Evidence for involvement of multiple forms of cytochrome P-450 in aflatoxin B1 metabolism in human liver.

Abstract

Liver cancer is a major cause of premature death in many areas of Africa and Asia and its incidence is strongly correlated with exposure to aflatoxin B1 (AFB1).Because AFB1 requires metabolic activation to achieve a biological response, there is a need for detailed knowledge of the mechanism of activation to assess individual risk. We have carried out an extensive study using a total of 19 human liver samples to determine the individual variability in the metabolism of the toxin to mutagenic or detoxification products and to identify the specific cytochrome P450 forms involved in these processes. Metabolism to the toxic 8,9-epoxide or to products mutagenic in the Ames test was found to exhibit very large individual variation. The rates of metabolic activation were highly correlated with both the level of proteins of the P450I1A gene family and with the total cytochrome P450 content of the microsomes. In agreement with this, antibodies reacting with P450IHA proteins were strong inhibitors of both

Determination of exposure to aflatoxins among Danish workers in animal-feed production through the analysis of aflatoxin B1 adducts to serum albumin.

“…However, these workers implemented different job functions. Another explanation for the different adduct levels with the same exposure could be an interindividual difference in the metabolism of aflatoxin B I to biologically active metabolites or detoxified products (19). One of the workers in the silo at factory B had a fairly high level of aflatoxin B I adducts to albumin although his estimated exposure to dust particles was low, less than 25 070 of the workhours.…”

Fecal and urinary excretion of aflatoxin B1 metabolites (AFQ1, AFM1 and AFB‐N7‐guanine) in young Chinese males

“…Members of the cytochrome P450 (CYP) enzyme family, CYP1A2, CYP3A4 and CYP2A6 have been shown to be responsible for the metabolism of the absorbed aflatoxins 7,8 ( Fig. 1).…”

“…Absorbed AFB 1 and its metabolites are excreted in urine, while elimination to feces is a route for both the unabsorbed AFB 1 and biliary excretion of metabolites formed from the absorbed toxin. Animal studies have shown that under normal conditions 50% of the orally administered dose of AFB 1 is quickly absorbed from the duodenal region of the small intestine 4 and enters the liver through the hepatic portal blood supply.5 AFB 1 is concentrated in the liver and to a lesser extent in kidney, 6 and it is also found in the mesenteric venous blood as free AFB 1 or its water-soluble metabolites.Members of the cytochrome P450 (CYP) enzyme family, CYP1A2, CYP3A4 and CYP2A6 have been shown to be responsible for the metabolism of the absorbed aflatoxins 7,8 (Fig. 1).…”

Involvement of Cytochrome P450, Glutathione S-Transferase, and Epoxide Hydrolase in the Metabolism of Aflatoxin B 1 and Relevance to Risk of Human Liver Cancer

“…Assays GS-AFB1 (products of exo and endo epoxides) and AFB,-8,9-dihydrodiol were separated by high-performance liquid chromatography (HPLC) and quantified (A360) as described elsewhere (25,31). Genotoxicity assays involved measurement of the umu (SOS) response in Salmonella typhimurium TA1535 harboring the plasmid pSK1001 using general procedures described elsewhere (32 (9,31,(34)(35)(36)(37) (Table 2). P450 1A2 and some other human P450s can also contribute, but they play a lesser role, even at relatively low AFB, concentrations (31,35,36,38,39).…”

“…Genotoxicity assays involved measurement of the umu (SOS) response in Salmonella typhimurium TA1535 harboring the plasmid pSK1001 using general procedures described elsewhere (32 (9,31,(34)(35)(36)(37) (Table 2). P450 1A2 and some other human P450s can also contribute, but they play a lesser role, even at relatively low AFB, concentrations (31,35,36,38,39). P450 3A4 forms only the genotoxic AFBI-8,9-exo-epoxide; P450 1A2 forms both the exo and the nongenotoxic endo isomers (Figure 1)(31).…”