Pharmacogenetic Factors Contributing to Variation in Response to Tamoxifen and Raloxifene

摘要

The purpose of these studies is to elucidate the pharmacogenetic factors that contribute to variation in human response to tamoxifen (TAM) and raloxifene (RAL). We had previously identified and partially characterized common genetic polymorphisms in two human drug-metabolizing genes, SULT1A1 and UGT1A6. We hypothesized that these polymorphisms contributed to variation in TAM or RAL metabolism. These studies were divided into three aims with the purpose of (1) biochemically characterizing the contribution of these enzymes to the metabolism of TAM and RAL; (2) developing cell model systems to study allele- specific differences in cellular response to these molecules and; (3) perform a clinical pharmacogenetic study to evaluate the association of common genetic polymorphisms in drug metabolizing genes with variable clinical response to TAM. Thus far we have determined that SULT1A1 and UGT1A6 contribute to the inactivation of 4-hydroxytamoxifen (OHT), the active metabolite of TAM, and that a separate enzyme, UGT1A9 catalyzed the glucuronidation of RAL. We have determined genotype/phenotype correlation for UGT1A6 alleles in a bank of human liver tissue and have generated HEK 293 cell lines that stably express each of the four UGT1A6 allozymes. The UGT1A6*2 allozyme, when expressed homozygously, is associated with high UGT1A6 activity. We established MCF-7 breast cancer cell lines stably expressing the wild type and variant SULT1A1 alleles and have measured allele-specific differences in the response of these cells to estrogens and OHT. These studies suggest that pharmacogenetic factors might contribute to variable cellular response to antiestrogenes.