N-Glucuronidation of Nicotine and Cotinine in Human: Formation of Cotinine Glucuronide in Liver Microsomes and Lack of Catalysis by 10 Examined UDP-Glucuronosyltransferases

doi:10.1124/dmd.30.9.991

QUICK SEARCH:

[advanced]

	Author:		Keyword(s):
Year:		Vol:		Page:

This Article

	Full Text
	Full Text (PDF)
	Submit a response
	Alert me when this article is cited
	Alert me when eLetters are posted
	Alert me if a correction is posted

Services

	Similar articles in this journal
	Similar articles in PubMed
	Alert me to new issues of the journal
	Download to citation manager

Citing Articles

	Citing Articles via HighWire
	Citing Articles via Google Scholar

Google Scholar

	Articles by Ghosheh, O.
	Articles by Hawes, E. M.
	Search for Related Content

PubMed

	PubMed Citation
	Articles by Ghosheh, O.
	Articles by Hawes, E. M.

Vol. 30, Issue 9, 991-996, September 2002

N-Glucuronidation of Nicotine and Cotinine in Human: Formation of Cotinine Glucuronide in Liver Microsomes and Lack of Catalysis by 10 Examined UDP-Glucuronosyltransferases

Omar Ghosheh and Edward M. Hawes

Drug Metabolism and Drug Disposition Group, University of Saskatchewan, Saskatoon, Saskatchewan, Canada

Two predominant human glucuronide metabolites of nicotine result from pyridine nitrogen atom conjugation. The present objectivesincluded determination of the kinetics of formation of S( $-$ )-cotinineN1-glucuronide in pooled human liver microsomes and investigationof the UDP-glucuronosyltransferases (UGTs) involved in N-glucuronidationof 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-performanceliquid chromatography with use of radiolabeled substrates. S( $-$ )-CotinineN1-glucuronide formation in human liver microsomes was provenby comparing the chromatographic behaviors and electrospray ionization-massspectral characteristics of the metabolite with a synthetic referencestandard. This glucuronide was formed by one-enzyme kinetics withK_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( $-$ )-nicotineN1-glucuronide (0.13 versus 1.2 µl/min/mg) using the same pooledmicrosomes. This comparison of values is consistent with the observationthat on smoking cigarettes, although the average S( $-$ )-cotinineplasma levels usually far exceed S( $-$ )-nicotine levels, the urinaryrecovery of S( $-$ )-cotinine N1-glucuronide only averages 3-foldgreater than for S( $-$ )-nicotine N1-glucuronide. None of the UGTsexamined catalyzed the N-glucuronidation of S( $-$ )-nicotine, R(+)-nicotine,and S( $-$ )-cotinine, including UGT1A3 and UGT1A4, the only isoformsknown to catalyze many substrates at a tertiary amine. Also, neitherS( $-$ )-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 andnicotine.

This article has been cited by other articles:

G. Chen, A. S. Blevins-Primeau, R. W. Dellinger, J. E. Muscat, and P. Lazarus
Glucuronidation of Nicotine and Cotinine by UGT2B10: Loss of Function by the UGT2B10 Codon 67 (Asp>Tyr) Polymorphism
Cancer Res., October 1, 2007; 67(19): 9024 - 9029.
[Abstract] [Full Text] [PDF]

S. Kaivosaari, P. Toivonen, L. M. Hesse, M. Koskinen, M. H. Court, and M. Finel
Nicotine Glucuronidation and the Human UDP-Glucuronosyltransferase UGT2B10
Mol. Pharmacol., September 1, 2007; 72(3): 761 - 768.
[Abstract] [Full Text] [PDF]

J. Hukkanen, P. Jacob III, and N. L. Benowitz
Metabolism and Disposition Kinetics of Nicotine
Pharmacol. Rev., March 1, 2005; 57(1): 79 - 115.
[Abstract] [Full Text] [PDF]

H. Yamanaka, M. Nakajima, M. Katoh, A. Kanoh, O. Tamura, H. Ishibashi, and T. Yokoi
TRANS-3'-HYDROXYCOTININE O- AND N-GLUCURONIDATIONS IN HUMAN LIVER MICROSOMES
Drug Metab. Dispos., January 1, 2005; 33(1): 23 - 30.
[Abstract] [Full Text] [PDF]

D. Zhang, W. Zhao, V. A. Roongta, J. G. Mitroka, L. J. Klunk, and M. Zhu
AMIDE N-GLUCURONIDATION OF MAXIPOST CATALYZED BY UDP-GLUCURONOSYLTRANSFERASE 2B7 IN HUMANS
Drug Metab. Dispos., May 1, 2004; 32(5): 545 - 551.
[Abstract] [Full Text] [PDF]

