The influence of environmental and genetic factors on CYP2D6, CYP1A2 and UDP-glucuronosyltransferases in man using sparteine, caffeine, and paracetamol as probes.

摘要: The impact of gender, use oral contraceptive steroids (OCS), coffee consumption and smoking on the metabolism sparteine, caffeine, paracetamol was studied in 194 randomly selected subjects (98 male 95 female). Thirty-eight volunteers were cigarette smokers, 40 female smokers and/or users OCS. metabolic ratio sparteine oxidation (MRs) showed a trimodal distribution. 7.7% had MRs > 20 thus poor metabolizers (PMs). Within extensive metabolizer (EM) subjects, distinct subgroup accounting for 11% observed with 1.2. Six 15 phenotypical PMs heterozygous EMs by genotyping. This indicates existence one or several CYP2D6 mutations which cannot be identified currently employed genotyping methods. In each subgroup, i.e. smokers/OCS non-smokers/non-OCS, cumulative frequency distribution (wt/B) phenotype caused shift to higher compared wild-type homozygotes (wt/wt). Thus, vivo activity CYP2D6, genetic determinants prevail over environmental factors. Smoking, steroids, caffeine consumption, gender no influence metabolism. glucuronide/paracetamol appeared unimodal although skewed. Glucuronidation capacity clearly affected OCS smoking. It than subjects. Male highest, non-smokers/non-OCS lowest ratio. CYP1A2 activity, as determined ((AFMU + 1X 1U)/1, 7U), multimodally distributed increased smokers. significantly correlated glucoronidation heavy (r=0.85), suggesting an element co-regulation conjugating UDP-glucuronosyltransferase isozymes, including UGTI.6.