title: Cytochrome P450 1A1 and 1B1 in human blood lymphocytes are not suitable as biomarkers of exposure to dioxin-like compounds: polymorphisms and interindividual variation in expression and inducibility.
abstract: Cytochrome P450 1A1 (CYP1A1) and 1B1 (CYP1B1) are phase I enzymes, the expression of which can be affected by many environmental compounds, including dioxins and dioxin-like compounds. Because CYP1A1 and CYP1B1 expression can easily be determined in peripheral blood lymphocytes, it is often suggested as biomarker of exposure to these compounds. In this study we investigated the interindividual differences in constitutive and induced CYP1A1-catalyzed ethoxyresorufin-O-deethylase (EROD) activity and CYP1A1 and CYP1B1 gene expression in human blood lymphocytes in a group of ten non-smoking females. Freshly isolated lymphocytes were cultured in medium containing the mitogen PHA and were exposed to the most potent dioxin, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or the less potent dioxin-like polychlorinated biphenyl 126 (PCB126). In addition, we determined the occurrence of the CYP1A1 MspI and CYP1B1 Leu432Val polymorphisms. All individuals showed a concentration-dependent increase of EROD activity by TCDD, which was significantly correlated with an increase in CYP1A1, but not CYP1B1 expression. The maximum induced EROD activity by TCDD was very different among the individuals, but the EC50 values were about the same. PCB126 also caused a concentration-dependent increase of EROD activity, but was a factor 100-1000 less potent than TCDD among the individuals. The allele frequencies for CYP1A1 MspI and CYP1B1 Leu432Val reflected a normal Caucasian population and in this study the polymorphisms had no apparent effect on the expression and activity of these enzymes. Our study shows a large interindividual variability in constitutive and induced EROD activity, and CYP1A1 and CYP1B1 expression in human lymphocytes. In addition, dioxin concentrations at which effects were observed in our in vitro study are about 10-fold higher than the human blood levels found in vivo, indicating that EROD activity and CYP1A1 and CYP1B1 expression in human lymphocytes might not be applicable as biomarkers of exposure to dioxin and dioxin-like compounds.
authors.affiliation: Institute for Risk Assessment Sciences (IRAS), Utrecht University, Yalelaan 2, PO Box 80176, 3508 TD, Utrecht, The Netherlands. M.vanDuursen@iras.uu.nl
authors.forename: Majorie B M
authors.initials: MB
authors.lastname: van Duursen
authors.forename: J Thomas
authors.initials: JT
authors.lastname: Sanderson
authors.forename: Martin
authors.initials: M
authors.lastname: van den Berg
mesh_terms: D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases; D015415:Biomarkers / Q000097:blood; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis* / Q000235:genetics; D065633:Cytochrome P-450 CYP1B1; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics; D004147:Dioxins / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004781:Environmental Exposure / Q000032:analysis*; D004790:Enzyme Induction / Q000187:drug effects / Q000235:genetics; D005260:Female; D014644:Genetic Variation; D006801:Humans; D066298:In Vitro Techniques; D008214:Lymphocytes / Q000187:drug effects* / Q000201:enzymology; D011078:Polychlorinated Biphenyls / Q000633:toxicity; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity; D011110:Polymorphism, Genetic
chemical_list: D015415:Biomarkers; D004147:Dioxins; D000072317:Polychlorinated Dibenzodioxins; D003577:Cytochrome P-450 Enzyme System; D011078:Polychlorinated Biphenyls; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; D019363:Cytochrome P-450 CYP1A1; D065633:Cytochrome P-450 CYP1B1; C023035:3,4,5,3',4'-pentachlorobiphenyl