title: Potential role of cytochrome P450-1B1 in the metabolic activation of 4-aminobiphenyl in humans.
abstract: 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 non-smoking 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.
authors.affiliation: Department of Health Risk Analysis and Toxicology, Maastricht University, Maastricht, The Netherlands.
authors.forename: Hans B
authors.initials: HB
authors.lastname: Ketelslegers
authors.forename: Roger W L
authors.initials: RW
authors.lastname: Godschalk
authors.forename: Bart J M
authors.initials: BJ
authors.lastname: Eskens
authors.forename: Jan W
authors.initials: JW
authors.lastname: Dallinga
authors.forename: Ralph W H
authors.initials: RW
authors.lastname: Gottschalk
authors.forename: Frederik J
authors.initials: FJ
authors.lastname: van Schooten
authors.forename: Joost H M
authors.initials: JH
authors.lastname: van Delft
authors.forename: Jos C S
authors.initials: JC
authors.lastname: Kleinjans
mesh_terms: D000328:Adult; D000611:Aminobiphenyl Compounds / Q000378:metabolism*; D001189:Aryl Hydrocarbon Hydroxylases; D015415:Biomarkers / Q000378:metabolism*; D001711:Biotransformation; D002273:Carcinogens / Q000378:metabolism*; D065633:Cytochrome P-450 CYP1B1; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology*; D018736:DNA Adducts; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006454:Hemoglobins / Q000378:metabolism; D006801:Humans; D008297:Male; D011110:Polymorphism, Genetic; D012307:Risk Factors; D012907:Smoking / Q000235:genetics*
chemical_list: D000611:Aminobiphenyl Compounds; D015415:Biomarkers; D002273:Carcinogens; D018736:DNA Adducts; D006454:Hemoglobins; C006757:4-biphenylamine; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; D065633:Cytochrome P-450 CYP1B1