A. Ghosal, N. Hapangama, Y. Yuan, J. Achanfuo-Yeboah, R. Iannucci, S. Chowdhury, K. Alton, J. E. Patrick, and S. Zbaida
IDENTIFICATION OF HUMAN UDP-GLUCURONOSYLTRANSFERASE ENZYME(S) RESPONSIBLE FOR THE GLUCURONIDATION OF POSACONAZOLE (NOXAFIL)
Drug Metab. Dispos., February 1, 2004; 32(2): 267 - 271.
[Abstract] [Full Text] [PDF]

G. E. Kuehl and S. E. Murphy
N-GLUCURONIDATION OF NICOTINE AND COTININE BY HUMAN LIVER MICROSOMES AND HETEROLOGOUSLY EXPRESSED UDP-GLUCURONOSYLTRANSFERASES
Drug Metab. Dispos., November 1, 2003; 31(11): 1361 - 1368.
[Abstract] [Full Text] [PDF]

O. Ghosheh and E. M. Hawes
Microsomal N-Glucuronidation of Nicotine and Cotinine: Human Hepatic Interindividual, Human Intertissue, and Interspecies Hepatic Variation
Drug Metab. Dispos., December 1, 2002; 30(12): 1478 - 1483.
[Abstract] [Full Text] [PDF]

S. C. Vashishtha, E. M. Hawes, D. J. McCann, O. Ghosheh, and L. Hogg
Quaternary Ammonium-Linked Glucuronidation of 1-Substituted Imidazoles by Liver Microsomes: Interspecies Differences and Structure-Metabolism Relationships
Drug Metab. Dispos., October 1, 2002; 30(10): 1070 - 1076.
[Abstract] [Full Text] [PDF]

				S. Kaivosaari, P. Toivonen, L. M. Hesse, M. Koskinen, M. H. Court, and M. Finel Nicotine Glucuronidation and the Human UDP-Glucuronosyltransferase UGT2B10 Mol. Pharmacol., September 1, 2007; 72(3): 761 - 768. [Abstract] [Full Text] [PDF]

				J. Hukkanen, P. Jacob III, and N. L. Benowitz Metabolism and Disposition Kinetics of Nicotine Pharmacol. Rev., March 1, 2005; 57(1): 79 - 115. [Abstract] [Full Text] [PDF]

				H. Yamanaka, M. Nakajima, M. Katoh, A. Kanoh, O. Tamura, H. Ishibashi, and T. Yokoi TRANS-3'-HYDROXYCOTININE O- AND N-GLUCURONIDATIONS IN HUMAN LIVER MICROSOMES Drug Metab. Dispos., January 1, 2005; 33(1): 23 - 30. [Abstract] [Full Text] [PDF]

				D. Zhang, W. Zhao, V. A. Roongta, J. G. Mitroka, L. J. Klunk, and M. Zhu AMIDE N-GLUCURONIDATION OF MAXIPOST CATALYZED BY UDP-GLUCURONOSYLTRANSFERASE 2B7 IN HUMANS Drug Metab. Dispos., May 1, 2004; 32(5): 545 - 551. [Abstract] [Full Text] [PDF]

				A. Ghosal, N. Hapangama, Y. Yuan, J. Achanfuo-Yeboah, R. Iannucci, S. Chowdhury, K. Alton, J. E. Patrick, and S. Zbaida IDENTIFICATION OF HUMAN UDP-GLUCURONOSYLTRANSFERASE ENZYME(S) RESPONSIBLE FOR THE GLUCURONIDATION OF POSACONAZOLE (NOXAFIL) Drug Metab. Dispos., February 1, 2004; 32(2): 267 - 271. [Abstract] [Full Text] [PDF]

				G. E. Kuehl and S. E. Murphy N-GLUCURONIDATION OF NICOTINE AND COTININE BY HUMAN LIVER MICROSOMES AND HETEROLOGOUSLY EXPRESSED UDP-GLUCURONOSYLTRANSFERASES Drug Metab. Dispos., November 1, 2003; 31(11): 1361 - 1368. [Abstract] [Full Text] [PDF]

				O. Ghosheh and E. M. Hawes Microsomal N-Glucuronidation of Nicotine and Cotinine: Human Hepatic Interindividual, Human Intertissue, and Interspecies Hepatic Variation Drug Metab. Dispos., December 1, 2002; 30(12): 1478 - 1483. [Abstract] [Full Text] [PDF]

				S. C. Vashishtha, E. M. Hawes, D. J. McCann, O. Ghosheh, and L. Hogg Quaternary Ammonium-Linked Glucuronidation of 1-Substituted Imidazoles by Liver Microsomes: Interspecies Differences and Structure-Metabolism Relationships Drug Metab. Dispos., October 1, 2002; 30(10): 1070 - 1076. [Abstract] [Full Text] [PDF]