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

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• 作者：Landry K. Kamdem ; Ingolf Meineke ; Ute G&ouml ; dtel-Armbrust ; Jü ; rgen Brockm&ouml ; ller ; and Leszek Wojnowski
• 刊名：Chemical Research in Toxicology
• 出版年：2006
• 出版时间：April 2006
• 年：2006
• 卷：19
• 期：4
• 页码：577 - 586
• 全文大小：181K
• 年卷期：v.19,no.4(April 2006)
• ISSN：1520-5010

文摘

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 couldaffect the individual risk of hepatocellular carcinoma (HCC). We investigated the metabolism of AFB₁in a panel of 13 human liver microsomal preparations using a hepatic abundance model, which takesinto 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 a22-fold variability in the production of the detoxification product AFQ₁. The ratio between the AFBOand the AFQ₁ production rates varied between 1:19 and 1:1.7. P450 3A4 contributed a majority of AFBOand AFQ₁, and its expression level was the most important determinant of the AFB₁ disposition towardthese primary metabolites. P450 3A5, which exclusively produced AFBO, was the second-most importantenzyme activating AFB₁ to AFBO, followed by P450 3A7 and P450 1A2. The relative contribution ofAFBO by P450 3A5 strongly depended on the concomitant expression of P450 3A4, and it was as highas 15% in a P450 3A5 high expressor with the lowest P450 3A4 expression of all livers. The P4501A2-specific AFB₁ detoxification product AFM₁ was not detected. In conclusion, the variable expressionof P450s has a major effect on the carcinogenic activation of AFB₁, which may affect the individualpredisposition to HCC. P450 3A4 expression is the most important determinant of AFB₁ activation toAFBO. The contribution of P450 1A2 to AFB₁ metabolism appears to be negligible and may have beenoverestimated. Targeted chemoprevention of AFB₁-associated HCC should consider P450 3A4 inhibitorsand avoidance of P450 3A4 inducers.