Metabolism

Metabolism plays a critical role in the biological activity and disposition of AF. To produce a DNA damage product, AFB1 undergoes an initial two-electron oxidation by the cytochrome P450 family members CYP1A2 and CYP3A4, yielding aflatoxin B1-8,9-oxide. This epoxide reacts with the N7 atom of guanine to form a pro-mutagenic DNA adduct (aflatoxin-N7-guanine). The aflatoxin-DNA adduct is unstable and undergoes depurina-tion, leading to its urinary excretion. Aflatoxin B1-8,9-oxide is also a substrate for several isoforms of human glutathione S-transferases (GSTs), which yield a stable, nontoxic, polar product that is excreted in the bile. The aflatoxin-glutathione product also undergoes sequential metabolism in the liver and kidneys to be excreted as a mercapturic acid (aflatoxin-N-acetylcysteine) in the urine. Afla-toxin B1 also undergoes extensive oxidation, which is catalyzed by cytochrome P450s. In addition to formation of the 8,9-oxide, oxidation by CYP1A2 yields a stable urinary metabolite, aflatoxin M1, that is excreted in milk. Aflatoxin M1 is less carcinogenic or mutagenic than aflatoxin B1, but it is equally toxic. The oxidation products of aflatoxin can be excreted without further biotransformation or can be conjugated by UDP-glucuronosyl transferases. Collectively, these end products of aflatoxin biotransformation are biomarkers of exposure to aflatoxin and risk of hepatocellular carcinoma.

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