Nicotine N-glucuronidation relative to N-oxidation and C-oxidation and UGT2B10 genotype in five ethnic/racial groups
Nicotine N-glucuronidation relative to N-oxidation and C-oxidation and UGT2B10 genotype in five ethnic/racial groups
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DOI：
10.1093/carcin/bgu191
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发表时间：
2014-11-01
期刊：
影响因子：
4.7
通讯作者：
Le Marchand, Loic
中科院分区：
文献类型：
--
作者：
Murphy, Sharon E.;Park, Sung-Shim L.;Le Marchand, Loic
尼古丁代谢影响吸烟行为，代谢差异可能导致肺癌风险的种族差异。我们在这里报告的尼古丁代谢的比例细胞色素P450 2A 6催化的C-氧化，UDP-葡萄糖醛酸转移酶2B 10（UGT 2B 10）催化的N-葡萄糖醛酸化和黄素单加氧酶3催化的N-氧化在5个种族/种族群体和UGT 2B 10基因型的作用，观察到的代谢模式。对非裔美国人（AA，n = 364）、夏威夷土著人（NH，n = 311）、白色人（n = 437）、拉丁裔（LA，n = 453）和日裔美国人（JA，n = 674）吸烟者尿液中的尼古丁及其代谢产物进行定量。计算总尼古丁当量、尼古丁和六种代谢物的总和以及尼古丁代谢表型。确定各组UGT 2B 10基因型与尼古丁代谢途径的关系;计算几何平均值，并根据年龄、性别、肌酐和体重指数进行校正。尼古丁代谢模式在各组中是独特的，JA和NH中的C-氧化最低（P < 0.0001），AA中的N-葡萄糖醛酸化最低（P < 0.0001）。白细胞与AA和LA之间的C-氧化没有差异。尼古丁和可替宁葡萄糖醛酸苷比率在AA中比白人低2倍和3倍。两种UGT变体，一种错义突变（Asp 67 Tyr，rs61750900）和一种剪接变体（rs 116294140）占葡萄糖醛酸化变异的33%。在AA中，剪接变体占尼古丁葡萄糖醛酸化减少的大部分。UGT 2B 10变异等位基因携带者的C-氧化水平升高（P = 0.0099）。我们的数据表明，尼古丁代谢途径的相对重要性因种族而异，在描述尼古丁代谢对吸烟行为和癌症风险的作用时，应考虑所有途径。
Nicotine metabolism influences smoking behavior and differences in metabolism probably contribute to ethnic variability in lung cancer risk. We report here on the proportion of nicotine metabolism by cytochrome P450 2A6-catalyzed C-oxidation, UDP-glucuronosyl transferase 2B10 (UGT2B10)-catalyzed N-glucuronidation and flavin monooxygenase 3-catalyzed N-oxidation in five ethnic/racial groups and the role of UGT2B10 genotype on the metabolic patterns observed. Nicotine and its metabolites were quantified in urine from African American (AA, n = 364), Native Hawaiian (NH, n = 311), White (n = 437), Latino (LA, n = 453) and Japanese American (JA, n = 674) smokers. Total nicotine equivalents, the sum of nicotine and six metabolites, and nicotine metabolism phenotypes were calculated. The relationship of UGT2B10 genotype to nicotine metabolic pathways was determined for each group; geometric means were computed and adjusted for age, sex, creatinine, and body mass index. Nicotine metabolism patterns were unique across the groups, C-oxidation was lowest in JA and NH (P < 0.0001), and N-glucuronidation lowest in AA (P < 0.0001). There was no difference in C-oxidation among Whites and AA and LA. Nicotine and cotinine glucuronide ratios were 2- and 3-fold lower in AA compared with Whites. Two UGT variants, a missense mutation (Asp67Tyr, rs61750900) and a splice variant (rs116294140) accounted for 33% of the variation in glucuronidation. In AA, the splice variant accounted for the majority of the reduced nicotine glucuronidation. UGT2B10 variant allele carriers had increased levels of C-oxidation (P = 0.0099). Our data indicate that the relative importance of nicotine metabolic pathways varies by ethnicity, and all pathways should be considered when characterizing the role of nicotine metabolism on smoking behavior and cancer risk.