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

• Published in: Cancer research (Chicago, Ill.) Vol. 69; no. 5; pp. 1892 - 1900
• Main Authors: Blevins-Primeau, Andrea S., Sun, Dongxiao, Chen, Gang, Sharma, Arun K., Gallagher, Carla J., Amin, Shantu, Lazarus, Philip
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.03.2009
• Subjects: Antineoplastic agents; Biological and medical sciences; Cell Line; Cytochrome P-450 CYP2D6 - genetics; Estrogen Antagonists - metabolism; Genotype; Glucuronosyltransferase - genetics; Glucuronosyltransferase - physiology; Humans; Medical sciences; Pharmacology. Drug treatments; Tamoxifen - analogs & derivatives; Tamoxifen - metabolism; Tumors; Antineoplastic agent; Genetic variability; UDP-glucuronosyltransferase; Enzyme; Metabolite; Transferases; Antiestrogen; Glycosyltransferases; Genotype; Antihormone; Metabolism; Tamoxifene; Variant; Selective estrogen receptor modulator; Hexosyltransferases; Pharmacokinetics; Non steroid compound
• ISSN: 0008-5472; 1538-7445; 1538-7445
• DOI: 10.1158/0008-5472.CAN-08-3708

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 UGT1A8173Ala/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 UGT1A8173Gly/277Cys or UGT1A10139Lys variants compared with their wild-type counterparts. For active hepatic UGTs, the UGT2B7268Tyr 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 UGT2B7268His. 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 UGT2B7268His 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]