Interindividual variability in nicotine metabolism: C-oxidation and glucuronidation.
Interindividual variability in nicotine metabolism: C-oxidation and glucuronidation.
复制标题
DOI：
10.2133/dmpk.20.227
复制
发表时间：
2005-08-01
影响因子：
2.1
通讯作者：
Yokoi, Tsuyoshi
中科院分区：
文献类型：
--
作者：
Nakajima, Miki;Yokoi, Tsuyoshi
尼古丁在吸烟成瘾、戒烟的替代疗法、作为治疗帕金森氏症、阿尔茨海默病和溃疡性结肠炎等多种疾病的潜在药物方面发挥作用。被吸收的尼古丁迅速和广泛地代谢并排出到尿液中。尼古丁代谢的一个主要途径是C-氧化为可替宁，该途径在人体肝脏中由CYP2A6催化。可替宁随后被CYP2A6代谢为反式-3‘-羟基可替宁。尼古丁和可替宁主要通过UGT1A4和部分UGT1A9被葡萄糖醛酸化为N-葡萄糖醛酸苷。反式-3‘-羟基可替宁主要由UGT2B7和部分UGT1A9糖醛酸化成O-葡萄糖醛酸苷。大约90%的总尼古丁摄取量作为这些代谢物和尼古丁本身被消除。尼古丁代谢是尼古丁清除的重要决定因素。最近，对尼古丁代谢的个体间变异性的理解取得了进展。有大量数据表明，可替宁形成的巨大个体间差异与CYP2A6基因的遗传多态有关。在可替宁的形成和CYP2A6等位基因频率上也观察到种族间的差异。由于CYP2A6基因的遗传多态对尼古丁清除有重要影响，已有研究表明其与吸烟行为或肺癌风险有关。人体内尼古丁、可替宁和反式-3‘-羟基可替宁的糖醛酸化代谢途径可能是造成尼古丁代谢个体差异的原因之一。本综述主要总结了我们最近的研究成果。
Nicotine has roles in the addiction to smoking, replacement therapy for smoking cessation, as a potential medication for several diseases such as Parkinson's disease, Alzheimer's disease, and ulcerative colitis. The absorbed nicotine is rapidly and extensively metabolized and eliminated to urine. A major pathway of nicotine metabolism is C-oxidation to cotinine, which is catalyzed by CYP2A6 in human livers. Cotinine is subsequently metabolized to trans-3'-hydroxycotinine by CYP2A6. Nicotine and cotinine are glucuronidated to N-glucuronides mainly by UGT1A4 and partly by UGT1A9. Trans-3'-hydroxycotinine is glucuronidated to O-glucuronide mainly by UGT2B7 and partly by UGT1A9. Approximately 90% of the total nicotine uptake is eliminated as these metabolites and nicotine itself. The nicotine metabolism is an important determinant of the clearance of nicotine. Recently, advances in the understanding of the interindividual variability in nicotine metabolism have been made. There are substantial data suggesting that the large interindividual differences in cotinine formation are associated with genetic polymorphisms of the CYP2A6 gene. Interethnic differences have also been observed in the cotinine formation and the allele frequencies of the CYP2A6 alleles. Since the genetic polymorphisms of the CYP2A6 gene have a major impact on nicotine clearance, its relationships with smoking behavior or the risk of lung cancer have been suggested. The metabolic pathways of the glucuronidation of nicotine, cotinine, and trans-3'-hydroxycotinine in humans would be one of the causal factors for the interindividual differences in nicotine metabolism. This review mainly summarizes recent results from our studies.