Pharmacogenetic Factors Contributing to Variation in Response to Tamoxifen at Raloxifene
Abstract
The purpose of these studies was 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. We determined that SULT1A1 and UGT1A6 contributed to the inactivation of 4-hydroxytamoxifen (OHT), the active metabolite of TAM, and that a separate enzyme, UGT1A9 catalyzed the glucuronidation of RAL. We established MCF-7 breast cancer cell lines stably expressing the wildtype 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 antiestrogens.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2004
- Accession Number
- ADA428541
Entities
People
- Rebecca B. Raftogianis
Organizations
- Fox Chase Cancer Center