Dominant Contribution of P450 3A4 to the Hepatic Carcinogenic Activation of Aflatoxin B₁

Abstract

The hepatic carcinogen aflatoxin B1 (AFB1) is metabolized in the liver by at least four different P450s, all of which exhibit large interindividual differences in the expression levels. These differences could affect the individual risk of hepatocellular carcinoma (HCC). We investigated the metabolism of AFB1 in a panel of 13 human liver microsomal preparations using a hepatic abundance model, which takes into account the specific kinetic parameters and the expression levels of these P450s. We found a 12-fold variability in the production rate of the carcinogenic metabolite AFB1-8,9-epoxide (AFBO) and a 22-fold variability in the production of the detoxification product AFQ1. The ratio between the AFBO and the AFQ1 production rates varied between 1:19 and 1:1.7. P450 3A4 contributed a majority of AFBO and AFQ1, and its expression level was the most important determinant of the AFB1 disposition toward these primary metabolites. P450 3A5, which exclusively produced AFBO, was the second-most important enzyme activating AFB1 to AFBO, followed by P450 3A7 and P450 1A2. The relative contribution of AFBO by P450 3A5 strongly depended on the concomitant expression of P450 3A4, and it was as high as 15% in a P450 3A5 high expressor with the lowest P450 3A4 expression of all livers. The P450 1A2-specific AFB1 detoxification product AFM1 was not detected. In conclusion, the variable expression of P450s has a major effect on the carcinogenic activation of AFB1, which may affect the individual predisposition to HCC. P450 3A4 expression is the most important determinant of AFB1 activation to AFBO. The contribution of P450 1A2 to AFB1 metabolism appears to be negligible and may have been overestimated. Targeted chemoprevention of AFB1-associated HCC should consider P450 3A4 inhibitors and avoidance of P450 3A4 inducers.

CYP3A4 Gene Is a Novel Biomarker for Predicting a Poor Prognosis in Hepatocellular Carcinoma

“…CYP3A4 is mainly expressed in the liver and intestine, and its enzymes are involved in the metabolism of about 50% of all drugs, participating in the metabolic activation and metabolism of several pre-carcinogens (25)(26)(27). Ba et al reported that benzo[a]pyrene, which is metabolized by CYP3A4, promoted HCC metastasis and progression in vitro and in mouse models.…”

“…Ethical approval for all experimental protocols and study was obtained from the institutional review board at the Shizuoka Cancer Center (Authorization Number: [25][26][27][28][29][30][31][32][33]. Written informed consent was obtained from all patients enrolled in the study.…”

Aflatoxin Contamination in Foods and Feeds: A Special Focus on Africa

“…It may well be that the highest liver cancer areas have a combination of both cancer forming factors plus others such as genetic ones. This certainly is the case for AFB 1 as it has been seen that AFB 1 needs to be activated by the cytochrome P 450 system in particular the CYP 3A4 version plus CYP3A5 and 3A7 (Kamdem et al, 2006). Hence those persons with genetics dictating less expression of these forms of cytochrome P 450 would, in theory, have less chance of developing the cancer and vice versa.…”

Do Gastroenterologists Consider Aflatoxins as Origin of Digestive System Cancers?

“…In Gambia, this mutation was detected in DNA in cases of HCC and was not frequent in the control cases [76][77][78][79]. Transversions G→T or transitions G→A are produced in the third base of codon 249 of the p53 gene and in the first or second base of codon 12 of the H-ras gene [80][81][82][83][84][85]. [86].…”