Potential Role of Cytochrome P450-1B1 in the Metabolic Activation of 4-Aminobiphenyl in Humans

Metabolites of the human carcinogen 4-aminobiphenyl (4-ABP) form hemoglobin (Hb) adducts, which represent a useful biomarker for exposure. However, not every individual responds to a similar degree to 4-ABP exposure, and variations in 4-ABP-Hb adduct formation might be explained by genetic polymorphisms in genes coding for enzymes involved in 4-ABP metabolism. 4-ABP-Hb adducts were measured in blood samples from 57 smoking and 10 nonsmoking volunteers. An association was found between cigarette smoking and 4-ABP-Hb adduct levels in smokers (R-2=0.5, P<0.001). Subsequently, subjects were genotyped for 12 polymorphisms in seven genes involved in biotransformation reactions. From this selection of polymorphisms, a significant impact was found for the CYP1B1 Leu(432)Val polymorphism (P=0.021), which has been reported to lead to a decrease in enzyme activity, Indeed higher levels of 4-ABP-Hb adducts were observed in homo-and heterozygous carriers of the CYP1B1(432)Leu as compared to the double CYP1B1(432)Val genotype. A significant interaction between these CYP1B1 genotypes and the level of exposure was found (P=0.003). Noteworthy, a saturation effect was observed for 4-ABP-Hb adduct formation at high smoking doses limited to carriers of the CYP1B1(432)Leu allele. No effect of polymorphisms in other genes were found. This is the first study in humans suggesting a crucial role of the CYP1B1 enzyme in 4-ABP metabolism, indicating a protective effect of the CYP1B1 Leu(432)Val polymorphism against the formation of 4-ABP-Hb adduct levels, depending on the smoking dose. (C) 2009 Wiley-Liss, Inc.