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Objective: This study was designed to better understand genetic variation in the cytochrome P450 (CYP) gene CYP1A2 and its impact on CYP1A2 activity in Chinese subjects., Methods: CYP1A2 genetic polymorphisms were screened by direct sequencing in 27 selected Chinese subjects. Plasma 1,7-dimethylxanthine/caffeine ratios 5 hours after a 100-mg caffeine administration, used as an index of CYP1A2 in vivo activity, were determined in 422 healthy subjects. Five single-nucleotide polymorphism markers, including G-860A (CYP1A2*1C), T-3594G, G-3113A, A-163C (CYP1A2*1F), and C5347T (CYP1A2*1B), were selected and genotyped by either polymerase chain reaction-restriction fragment length polymorphism or direct sequencing., Results: Thirteen polymorphisms and 2 linkage disequilibrium blocks with a boundary around -2467 were identified at this locus. The allele frequency for -3860A, -3594G, -3113A, -163C, and 5347T was 0.21, 0.15, 0.10, 0.36, and 0.14, respectively, in the CYP1A2-phenotyped cohort. A significant difference in CYP1A2 activity was observed among genotypes of polymorphism G-3113A (P = .038), and CYP1A2 activity in subjects carrying the AA genotype was lower than that in those carrying the GA (P = .096) and GG genotypes (P = .036): -0.45 +/- 0.05 (mean +/- SD), -0.32 +/- 0.16, and -0.29 +/- 0.16, respectively. Further analysis based on haplotype pairs found a 1.92-fold variation (95% confidence interval, 1.13-2.71) in mean CYP1A2 activity between haplotype pairs 13 and 15, and the difference was significant (-0.19 +/- 0.15 versus -0.45 +/- 0.05, P = .016). As compared with haplotype pair 10, haplotype pairs 9 and 15 and most haplotype pairs heterozygous for the haplotype with an A allele at -3113, including pairs 5, 8, and 12, also showed significantly lower CYP1A2 activity (P = .015, .048, .008, .024, and .014 for pairs 5, 8, 9, 12, and 15, respectively). In addition, haplotype pairs 5, 9, and 12 also showed significantly lower CYP1A2 activity than pair 13 (P = .034, .020, and .037 for pairs 5, 9, and 12, respectively)., Conclusions: The G-3113A polymorphism is associated with decreased CYP1A2 activity, haplotype pairs 10 and 13 are responsible for high CYP1A2 activity, and haplotype pairs 5, 8, 9, 12, and 15 are responsible for low CYP1A2 activity in Chinese subjects.

Objective: The acetylation polymorphism is a common inherited variation in human drug and carcinogen metabolism. Because N-acetyltransferase (NAT2) is important for the detoxification and/or bioactivation of drugs and carcinogens, this polymorphism has important implications in therapeutics and cancer susceptibility. A high correlation between acetylation phenotype and genotype has been demonstrated in several studies. However, no such data exist for Chinese females. The aim of the present study was to compare acetylation phenotype with NAT2 genotype in a population of primarily non-smoking Chinese females., Methods: In the present study, the correlation between N-acetyltransferase activity and NAT2 genotype was evaluated in 103 unrelated Chinese female controls derived from a hospital-based case-control study of lung cancer in Singapore. Acetylation phenotype and genotype were respectively determined using caffeine and an allele-specific polymerase chain reaction (PCR)., Results: The proportions of rapid and slow phenotypes were 78% and 22%, respectively, while the distribution of rapid (heterozygotes and homozygotes combined) and slow acetylator genotypes was 76% and 24%, respectively. The distribution of the various NAT2 genotypes did not differ significantly (chi2 = 1.45, P > 0.05) from that predicted by the Hardy-Weinberg Law. All slow acetylators were accurately predicted (100%), whereas 2 of 80 rapid acetylators were erroneously predicted as slow (2.5%). The overall prediction rate of the PCR-based test for the acetylation phenotype was at 98.1% in our Chinese population., Conclusion: Our results suggest that genotyping with PCR may well become the preferred method for the determination of acetylation polymorphism in epidemiological studies in this Asian population.

Aims: To investigate the distribution characteristics of CYP1A2 in a Chinese population, and to examine gender-related differences in CYP1A2 activity., Methods: Two hundred and twenty-nine healthy subjects, 120 men and 109 women, were enrolled in this study. CYP1A2 activity was measured by plasma paraxanthine/caffeine (1,7X/1,3,7X) ratio 6 h after administration of 300 mg caffeine. The concentrations of paraxanthine and caffeine in plasma were detected by h.p.l.c., Results: A 16-fold variation of CYP1A2 activity (range 0. 09 to 1.46) was shown in this study. The coefficient of variation (CV %) of CYP1A2 activity was 62.9%. Non-normal distribution of CYP1A2 activity was indicated by the Shapiro-Wilk test (P<0.001). Probit plots of CYP1A2 activity revealed a bimodal distribution with breakpoint of 1,7X/1,3,7X ratio of 0.12. The percentage of poor metabolizers (PMs) was 5.24% (95% CI: 2.35% approximately 8.13%) in this Chinese population. Residual analysis of the data also supported bimodality (P<0.01). The CYP1A2 activity of men was higher than that of women (median: 0.33 vs 0.23, P<0.001). A probit plot of CYP1A2 activity in men was shifted to the left compared with that in women. Based on phenotype, the gender-related difference was observed in extensive metabolizers (EMs) (P<0.001), but not in PMs (P >0.1). In addition, there was no sex-related difference in the incidence of PMs (P >0.1)., Conclusions: There is a phenotypic polymorphism in CYP1A2 activity in this Chinese population, and CYP1A2 activity is higher in men than that in women.