UGT1A9 Genetic Polymorphisms and Raloxifene Pharmacogenetics
Final rept. 1 May 2001-30 Apr 2003
FOX CHASE CANCER CENTER PHILADELPHIA PA
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The goal of this DOD Breast Concept award was to identify and functionally characterize common genetic polymorphisms in the human UDP-glucuronosyltransferase gene, UGT1A9. We had previously determined that UGT1A9, a metabolic enzyme expressed predominantly in the human liver, catalyzes the glucuronidation and inactivation of the antiestrogen raloxifene RAL. The pharmacokinetics of RAL is known to be subject to significant interindividual variation, possibly associated with variable clinical efficacy. We hypothesized that genetic variation in the human UGTlA9 gene contributed to the known variation in RAL pharmacokinetics in humans. The aims of this proposal were to 1 identify genetic polymorphisms within the coding regions of the human UGTlA9 gene, 2 functionally characterize recombinant UGTlA9 allozymes with regard to capacity to glucuronidate RAL and 3 express variant UGT1A9 cDNAs in MCF-7 cells and assess antiestrogenic response of cells to RAL.
- Anatomy and Physiology
- Medicine and Medical Research