Function of activation and deactivation enzymes for carcinogens-s and risk for cancer

我们以前曾报道过细胞色素P450 2A 6（CYP 2AG）^*4纯合子受试者患肺癌的风险较低。对1094例日本男性吸烟者和611例对照者进行了流行病学研究。发现CYP 2A 6基因型为^*4/^*7、^*4/^*10、^*7/^*7、^*7/^* 9和^*4/^*4的个体每日吸烟量显著低于携带^*1/^*1基因型的个体（P<0.01）。即使在调整了吸烟量后，携带CYP 2A 6的受试者中肺癌的校正比值比（OR）也显著较低：^*1/^*4、^*1/^*7、^* 1/^*9、^*1/^*10、^*4/^*4、^*4/^*7、^*4/^* 9、^*4/^*10、^*4/^*7、^*4/^*9、具有^*7/^*7和^*7/^*9基因型者与具有^*1/^*1基因型者相比差异有统计学意义（P <0.05）。当参与者根据CYP 2A 6基因型分为四组时，第1组（^*1/^*1），第2组（*I和变异等位基因的杂合子），第3组（除了^*4/^*4之外的变异等位基因的杂合子和纯合子） ...更多信息 第4组（^*4/^*4），发现CYP 2A 6等位基因变异的受试者患肺癌的风险较低（第2组，OR为0.59 [95%置信区间（CI），0.44-0.79] ;第3组，OR为0.52（95% CI，0.37-0.72）;第4组，OR为0.30（95% CI，0.16-0.57）}。重度吸烟者比轻度吸烟者患肺癌的风险降低得更明显。额外分层分析显示，第4组中鳞状细胞癌（OR为0.07）和小细胞癌（OR为0.10）的OR低于腺癌（OR为0.39）。这些结果表明，CYP 2A 6是一个主要的决定因素，不仅影响吸烟行为，而且对烟草相关肺癌的易感性。我们还研究了甲基胆蒽对大鼠CYP 1A 2基因的转录激活机制，阐明了（1）一个增强子元件（2）从小鼠肾脏中纯化了3种XRE II结合蛋白，并鉴定为LBP-1a，LBP-1b和LBP-1c通过肽图谱和微测序证实：（3）LBP-1家族成员直接与Ah受体和Arnt相互作用;（4）AhR-Arnt异二聚体和LBP-1b协同激活启动子区带有XRE II的报告基因的转录。少

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) … More 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