Nicotine Metabolism in African Americans and European Americans: Variation in Glucuronidation by Ethnicity and UGT2B10 Haplotype
Nicotine Metabolism in African Americans and European Americans: Variation in Glucuronidation by Ethnicity and UGT2B10 Haplotype
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DOI：
10.1124/jpet.109.159855
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发表时间：
2010-01-01
影响因子：
3.5
通讯作者：
Murphy, Sharon E.
中科院分区：
文献类型：
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作者：
Berg, Jeannette Zinggeler;Mason, Jesse;Murphy, Sharon E.
尼古丁是烟草烟雾中的主要成瘾剂，通过氧化和葡萄糖醛酸苷结合广泛代谢。研究了种族和UGT 2B 10单倍型对尼古丁代谢变异的贡献。在两个吸烟人群中评价尼古丁代谢。在一个非裔美国人和欧洲裔美国人吸烟者人群（n = 93）中，分析了3天内血浆和24小时尿液中的尼古丁及其代谢产物，同时受试者戒烟并处于尼古丁贴片的稳态。在第二项吸烟者研究（n = 84）中，确定了与D 67 Y相关的UGT 2B 10单倍型与尼古丁和可替宁葡萄糖醛酸化水平的关系。我们观察到非裔美国人种族和UGT 2B 10 D 67 Y等位基因均与低葡萄糖醛酸化表型相关。与欧洲裔美国人相比，非裔美国人以葡萄糖醛酸结合物形式排泄的尼古丁和可替宁较少;尼古丁葡萄糖醛酸化百分比为18.1 vs 29.3（p < 0.002），可替宁葡萄糖醛酸化百分比为41.4 vs 61.7（p < 0.0001）。在携带UGT 2B 10 Tyr 67等位基因的吸烟者中，尼古丁和可替宁的葡萄糖醛酸结合比不携带该等位基因的吸烟者减少20%。这里报告了两个关键成果。首先，非裔美国人尼古丁和可替宁葡萄糖醛酸化较低的观察结果在尼古丁贴片戒烟人群中得到证实。其次，我们提供了第一个令人信服的证据，表明UGT 2B 10是这些体内葡萄糖醛酸化途径的关键催化剂。
Nicotine is the major addictive agent in tobacco smoke, and it is metabolized extensively by oxidation and glucuronide conjugation. The contributions of ethnicity and UGT2B10 haplotype on variation in nicotine metabolism were investigated. Nicotine metabolism was evaluated in two populations of smokers. In one population of African American and European American smokers (n = 93), nicotine and its metabolites were analyzed in plasma and 24-h urine over 3 days while participants were abstinent and at steady state on the nicotine patch. In a second study of smokers (n = 84), the relationship of a UGT2B10 haplotype linked with D67Y to nicotine and cotinine glucuronidation levels was determined. We observed that both African American ethnicity and the UGT2B10 D67Y allele were associated with a low glucuronidation phenotype. African Americans excreted less nicotine and cotinine as their glucuronide conjugates compared with European Americans; percentage of nicotine glucuronidation, 18.1 versus 29.3 (p < 0.002) and percentage of cotinine glucuronidation, 41.4 versus 61.7 (p < 0.0001). In smokers with a UGT2B10 Tyr67 allele, glucuronide conjugation of nicotine and cotinine was decreased by 20% compared with smokers without this allele. Two key outcomes are reported here. First, the observation that African Americans have lower nicotine and cotinine glucuronidation was confirmed in a population of abstinent smokers on the nicotine patch. Second, we provide the first convincing evidence that UGT2B10 is a key catalyst of these glucuronidation pathways in vivo.