| Research Abstract |
We reported previously that subjects homozygous for the cytochrome P450 2A6 (CYP2AG) ^*4 have a lower risk of lung cancer. 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/^*9and ^*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 *I and a variant allele), group 3 (heterozygotes and homozygotes for variant alleles except for ^*4/^*4)
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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. We also investigated the transcriptional activation mechanism of the rat CYP1A2 gene by methylcholanthrene, and clarified that (1) an enhancer element (termed XRE II) responsible for induction was localized 2 kb upstream of the transcription-initiation site of the gene, (2) 3 XRE II-binding proteins were purified from mouse kidneys, and identified as LBP-1a, LBP-1b and LBP-1c by peptide mapping and microsequencing, (3) members of LBP-1 family directly interacted with the Ah receptor and Arnt and (4) AhR-Arnt heterodimer and LBP-1b synergistically activated transcription of a reporter with XRE II in the promoter region. Less
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