovery of drugs based on natural
products that work against cancer is gaining more popularity, with a few demonstrating
efficacy and little toxicity in the management and treatment of the cancer-causing process.
The peels of citrus fruits and other comparable extracts have demonstrated promising
anti-cancer effectiveness due to the presence of high flavonoid content. To conclude, in vivo
studies reveal that citrus peel flavonoids, such as citrus peel extracts and nobiletin, have
significant anti-tumor properties in the treatment of malignancies of the colon, skin, lung,
prostate, and liver cancer. Inflammation, angiogenesis, proliferation, and apoptosis may
all be inhibited as part of the therapeutic strategy [107]. The health benefits of citrus
fruits have been known for a long time, making them the most often consumed fruits
in the Mediterranean diet. Observational studies have shown a correlation between the
consumption of flavonoids in one’s diet and a reduced risk of cardiovascular disease and
cancer [108]. Citrus fruits appear to be important for human health due to the presence of
vitamins, minerals, and fiber content. The anti-inflammatory and antioxidant properties of
citrus fruits have been found to be promising for preventing chronic degenerative illnesses,
including cancer and atherosclerosis. Citrus fruits provide critical nutrients such as mineral
salts, vitamins, and trace elements, as well as a variety of functional molecules that help the
body to maintain its natural homeostasis. Citrus flavonoids can be used in the treatment
and prevention of atherosclerosis and cancer in humans [109].

6.3. Mental Health and Metabolism

As people live longer, age-related disorders such as Alzheimer’s disease have emerged
as major health problems throughout the world. Amyloid buildup, oxidative stress, hy-
perphosphorylation of tau, and neuroinflammation are hallmarks of Alzheimer’s disease.
Furthermore, lifestyle-related disorders such as diabetes, dyslipidemia, vascular dysfunc-
tion, and obesity have been associated with an increased risk of dementia. Therefore, the
interest of scientists and researchers have been increased towards the development of
new methods to maintain brain function and prevent dementia in older and pre-clinical
individuals. Citrus fruits are rich in polymethoxylated flavones and flavanones that are
beneficial for brain function. In this pre-clinical research, results showed that they had
neuroprotective properties in dementia models such as Alzheimer’s disease [110]. Similarly,
in another clinical and epidemiological study, flavonoids in citrus peels and extracts led to
greater cognitive performance and lowered the disease risk of depression and dementia.
Results confirmed the citrus peels’ and extracts’ positive impacts on human cognition and
associated functions [111].

6.4. Citrus’ Role in the Prevention of Oxidative Damage and Cardiovascular Disease
Cardiovascular illnesses are a serious concern worldwide, with many deaths reported
each year, and treatment resistance is becoming increasingly common. This area of research
needs more attention from scientists and researchers in order to discover new, natural meth-
ods to isolate beneficial chemicals from citrus fruits such as lemons, sweet oranges, and
grapefruits, which are used in the treatment of hypertension. Citrus extract has the ability
to significantly reduce hemorrhages. Citrus fruits contain the flavonoids chrysin, luteolin,
and 7-hydroxy flavone, which play a major role in lipoprotein induction in the umbilical
vein. Endothelial cells in the human body oxidize low-density lipoprotein (LDL) and create
more reactive oxygen species inside the cells. LDL regulates the bioactive chemicals in
our bodies. Bioactive chemicals are more effective in controlling hypercholesterolemia
and atherosclerosis [112]. Citrus flavonoids, among other qualities, scavenge free radi-
Molecules 2023, 28, 1636 13 of 20

cals, change lipid metabolism, increase glucose tolerance and insulin resistance, promote
adipocyte differentiation, alleviate endothelial dysfunction, and reduce inflammation and
apoptosis. It has been found that flavonoids present in citrus fruits can lead to better
outcomes for cardiovascular health [71].
Effective heart failure self-care has been linked to depression, but more recent re-
search suggests that the connection between the two is more complex than previously
thought [113]. In patients with chronic heart failure, insufficient daily intake of citrus fruits
was associated with an increased risk of developing depression. Our findings support the
theory that consuming citrus fruits daily can help to prevent and manage depression in
chronic heart failure patients [114].

