Yuan Jian-Min, Nelson Heather H, Carmella Steven G, Wang Renwei, Kuriger-Laber Jacquelyn, Jin Aizhen, Adams-Haduch Jennifer, Hecht Stephen S, Koh Woon-Puay, Murphy Sharon E
Division of Cancer Control and Population Sciences, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
Carcinogenesis. 2017 Apr 1;38(4):411-418. doi: 10.1093/carcin/bgx012.
Cytochrome P450 2A6 (CYP2A6) catalyzes the metabolism of nicotine and the tobacco-specific lung carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Genetic variation in CYP2A6 may affect smoking behavior and contribute to lung cancer risk. A nested case-control study of 197 lung cancer cases and 197 matched controls was conducted within a prospective cohort of 63 257 Chinese men and women in Singapore. Quantified were five genetic variants of CYP2A6 (*1A, *4, *7, *9 and *12) and urinary metabolites of nicotine [total nicotine, total cotinine, total trans-3'-hydroxycotinine (3HC)] and NNK (total NNAL, free NNAL, NNAL-glucuronide, NNAL-N-glucuronide, and NNAL-O-glucuronide). Higher urinary metabolites of nicotine and NNK were significantly associated with a 2- to 3-fold increased risk of lung cancer after adjustment for smoking intensity and duration. Lower CYP2A6-determined nicotine metabolizer status was significantly associated with a lower ratio of total 3HC over total cotinine, lower total nicotine equivalent and reduced risk of developing lung cancer (all Ptrend < 0.001). Compared with normal metabolizers, odds ratios (95% confidence intervals) of developing lung cancer for intermediate, slow and poor metabolizers determined by CYP2A6 genotypes were 0.85 (0.41-1.77), 0.55 (0.28-1.08) and 0.32 (0.15-0.70), respectively, after adjustment for smoking intensity and duration and urinary total nicotine equivalents. Thus the reduced risk of lung cancer in smokers with lower CYP2A6 activity may be explained by lower consumption of cigarettes, less intense smoking and reduced CYP2A6-catalyzed activation of the tobacco-specific lung carcinogen NNK.
细胞色素P450 2A6（CYP2A6）催化尼古丁以及烟草特有的肺癌致癌物4-（甲基亚硝胺基）-1-（3-吡啶基）-1-丁酮（NNK）的代谢。CYP2A6的基因变异可能会影响吸烟行为，并增加患肺癌的风险。在新加坡一项针对63257名中国男性和女性的前瞻性队列研究中，开展了一项巢式病例对照研究，研究对象包括197例肺癌病例和197例匹配的对照。对CYP2A6的五个基因变异（*1A、*4、*7、9和12）以及尼古丁的尿代谢物[总尼古丁、总可替宁、总反式-3'-羟基可替宁（3HC）]和NNK（总NNAL、游离NNAL、NNAL-葡萄糖醛酸苷、NNAL-N-葡萄糖醛酸苷和NNAL-O-葡萄糖醛酸苷）进行了定量分析。在调整吸烟强度和持续时间后，较高的尼古丁和NNK尿代谢物与患肺癌风险增加2至3倍显著相关。较低的CYP2A6确定的尼古丁代谢状态与总3HC与总可替宁的比例较低、总尼古丁当量较低以及患肺癌风险降低显著相关（所有Ptrend<0.001）。在调整吸烟强度、持续时间和尿总尼古丁当量后，与正常代谢者相比，由CYP2A6基因型确定的中间、缓慢和不良代谢者患肺癌的优势比（95%置信区间）分别为0.85（0.41-1.77）、0.55（0.28-1.08）和0.32（0.15-0.70）。因此，CYP2A6活性较低的吸烟者患肺癌风险降低，可能是由于香烟消费量较低、吸烟强度较小以及CYP2A6催化的烟草特异性肺癌致癌物NNK的活化减少所致。
