383
revealed that this AFs come from A. flavus [12, 13]. During the same year, another
AFs outbreak was reported in northwest India that equally affected humans and
animals [13, 14]. In 1981, another major AFs outbreak was reported in Kenya [15].
Since 2004, numerous aflatoxicosis outbreaks have been documented by the Centers
for Disease Control and Prevention globally, resulted in 500 cases of acute illness
and a total of 200 deaths [16, 17]. Many outbreaks have been documented in Kenya
in 2004 that was due to maize grown at home. Later on, it was found that this maize
was contaminated with molds [16]. In 2013, many European countries (Romania,
Croatia, and Serbia) reported the AFs contamination of milk nationwide [18].
Biotransformation of Aflatoxin
Biotransformation of AFs majorly happens in the liver. AFs passes through both
phase-I and phase-II type of metabolism. Phase-I metabolism majorly includes oxidation, reduction, and hydrolysis. Phase-I metabolism products serve as reactants
for phase-II metabolism, which majorly involves the conjugation reactions. Phase-I
metabolism results in either detoxification or activation of a given compound. While
phase-II metabolism leads either to detoxification or generation of biochemical
lesions. Cytochrome P450 (CYP450) system is majorly involved in phase-I metabolism, while phase-II metabolism includes sulfation, glucuronidation and amino
acid, and glutathione conjugation reactions [19].
Phase-I Metabolism of Aflatoxins
CYP450 subfamilies are involved in the oxidation of AFB1 and converted it into
several other metabolites. Among all metabolites of AFB1, AFB1 epoxide has been
recognized as mutagenic while all others are harmless detoxified products.
AFB1epoxide (highly potent metabolite) is an active electrophile and it has a strong
affinity with nucleophilic oxygen, nitrogen, and sulfur-like heteroatoms found in
cellular constituents [20]. Conversion of AFB1 to AFB1 epoxide is an important
reaction that promotes the covalent binding of AF to various cellular macromolecules including protein and DNA. This reaction takes place with the help of CYP1A2
and 3A4 [21]. CYP3A4 may be involved in both activation as well as detoxification
of AFB1. CYP3A4 is abundantly found in the liver and small intestine. During the
intestinal biotransformation, epoxidation does not enhance the risk of liver cancer.
CYP3A4, abundantly found in the liver, is majorly involved in the activation of
AFB1. Moreover, CYP1A2 and few other CYP450 enzymes also contribute to its
activation to some extent [22, 23]. CYP3A4 mostly forms AFB-2,3-epoxide (genotoxic), while CYP1A2 produces the nongenotoxic endoisomers [22]. CYP1A2
shows a great affinity for activation of AF-B1 at low concentrations after dietary
exposure [24]. Some intermediates of the AFB1 pass through some other chemical
23 Role of Aflatoxins as EDCs in Metabolic Disorders
revealed that this AFs come from A. flavus [12, 13]. During the same year, another
AFs outbreak was reported in northwest India that equally affected humans and
animals [13, 14]. In 1981, another major AFs outbreak was reported in Kenya [15].
Since 2004, numerous aflatoxicosis outbreaks have been documented by the Centers
for Disease Control and Prevention globally, resulted in 500 cases of acute illness
and a total of 200 deaths [16, 17]. Many outbreaks have been documented in Kenya
in 2004 that was due to maize grown at home. Later on, it was found that this maize
was contaminated with molds [16]. In 2013, many European countries (Romania,
Croatia, and Serbia) reported the AFs contamination of milk nationwide [18].
Biotransformation of Aflatoxin
Biotransformation of AFs majorly happens in the liver. AFs passes through both
phase-I and phase-II type of metabolism. Phase-I metabolism majorly includes oxidation, reduction, and hydrolysis. Phase-I metabolism products serve as reactants
for phase-II metabolism, which majorly involves the conjugation reactions. Phase-I
metabolism results in either detoxification or activation of a given compound. While
phase-II metabolism leads either to detoxification or generation of biochemical
lesions. Cytochrome P450 (CYP450) system is majorly involved in phase-I metabolism, while phase-II metabolism includes sulfation, glucuronidation and amino
acid, and glutathione conjugation reactions [19].
Phase-I Metabolism of Aflatoxins
CYP450 subfamilies are involved in the oxidation of AFB1 and converted it into
several other metabolites. Among all metabolites of AFB1, AFB1 epoxide has been
recognized as mutagenic while all others are harmless detoxified products.
AFB1epoxide (highly potent metabolite) is an active electrophile and it has a strong
affinity with nucleophilic oxygen, nitrogen, and sulfur-like heteroatoms found in
cellular constituents [20]. Conversion of AFB1 to AFB1 epoxide is an important
reaction that promotes the covalent binding of AF to various cellular macromolecules including protein and DNA. This reaction takes place with the help of CYP1A2
and 3A4 [21]. CYP3A4 may be involved in both activation as well as detoxification
of AFB1. CYP3A4 is abundantly found in the liver and small intestine. During the
intestinal biotransformation, epoxidation does not enhance the risk of liver cancer.
CYP3A4, abundantly found in the liver, is majorly involved in the activation of
AFB1. Moreover, CYP1A2 and few other CYP450 enzymes also contribute to its
activation to some extent [22, 23]. CYP3A4 mostly forms AFB-2,3-epoxide (genotoxic), while CYP1A2 produces the nongenotoxic endoisomers [22]. CYP1A2
shows a great affinity for activation of AF-B1 at low concentrations after dietary
exposure [24]. Some intermediates of the AFB1 pass through some other chemical
23 Role of Aflatoxins as EDCs in Metabolic Disorders