6.5. Citrus’ Role in the Prevention of Obesity

Obesity is a chronic and life-threatening condition affecting people worldwide. Anti-
obesity drugs can have serious side effects, and there is no assurance that these treatments
can aid patients in the long term [115]. In the last few decades, complementary and al-
ternative medicines have gained a great deal of attention due to their excellent health
properties. Citrus phytochemicals have shown great promise in a variety of methods in
treating obesity disorders. Citrus fruits have been identified as the main active biolog-
ical ingredient that contains higher amounts of flavonoids and p-synephrine. In many
research works, it was revealed that citrus fruits have anti-obesity properties through a
variety of mechanisms, including energy intake and expenditure control, lipid metabolism
modulation, and adipogenesis regulation [116]. They possess anti-obesity characteristics
through a range of pathways, some of which include the control of energy intake and
expenditure, the modification of lipid metabolism, and the regulation of adipogenesis. In
another research study on citrus phytochemicals and their anti-obesity benefits, as well
as an update of studies conducted within the past ten years, the active components and
mechanisms involved in their anti-obesity action were considered. Citrus phytochemicals
have been shown to reduce the risk of developing obesity [117]. According to in vitro and
in vivo research, hydroxyl PMFs and polymethoxyflavones present in citrus peels have
shown anti-obesity potential. This study investigated the anti-obesity potential of two
citrus peel extracts and findings indicated that orange peel extracts reduced fat storage in
both in vivo and in vitro analysis and that they should be investigated as a treatment for
obesity and overweight [118].

6.6. Regulation of Lipoprotein Metabolism

Citrus fruits have been recognized as a rich source of flavonoids, vitamins, carotenoids,
and polyphenolic compounds with excellent biological properties. Recent studies have
focused on the potential of citrus flavonoids to influence lipid metabolism, along with
other metabolic factors relating to metabolic syndrome, heart disorders, type 2 diabetes,
and atherosclerosis disorders. Nobiletin, naringenin, tangeretin, and hesperidin are major
citroflavonoids that have emerged as promising nutraceutical and therapeutic agents for
the treatment of metabolic dysregulation [119]. According to epidemiological studies, the
consumption of citrus flavonoid-rich foods is associated with a lower risk of cardiovascular
disorders, inflammation, and metabolic disorders. In another clinical research work, it was
found that citrus flavonoids are promising antibiotic, antihypertensive, insulin-sensitizing,
lipid-lowering, antidiabetic, and anti-inflammatory agents [120]. In animal models, the use
of citrus flavonoids as a dietary supplement in mice diets reduced the risk of hepatic steato-
sis, dyslipidemia, and insulin resistance by inhibiting hepatic fatty acid production and
increasing fatty acid oxidation. Citrus flavonoids also reduced inflammation in metabol-
ically essential tissues such as the liver, adipose tissue, kidneys, and aorta. In another
recent research work, citrus flavonoids have been shown to help with insulin resistance,
dyslipidemia, obesity, hepatic steatosis, and atherosclerosis [121].
Molecules 2023, 28, 1636 14 of 20

6.7. Phytochemicals as Antiaging Agents

All living organisms change with aging due to a natural physiological process, and the
most exogenous factors influencing the degree of ageing are hormones, smoking, nutrition,
and direct and indirect exposure to sunshine. This process produces reactive oxygen
species, which are unstable molecules and prevent key enzymes from performing their
functions in the cell matrix. Antioxidants are able to neutralize free radicals. Lime plants
have natural phytochemical compounds that act as antioxidants and anti-aging [122]. These
natural phytochemical compounds play important roles in several biological features and
physiological activities. Products derived from citrus fruits and their waste are viewed
as sustainable, low-cost sources of chemicals with potential use in the pharmacological,
cosmetic, culinary, and nutraceutical fields [123].

