384
reactions in Phase II after binding with GSH to produce the less toxic polar compounds that are directly excreted through bile and urine. However, aflatoxin B1-8,9epoxide (AFBO) and AFB1-dihydroxide intermediates have carcinogenic
properties, while AF-B2 induces acute toxicity, hepatic necrosis, and cellular
enzyme inhibition [25].
Phase-II Metabolism
Phase-II reactions leading towards the detoxification include conjugation to GSH,
sulfate, and glucuronic acid. The AFB1 metabolites obtained from Phase-I metabolism undergo phase-II enzymatic reactions with the help of glutathione-Stransferases that predominantly catalyze the conjugation reactions. After phase-I
oxidation reaction, AFs may be rapidly conjugated with thiol (SH) group (during
Phase-II reactions) resulting in detoxification and elimination of toxic products
[26, 27].
Mechanism of Toxicity
Aflatoxin-Induced Oxidative Stress
Oxidative stress serves as a key mechanism behind aflatoxicosis. Both AFs and
their metabolites may induce oxidative stress. AFB1, a carcinogenic food contaminant, is generally categorized among the most potent hepatocarcinogens in both
human and experimental animals. AFB1 metabolism potentiates free radicals production leading to cell damage [19, 24]. AFB1 is metabolized in the liver with the
help of CYP450 to AFBO, which binds with protein and DNA and makes the
adducts. The hazardous effects of AF generally produce owing to the binding of
epoxide derivative with DNA. CYP450 enzymes produce superoxide and hydrogen
peroxide as intermediate compounds resulting in some cellular pathological
changes and apoptosis [20]. The genotoxicity of AFB1 may be partly owing to the
excessive production of ROS like OH, O 2
−
, and H 2 O 2 during the metabolism of
AFB1 by CYP450s in hepatic tissues. ROS may attack various soluble cellular
compounds and membranes resulting in impairment of different cellular functions
and eventually, cytolysis occurs [28]. It is being reported that free radicals production during AFB1 metabolism followed by the oxidative damage may be one kind
of damage induced by AFB1 [21]. Oxidative damage from these ROS may, in turn,
induce tissue damage through various mechanisms comprising DNA damage, protein oxidation, lipid peroxidation, and thiol depletion. Studies have shown that
AFB1 may alter the cell cycle and trigger the apoptotic-signaling pathways in hepatocytes in vitro [29].
S. Sabir et al.
reactions in Phase II after binding with GSH to produce the less toxic polar compounds that are directly excreted through bile and urine. However, aflatoxin B1-8,9epoxide (AFBO) and AFB1-dihydroxide intermediates have carcinogenic
properties, while AF-B2 induces acute toxicity, hepatic necrosis, and cellular
enzyme inhibition [25].
Phase-II Metabolism
Phase-II reactions leading towards the detoxification include conjugation to GSH,
sulfate, and glucuronic acid. The AFB1 metabolites obtained from Phase-I metabolism undergo phase-II enzymatic reactions with the help of glutathione-Stransferases that predominantly catalyze the conjugation reactions. After phase-I
oxidation reaction, AFs may be rapidly conjugated with thiol (SH) group (during
Phase-II reactions) resulting in detoxification and elimination of toxic products
[26, 27].
Mechanism of Toxicity
Aflatoxin-Induced Oxidative Stress
Oxidative stress serves as a key mechanism behind aflatoxicosis. Both AFs and
their metabolites may induce oxidative stress. AFB1, a carcinogenic food contaminant, is generally categorized among the most potent hepatocarcinogens in both
human and experimental animals. AFB1 metabolism potentiates free radicals production leading to cell damage [19, 24]. AFB1 is metabolized in the liver with the
help of CYP450 to AFBO, which binds with protein and DNA and makes the
adducts. The hazardous effects of AF generally produce owing to the binding of
epoxide derivative with DNA. CYP450 enzymes produce superoxide and hydrogen
peroxide as intermediate compounds resulting in some cellular pathological
changes and apoptosis [20]. The genotoxicity of AFB1 may be partly owing to the
excessive production of ROS like OH, O 2
−
, and H 2 O 2 during the metabolism of
AFB1 by CYP450s in hepatic tissues. ROS may attack various soluble cellular
compounds and membranes resulting in impairment of different cellular functions
and eventually, cytolysis occurs [28]. It is being reported that free radicals production during AFB1 metabolism followed by the oxidative damage may be one kind
of damage induced by AFB1 [21]. Oxidative damage from these ROS may, in turn,
induce tissue damage through various mechanisms comprising DNA damage, protein oxidation, lipid peroxidation, and thiol depletion. Studies have shown that
AFB1 may alter the cell cycle and trigger the apoptotic-signaling pathways in hepatocytes in vitro [29].
S. Sabir et al.