Ghosheh Omar, Hawes Edward M
Drug Metabolism and Drug Disposition Group, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
Drug Metab Dispos. 2002 Dec;30(12):1478-83. doi: 10.1124/dmd.30.12.1478.
Two of the abundant conjugates of human nicotine metabolism result from the N-glucuronidation of S-(-)-nicotine and S-(-)-cotinine, transformations we recently demonstrated in liver microsomes. We further studied these microsomal N-glucuronidation reactions with respect to human hepatic interindividual, human intertissue, and interspecies hepatic variation. The reactivities of microsomes from human liver (n = 12), various human tissues, and liver from eight species toward the N-glucuronidation of S-(-)-nicotine and S-(-)-cotinine, and also R-(+)-nicotine in human liver were examined. Assays with (14)C-labeled substrates involved radiometric high-performance liquid chromatography. For the human liver samples examined there were 13- to 17-fold variations in the catalytic activities observed toward S-(-)-nicotine, R-(+)-nicotine, and S-(-)-cotinine. Gender and smoking effects were studied, and after exclusion of an outlier a decrease in catalytic activity in females was observed. Significant correlations were observed between all three analytes, indicating that the same UDP-glucuronosyltransferase(s) enzyme is likely to be involved in these transformations. Catalytic activities were not observed for human gastrointestinal tract (colon, duodenum, ileum, jejunum, and stomach), kidney, or lung microsomes. For the seven animal species examined, activity was measurable only for monkey, guinea pig, and minipig, and only for S-(-)-nicotine N-glucuronidation and at rates 10- to 40-fold lower than humans. Activity was not measurable in the case of dog, mouse, rabbit, or rat, for the latter under five different treatment conditions for one of the strains. In conclusion, there are large hepatic interindividual variations in N-glucuronidation of S-(-)-nicotine and S-(-)-cotinine, in human extrahepatic metabolism seems limited, and none of the animal strains examined resembled human.
人类尼古丁代谢中两种丰富的共轭物是由S-(-)-尼古丁和S-(-)-可替宁的N-葡萄糖醛酸化产生的，我们最近在肝微粒体中证实了这些转化过程。我们进一步研究了这些微粒体N-葡萄糖醛酸化反应在人类肝脏个体间、人体组织间以及种间肝脏差异方面的情况。检测了来自人类肝脏（n = 12）、各种人体组织以及八个物种肝脏的微粒体对S-(-)-尼古丁、S-(-)-可替宁以及人类肝脏中R-(+)-尼古丁的N-葡萄糖醛酸化反应活性。使用(14)C标记底物的检测涉及放射性高效液相色谱法。在所检测的人类肝脏样本中，观察到对S-(-)-尼古丁、R-(+)-尼古丁和S-(-)-可替宁的催化活性存在13至17倍的差异。研究了性别和吸烟的影响，排除一个异常值后，观察到女性的催化活性降低。在所有三种分析物之间观察到显著相关性，表明相同的UDP-葡萄糖醛酸基转移酶可能参与了这些转化过程。在人类胃肠道（结肠、十二指肠、回肠、空肠和胃）、肾脏或肺微粒体中未观察到催化活性。在所检测的七种动物物种中，仅在猴子、豚鼠和小型猪中检测到活性，且仅针对S-(-)-尼古丁的N-葡萄糖醛酸化反应，其速率比人类低10至40倍。在狗、小鼠、兔子或大鼠中未检测到活性，对于其中一个品系的大鼠，在五种不同处理条件下均未检测到活性。总之，S-(-)-尼古丁和S-(-)-可替宁的N-葡萄糖醛酸化在肝脏个体间存在很大差异，人体肝外代谢似乎有限，且所检测的动物品系均与人类不同。
