Caffeine as a common probe for noninvasive phenotype-genotype analysis of FMO3 and CYP1A2

초록

We have previously reported the common genetic polymorphisms in human flavin-containing monooxygenase 3 (FMO3), hepatic metabolizing enzyme, affecting the N-oxidation of ranitidine (RA). Caffeine (CA) N3-demethylation is widely accepted as a major pathway reflecting the individual cytochrome P450 1A2 (CYP1A2) activity. Caffeine is an attractive chemical as a noninvasive probe for phenotyping of drug metabolizing enzymes, because it is easy to measure of caffeine and its metabolites in biological fluid and is safe. Furthermore, there is little in vivo probe for phenotyping of the human FMO3 activity, except our previous reports. Therefore, we tried to determine the individual FMO3 activity using the attractive substrate, CA, for detection of the correlation between the activity (N1-demethylation of CA) and the common FMO3 genotypes. We studied 87 normal Korean adult volunteers in a crossover design at intervals of 1 week to evaluate the relationship between common mutations of FMO3 and their activity determined by 2 different substrates, CA or RA. The PX/CA ratios with wild FMO3 genotype were significantly higher than those of mutant genotypes (p=0.0032). Within smokers group, the effect of FMO3 genotypes on PX/CA ratio was blunted (p=0.121). As consistent with our previous report, RANO/RA ratios of wild genotype were significantly higher than those of mutant genotype (p<0.0001). Also, the significant correlation between PX/CA ratios and RANO/RA ratios was observed (Pearson r=0.384, p=0.0002). In nonsmokers group, the correlation was the more profound (Pearson r=0.427, p=0.0025), and that was weak but statistically significant in smokers (Pearson r=0.33, p=0.04). These results suggest that caffeine N3-demethylation activity could be used as an indicator for phenotype-genotype analysis of FMO3, although the caffeine is not an appropriate probe for FMO3 phenotyping.