THE INFLUENCE OF ENVIRONMENTAL AND GENETIC-FACTORS ON CYP2D6, CYP1A2 AND UDP-GLUCURONOSYLTRANSFERASES IN MAN USING SPARTEINE, CAFFEINE, ANDPARACETAMOL AS PROBES

The impact of gender, use of oral contraceptive steroids (OCS), coffee consumption and of smoking on the metabolism of sparteine, caffeine, and paracetamol was studied in 194 randomly selected subjects (98 male and 95 female). Thirty-eight of the male volunteers were cigarette sm okers, 40 of the female subjects were smokers and/or users of OCS. The metabolic ratio of sparteine oxidation (MR(s)) showed a trimodal dist ribution. 7.7% of the subjects had a MR(s) > 20 and thus were poor met abolizers (PMs). Within the extensive metabolizer (EM) subjects, a dis tinct subgroup accounting for 11% was observed with 20 > MR(s) > 1.2. Six of the 15 phenotypical PMs were heterozygous EMs by genotyping. Th is indicates the existence of one or several CYP2D6 mutations which ca nnot be identified by the currently employed genotyping methods. In ea ch subgroup, i.e. smokers/OCS and non-smokers/non-OCS, the cumulative frequency distribution of the heterozygous (wt/B) phenotype caused a s hift to higher MR(s) compared with the wild-type homozygotes (wt/wt). Thus, for the in vivo activity of CYP2D6, genetic determinants prevail over environmental factors. Smoking, use of oral contraceptive steroi ds, caffeine consumption, or gender had no influence on sparteine meta bolism. The distribution of the paracetamol glucuronide/paracetamol me tabolic ratio appeared to be unimodal although skewed. Glucuronidation capacity was clearly affected by gender, OCS use and smoking. It was higher in male than in female subjects. Male smokers had the highest, and female non-smokers/non-OCS users the lowest metabolic ratio. CYP1A 2 activity, as determined by a caffeine metabolic ratio ((AFMU + 1X 1U)/1,7U), was multimodally distributed and was clearly increased in s mokers. It was significantly correlated to paracetamol glucuronidation in male heavy smokers (r = 0.85), suggesting an element of co-regulat ion of CYP1A2 and of paracetamol conjugating UDP-glucuronosyltransfera se isozymes, including UGT1.6.