This Article Full Text Full Text (PDF) All Versions of this Article: 0008-5472.CAN-08-3708v1 69/5/1892    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend 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 Blevins-Primeau, A. S. Articles by Lazarus, P. Search for Related Content PubMed PubMed Citation Articles by Blevins-Primeau, A. S. Articles by Lazarus, P.

Functional Significance of UDP-Glucuronosyltransferase Variants in the Metabolism of Active Tamoxifen Metabolites

¹ Cancer Control and Population Sciences and ² Chemical Carcinogenesis and Chemoprevention Programs, Penn State Cancer Institute; Departments of ³ Pharmacology and ⁴ Public Health Sciences, Penn State University College of Medicine, Hershey, Pennsylvania

Requests for reprints: Philip Lazarus, Penn State University College of Medicine, Room C3739D, MC-H069, 500 University Drive, Hershey, PA 17033. Phone: 717-531-5743; Fax: 717-531-0480; E-mail: plazarus{at}psu.edu.

Key Words: Tamoxifen • UGTs

Tamoxifen (TAM) is a selective estrogen receptor modulator widely used in the prevention and treatment of breast cancer. A major mode of metabolism of the major active metabolites of TAM, 4-OH-TAM and endoxifen, is by glucuronidation via the UDP-glucuronosyltransferase (UGT) family of enzymes. To examine whether polymorphisms in the UGT enzymes responsible for the glucuronidation of active TAM metabolites play an important role in interindividual differences in TAM metabolism, cell lines overexpressing wild-type or variant UGTs were examined for their activities against TAM metabolites in vitro. For variants of active extrahepatic UGTs, the UGT1A8^{173Ala/277Tyr} variant exhibited no detectable glucuronidation activity against the trans isomers of either 4-OH-TAM or endoxifen. Little or no difference in TAM glucuronidating activity was observed for the UGT1A8^{173Gly/277Cys} or UGT1A10^139Lys variants compared with their wild-type counterparts. For active hepatic UGTs, the UGT2B7^268Tyr variant exhibited significant (P < 0.01) 2- and 5-fold decreases in activity against the trans isomers of 4-OH-TAM and endoxifen, respectively, compared with wild-type UGT2B7^268His. In studies of 111 human liver microsomal specimens, the rate of O-glucuronidation against trans-4-OH-TAM and trans-endoxifen was 28% (P < 0.001) and 27% (P = 0.002) lower, respectively, in individuals homozygous for the UGT2B7 Tyr²⁶⁸Tyr genotype compared with subjects with the UGT2B7 His²⁶⁸His genotype, with a significant (P < 0.01) trend of decreasing activity against both substrates with increasing numbers of the UGT2B7^268His allele. These results suggest that functional polymorphisms in TAM-metabolizing UGTs, including UGT2B7 and potentially UGT1A8, may be important in interindividual variability in TAM metabolism and response to TAM therapy. [Cancer Res 2009;69(5):1892–900]

This article has been cited by other articles:

				K. Brown Is tamoxifen a genotoxic carcinogen in women? Mutagenesis, September 1, 2009; 24(5): 391 - 404. [Abstract] [Full Text] [PDF]

				R. M. Balliet, G. Chen, C. J. Gallagher, R. W. Dellinger, D. Sun, and P. Lazarus Characterization of UGTs Active against SAHA and Association between SAHA Glucuronidation Activity Phenotype with UGT Genotype Cancer Res., April 1, 2009; 69(7): 2981 - 2989. [Abstract] [Full Text] [PDF]