7. Toxicity of Phytochemicals Extracted from Citrus L.

The consumption of plants has been a common practice since the dawn of civilization
due to their health benefits, prevention or treatment of diseases, or medicinal purposes.
Many plants (including fruits and vegetables) contain phytochemicals that are not nec-
essary nutrients, such as vitamins or minerals, but are frequently consumed or used as
herbal remedies or dietary supplements due to their alleged health benefits. The Food
and Drug Administration (FDA) does not regulate the majority of phytochemicals in the
United States, and little is known about their potential toxicity. The use of phytochem-
ical dietary supplements and herbal remedies has increased in recent years, especially
in western nations. In the U.S., 49% of the population (45% of men and 53% of women)
reported using supplements [124]. Despite their popularity, the safety and effectiveness of
the majority of individual phytochemicals are understood in preventing or treating chronic
diseases such as cancer [125]. According to epidemiological studies, many consumers of
dietary supplements believe that these ingredients are secure and could serve as a more
natural substitute for prescription drugs [126]. In fact, some studies have indicated that
phytochemicals, such as resveratrol or epigallocatechin gallate (EGCG), may be helpful in
the prevention or treatment of chronic diseases [127,128]. Medicinal plants are a diverse
source of bioactive compounds that, depending on the species, plant part, and dosage used,
may be beneficial or harmful to human health [129,130]. The idea that medicinal plants
and herbs are safe and do not exert any toxic effects on humans has been prevalent for
a very long time. However, despite the increased reliance on medicinal plants globally,
it has not been acknowledged that these plants can contain either beneficial or harmful
bioactive compounds [131]. Some constituents may cause the dysfunction of vital organs
(including the kidneys, liver, and stomach, as well as the nervous system) [132]. Toxicity
studies are a crucial prerequisite in identifying non-toxic, safe, and pharmacologically
active plants correctly. One of the main components of citrus essential oils is limonene,
which causes high mortality at increased doses and has favorable effects on the life history
traits of adult medflies when they are exposed to it at low sub-lethal doses [133]. One
of the most widely consumed citrus fruits is the pomelo (Citrus grandis L. Osbeck). The
common flavonoids reported to be present in pomelo juice in significant amounts include
neohesperidin, hesperidin, naringenin, naringin, and rutin [134,135]. According to reports
from Mokbel and Suganuma [136] and Do Ngoc et al. [137], the fruit extract has a number of
pharmacological advantages, including anti-obesity, antimicrobial, antioxidant, and antidi-
abetic properties. Despite having many different uses, there is still a lack of information on
the safe dosage, safety, and toxicology profiles of many medicinal plants, including pomelo.
Citrus limon has a long history of use, but little is known about its toxicity. This study was
conducted to assess the juice’s potential acute and subacute toxicity. Although it could be
regarded as non-toxic and incredibly safe for consumption, even at concentrations above
80%, Citrus limon juice does not exhibit potential hazards that are harmful to experimental
animals [138]. Citrus peels contain a large amount of essential oils and are toxic to a variety
of insect species. The use of essential oils to control insect pests is also environmentally
friendly. A waste product called Citrus maxima peel essential oil (CMEO) was described
Molecules 2023, 28, 1636 15 of 20

and its potential for controlling insect pests was assessed. Limonene and pinene are the two
main terpenoids in CMEO. CMEO demonstrated potential for toxicity-based contact and
fumigant-based insect pest control. Additionally, Armigeres subalbatus was more resistant
to CMEO’s larvicidal effects than the Culex tritaeniorhynchus and Aedes aegypti species of
mosquitoes. A discernible germination inhibition was found in comparison to the control
group when the essential oil’s biological safety was not tested on stored seeds [139].

8. Conclusions
It is concluded that different parts of citrus fruit waste (peel, seeds, and pomace)
contained various phytochemicals. This waste, produced during the processing of citrus
fruits, contains numerous essential oils (EOs), ascorbic acid, sugars, carotenoids, flavonoids,
dietary fiber, polyphenols, and numerous trace components. These compounds are ex-
tracted by using different extraction techniques, including ultrasonic extraction, microwave-
assisted extraction, and enzymatic extraction. These extracts are being used in the develop-
ment of different functional food products. These food products play an important role in
health. Polyphenols present in citrus waste foods have a variety of potential health ben-
efits, including antiaging, anti-mutagenic, antidiabetic, anti-carcinogenic, anti-allergenic,
antioxidative, anti-inflammatory, neuroprotective, and cardiovascular-protective activity.

Author Contributions: Conceptualization, Z.M. and W.K.; methodology, H.K.; software, W.K.; vali-
dation, H.T.A.; formal analysis, M.A. (Mohammed Almarzuq); investigation, H.K.; resources, W.K.;
data curation, Z.J.; writing—original draft preparation, W.K.; writing—review and editing, H.T.A.,
Z.J.; visualization, S.K.A.; supervision, W.K.; project administration, A.A.-F.; funding acquisition,
M.A. (Mohamed Afifi), L.A.A.-S., D.M.D.B., M.A. (Mohammed Almarzuq) and A.A.-F. All authors
have read and agreed to the published version of the manuscript.
Funding: This research was funded by Princess Nourah bint Abdulrahman University Researchers
Supporting Project number (PNURSP2023R365) and Deanship of Scientific Research at King Khalid
University under grant number (R.G.P.2/77/44).
Institutional Review Board Statement: This study does not contain any experiments performed by
any of the authors with human or animal subjects.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Acknowledgments: Princess Nourah bint Abdulrahman University Researchers Supporting Project
number (PNURSP2023R365), Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia.
The authors extend their appreciation to the Deanship of Scientific Research at King Khalid University
for funding this work through Large Groups Project under grant number (R.G.P.2/77/44).
Conflicts of Interest: The authors declare no conflict of interest.
Sample Availability: Samples of the compounds are available from the authors.

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