Genetic polymorphism of induction of CYP1A1 (EROD) activity

Abstract

CYP1A1 is a cytochrome P450 which is inducible by polycyclic aromatic hydrocarbons (PAH). This induction is mediated via the Ahr locus which encodes the cytosolic Aryl hydrocarbon receptor. The induced activity of CYP1A1 can be measured in vitro by the ethoxyresorufin-O-deethylase (EROD) activity in lymphocytes after induction by benz(a)anthracene (B(a)A). Our purpose was to determine, using this assay, the genetic polymorphism of CYP1A1 induction. With this aim, a population and family study was undertaken. Using the statistical SKUMIX method, a bimodal distribution (two peaks) of the induced EROD activity among 102 unrelated individuals was obtained. We were unable to discriminate three classes of CYP1A1 induction phenotype since a trimodal distribution did not significantly improve the fit to the data (chi 2(1) = 0.37, p > 0.9). Segregation analysis performed on 57 nuclear families gave evidence of a major gene effect together with a polygenic component. The frequency of the high induction allele is equal to 0.11 with dominance on the low induction allele. This is an accordance with two distributions, with individuals showing low and high CYP1A1 induction phenotypes in proportions of 89% and 21% respectively. However, some degree of overlap between the two distributions prevented a clear genotype classification on the basis of the phenotype measured with the EROD assay. Further analyses should not be made with a dichotomized phenotype (low and high inducers) but should use quantitative measurements.