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  • Title: N-glucuronidation of nicotine and cotinine in human: formation of cotinine glucuronide in liver microsomes and lack of catalysis by 10 examined UDP-glucuronosyltransferases.
    Author: Ghosheh O, Hawes EM.
    Journal: Drug Metab Dispos; 2002 Sep; 30(9):991-6. PubMed ID: 12167564.
    Abstract:
    Two predominant human glucuronide metabolites of nicotine result from pyridine nitrogen atom conjugation. The present objectives included determination of the kinetics of formation of S(-)-cotinine N1-glucuronide in pooled human liver microsomes and investigation of the UDP-glucuronosyltransferases (UGTs) involved in N-glucuronidation of nicotine isomers and S(-)-cotinine by use of recombinant enzymes (UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A7, UGT1A8, UGT1A9, UGT1A10, UGT2B7, and UGT2B15). Quantification was by radiochemical high-performance liquid chromatography with use of radiolabeled substrates. S(-)-Cotinine N1-glucuronide formation in human liver microsomes was proven by comparing the chromatographic behaviors and electrospray ionization-mass spectral characteristics of the metabolite with a synthetic reference standard. This glucuronide was formed by one-enzyme kinetics with K(m) and V(max) values of 5.4 mM and 696 pmol/min/mg, respectively, and the apparent intrinsic clearance value (V(max/Km)) was 9-fold less than that previously determined for S(-)-nicotine N1-glucuronide (0.13 versus 1.2 microl/min/mg) using the same pooled microsomes. This comparison of values is consistent with the observation that on smoking cigarettes, although the average S(-)-cotinine plasma levels usually far exceed S(-)-nicotine levels, the urinary recovery of S(-)-cotinine N1-glucuronide only averages 3-fold greater than for S(-)-nicotine N1-glucuronide. None of the UGTs examined catalyzed the N-glucuronidation of S(-)-nicotine, R(+)-nicotine, and S(-)-cotinine, including UGT1A3 and UGT1A4, the only isoforms known to catalyze many substrates at a tertiary amine. Also, neither S(-)-nicotine or S(-)-cotinine affected enzyme inhibition of trifluoperazine, a UGT1A4 substrate. It would appear that the same, as yet unexamined, UGT catalyzes the N-glucuronidation of both cotinine and nicotine.
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