QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: dmd.107.017145v1 35/11/2006    most recent 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 Sun, D. Articles by Lazarus, P. Search for Related Content PubMed PubMed Citation Articles by Sun, D. Articles by Lazarus, P.

Glucuronidation of Active Tamoxifen Metabolites by the Human UDP Glucuronosyltransferases

Cancer Prevention and Control (D.S., R.W.D., A.S.B.-P., R.M.B., G.C., P.L.) and Chemical Carcinogenesis and Chemoprevention (A.K.S., T.B., S.A.) Programs, Penn State Cancer Institute, and Departments of Pharmacology (D.S., A.K.S., R.D., A.S.B.-P., R.M.B., S.A., P.L.), Biochemistry and Molecular Biology (T.B.), and Public Health Sciences (G.C., P.L.), Penn State University College of Medicine, Hershey, Pennsylvania

Tamoxifen (TAM) is an antiestrogen that has been widely used in the treatment and prevention of breast cancer in women. One of the major mechanisms of metabolism and elimination of TAM and its major active metabolites 4-hydroxytamoxifen (4-OH-TAM) and 4-OH-N-desmethyl-TAM (endoxifen; 4-hydroxy-N-desmethyl-tamoxifen) is via glucuronidation. Although limited studies have been performed characterizing the glucuronidation of 4-OH-TAM, no studies have been performed on endoxifen. In the present study, characterization of the glucuronidating activities of human UDP glucuronosyltransferases (UGTs) against isomers of 4-OH-TAM and endoxifen was performed. Using homogenates of individual UGT-overexpressing cell lines, UGTs 2B7 1A8 > UGT1A10 exhibited the highest overall O-glucuronidating activity against trans-4-OH-TAM as determined by V_max/K_M, with the hepatic enzyme UGT2B7 exhibiting the highest binding affinity and lowest K_M (3.7 µM). As determined by V_max/K_M, UGT1A10 exhibited the highest overall O-glucuronidating activity against cis-4-OH-TAM, 10-fold higher than the next-most active UGTs 1A1 and 2B7, but with UGT1A7 exhibiting the lowest K_M. Although both N- and O-glucuronidation occurred for 4-OH-TAM in human liver microsomes, only O-glucuronidating activity was observed for endoxifen; no endoxifen-N-glucuronidation was observed for any UGT tested. UGTs 1A10 1A8 > UGT2B7 exhibited the highest overall glucuronidating activities as determined by V_max/K_M for trans-endoxifen, with the extrahepatic enzyme UGT1A10 exhibiting the highest binding affinity and lowest K_M (39.9 µM). Similar to that observed for cis-4-OH-TAM, UGT1A10 also exhibited the highest activity for cis-endoxifen. These data suggest that several UGTs, including UGTs 1A10, 2B7, and 1A8 play an important role in the metabolism of 4-OH-TAM and endoxifen.

This article has been cited by other articles:

				V. O. Dezentje, H.-J. Guchelaar, J. W.R. Nortier, C. J.H. van de Velde, and H. Gelderblom Clinical Implications of CYP2D6 Genotyping in Tamoxifen Treatment for Breast Cancer Clin. Cancer Res., January 1, 2009; 15(1): 15 - 21. [Abstract] [Full Text] [PDF]

				P. J. Murphy The Development of Drug Metabolism Research as Expressed in the Publications of ASPET: Part 3, 1984-2008 Drug Metab. Dispos., October 1, 2008; 36(10): 1977 - 1982. [Abstract] [Full Text] [PDF]