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Vol. 30, Issue 12, 1484-1490, December 2002

Characterization of Nicotine and Cotinine N-Glucuronidations in Human Liver Microsomes

Miki Nakajima, Eriko Tanaka, Jun-Tack Kwon, and Tsuyoshi Yokoi

Division of Drug Metabolism, Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa, Japan

The nicotine and cotinine N-glucuronidations in human liver microsomes were characterized. The Eadie-Hofstee plots of nicotine N-glucuronidation in human liver microsomes were clearly biphasic, indicating the involvement of multiple enzymes. The apparent Km and Vmax values were 33.1 ± 28.1 µM and 60.0 ± 21.0 pmol/min/mg and 284.7 ± 122.0 µM and 124.0 ± 44.0 pmol/min/mg for the high- and low-affinity components, respectively, in human liver microsomes (n = 4). However, the Eadie-Hofstee plots of cotinine N-glucuronidation in human liver microsomes were monophasic (apparent Km = 1.9 ± 0.3 mM, Vmax = 655.6 ± 312.3 pmol/min/mg). The nicotine and cotinine N-glucuronidations in the recombinant human UDP-glucuronosyltransferases (UGTs) (UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A7, UGT1A8, UGT1A9, UGT1A10, UGT2B7, and UGT2B15) expressed in baculovirus-infected insect cells or human B-lymphoblastoid cells that are commercially available were determined. However, no recombinant UGT isoforms showed detectable nicotine and cotinine N-glucuronides (the concentrations of nicotine and cotinine were 0.5 and 2 mM, respectively). Nicotine and cotinine N-glucuronidations in pooled human liver microsomes were competitively inhibited by bilirubin as a substrate for UGT1A1 (Ki = 3.9 and 3.3 µM), imipramine as a substrate for UGT1A4 (Ki = 6.1 and 2.7 µM), and propofol as a substrate for UGT1A9 (Ki = 6.0 and 12.0 µM). The nicotine N-glucuronidation (50 µM nicotine) in 14 human liver microsomes was significantly (r = 0.950, P < 0.0001) correlated with the cotinine N-glucuronidation (0.2 mM cotinine), indicating that the same isoform(s) is involved in both glucuronidations. Furthermore, weak correlations between imipramine N-glucuronidation and nicotine N-glucuronidation (r = 0.425) or cotinine N-glucuronidation (r = 0.517) were observed. In conclusion, the involvement of UGT1A1 and UGT1A9 as well as UGT1A4 in nicotine and cotinine N-glucuronidations in human liver microsomes was suggested, although the contributions of each UGT isoform could not be determined conclusively.

Copyright © 2002 by The American Society for Pharmacology and Experimental Therapeutics


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