A POPULATION AND FAMILY STUDY OF CYP1A2 USING CAFFEINE URINARY METABOLITES

CYP1A2 is a cytochrome P450 which is inducible by polycyclic aromatic hydrocarbons. This induction could be mediated via the Ah locus, which encodes a cytosolic receptor responsible for the regulation of the CY P1A1 gene. Enzyme activity in vivo can be measured by the urinary caff eine metabolite ratio (AFMU + 1X + 1U)/17U. Our goal was to determine, using this ratio, the possible existence of a genetic polymorphism in CYP1A2 induction. For this purpose, a population and family study, in cluding smokers, were undertaken. In a first step, we investigated fac tors influencing enzyme activity in a population of 245 unrelated indi viduals. The induction effect of smoking and inhibiting effect of oral contraceptive use were confirmed. None: of the other factors examined (age, sex, level of cigarette consumption, nicotine or tar amounts, f ilter, inhalation) accounted for the interindividual variability in th e metabolic ratio. Using the statistical SKUMIX method, a unimodal (on e peak) distribution of the ratio was concluded in 164 unrelated smoke rs, since a second distribution did not significantly improve the fit to the data (chi(2)1 = 1.39, P > 0.2). Segregation analysis was perfor med on 68 nuclear families and no major gene effect could be shown. Fu rthermore, the polygenic model did not provide a higher likelihood tha n the sporadic one, which argues against the existence of any familial resemblance. Although we cannot rule out the possibility that some en vironmental factors could obscure the phenotypes and occult a genetic determinism, we conclude that genetic factors are probably negligible in the determination of CYP1A2 activity measured by this method. These results suggest that CYP1A2 induction via the Ah locus would not be s imilar to that of CYP1A1.