Functional significance of UDP-Glucuronosyltransferase variants in the metabolism of active tamoxifen metabolites

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 metab-olites in vitro. For variants of active extrahepatic UGTs, the UGTlA817aAla/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 uGTlA8mGly/277Cys or UGTlAlO139Lys 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 UGT2B7268H1". In studies of 111 human liver microsomal specimens, the rate of O-glucuronidation against trans-4-OH-TAM and ¿rons-endoxifen was 28% (P < 0.001) and 27% (P = 0.002) lower, respectively, in individuals homozygous for the UGT2B7 TyT268TyT genotype compared with subjects with the UGT2B7 His26SHis genotype, with a significant (P < 0.01) trend of decreasing activity against both substrates with increasing numbers of the UGTZBT268"1" 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.