We reported previously that subjects homozygous for the cytochrome P450 2A6 (CYP2A6) (*)4 have a lower risk of lung cancer. The purpose of this study was to clarify whether or not the alterations of smoking behavior and risk for lung cancer could be found in subjects possessing novel CYP2A6 variants discovered recently. An epidemiological study was performed with 1094 cases and 611 controls in male Japanese smokers. It was found that the amounts of daily cigarette consumption in subjects who harbored CYP2A6(*)4/(*)7, (*)4/(*)10, (*)7/(*)7, (*)7/(*)9 and (*)4/(*)4 genotypes were significantly less than those in subjects carrying the (*)1/(*)1 genotype (P < 0.01). Even after adjustment with cigarette consumption, the adjusted odds ratios (ORs) for lung cancer were significantly lower in subjects who harbored CYP2A6(*)1/(*)4, (*)1/(*)7, (*)1/(*)9, (*)1/(*)10, (*)4/(*)4, (*)4/(*)7, (*)4/(*)9, (*)7/(*)7 and (*)7/(*)9 genotypes than those who possessed the (*)1/(*)1 genotype (P < 0.05). When participants were classified into four groups according to the CYP2A6 genotypes, group 1 ((*)1/(*)1), group 2 (heterozygotes for the (*)1 and a variant allele), group 3 (heterozygotes and homozygotes for variant alleles except for (*)4/(*)4) and group 4 ((*)4/(*)4), lung cancer risk was found to be less in subjects with the variant of CYP2A6 alleles [group 2, OR of 0.59 [95% confidence interval (CI), 0.44-0.79]; group 3, OR of 0.52 (95% CI, 0.37-0.72); group 4, OR of 0.30 (95% CI, 0.16-0.57)]. The reduced risk for lung cancer was seen more clearly in heavy smokers than in light smokers. Additional stratification analysis showed that the ORs for squamous cell carcinoma (OR of 0.07) and small cell carcinoma (OR of 0.10) were lower than that of adenocarcinoma (OR of 0.39) in group 4. These results suggest that the CYP2A6 is one of the principal determinants affecting not only smoking behavior but also susceptibility to tobacco-related lung cancer.

CYP3A4, the most abundant form of cytochrome P450 in the human adult liver, shows wide interindividual variation in its activity. This variability is thought to be caused largely by transcriptional and genetic factors, yet the underlying mechanisms are poorly understood. The purpose of this study was to clarify the mechanisms controlling the CYP3A4 gene transcription and to search for genetic polymorphisms in the 5Ј-flanking region of the CYP3A4 gene. Transient transfection of human hepatoma HepG2 cells and of normal human hepatocytes with a series of CYP3A4 promoter-luciferase reporter plasmids revealed that a region from Ϫ11.4 to Ϫ10.5 kilobases, designated the constitutive liver enhancer module of CYP3A4 (CLEM4), was important for the constitutive activation of the CYP3A4 gene. Gel shift assay using nuclear extracts prepared from HepG2 cells showed that HNF-1␣, HNF-4␣, USF1, and AP-1 interacted with CLEM4. Furthermore, the introduction of mutations into their binding sites demonstrated that essentially all sites were required for the maximal enhancer activity. Screening for genetic polymorphisms within CLEM4 in genomic DNA from French persons, we identified the novel variant, TGT insertion between Ϫ11,129 and Ϫ11,128 (Ϫ11,129_Ϫ11,128insTGT), whose allele frequency was 3.1%. The Ϫ11,129_Ϫ11,128insTGT resulted in the disruption of USF1 binding and a 36% reduction of the enhancer activity. These results suggest that CLEM4 is a constitutive enhancer of the CYP3A4 gene in the liver and that Ϫ11,129_Ϫ11,128insTGT may at least partly contribute to the interindividual variability of CYP3A4 expression.Cytochromes P450 play important roles in the metabolism of various xenobiotics and endogenous compounds (Wrighton and Stevens, 1992). The most abundant form of P450 in the human liver is CYP3A, which accounts for ϳ30% of the total P450s (Shimada et al., 1994). The human CYP3A subfamily consists of four members, CYP3A4, CYP3A5, CYP3A7, and CYP3A43, which are aligned in tandem on 7q22.1 (Gellner et al., 2001). Although the nucleotide sequences of CYP3A cDNAs resemble one another, their expression patterns are quite different. CYP3A4 is predominantly expressed in human adult liver and intestine (Beaune et al., 1986;Watkins et al., 1987), whereas CYP3A7 is expressed in human fetal liver (Komori et al., 1990). CYP3A5 is polymorphically expressed in various tissues, especially the adult liver, kidney, and lung (Aoyama et al., 1989;Schuetz et al., 1992;Anttila et al., 1997). CYP3A43 is highly expressed in the adult prostate and is detectable at a low level in several other tissues (Gellner et al., 2001). These facts imply that the transcription of the human CYP3A genes is regulated through different mechanisms.CYP3A4 is responsible for the metabolism of more than 30% of clinically used drugs, such as the immunosuppressant cyclosporin, the calcium blocker nifedipine, and the antibiotic erythromycin (Li et al., 1995). Moreover, CYP3A4 catalyzes the 6␤-hydroxylation of testosterone and cortisol (Brian et al., 1990) and is...

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Our results suggest that putative poor metabolizers of xanthine oxidase activities exist in a Japanese population and that a decreased 1,7-dimethyluric acid formation from caffeine in poor metabolizers of CYP2A6 appears to affect the metabolic ratio used for the assessment of CYP1A2 activity.