Interdisciplinary Training

Wendy Kuehl

"Effects of UGT1A6 and CYP2C9 Polymorphisms in the Metabolism of Aspirin"

Genetic polymorphisms are prevalent among enzymes that catalyze the metabolism of many pharmaceutical drugs.  Aspirin is a common nonsteriodal anti-inflammatory drug (NSAID) used in the treatment of arthritis and as a secondary prevention of cardiovascular disease.  An inverse relationship between the regular use of aspirin and the incidence of colorectal cancer has been observed.  Among aspirin users, the risk of colorectal cancer incidence is modified by polymorphisms in certain drug-metabolizing enzymes. 

Aspirin, acetylsalicylic acid, is rapidly deacetylated to form salicylic acid.  Four metabolites of salicylic acid have been detected in urine: salicyluric acid, salicylic acid phenolic glucuronide, salicylic acid acyl glucuronide and gentisic acid.  UDP-glucuronosyltransferase (UGT) enzymes catalyze the formation of salicylic acid glucuronides.  Cytochrome P450 (CYP) enzymes catalyze the oxidation of a variety of pharmaceutical drugs to form hydroxylated metabolites such as gentisic acid.  Polymorphisms in UGT1A6 and CYP2C9 alleles have been associated with altered risks of colorectal cancer among aspirin users suggesting that these enzymes are involved in aspirin metabolism.  We will explore this hypothesis in two ways.  First, we will investigate the ability of wild type and variant UGT1A6 and CYP2C9 to catalyze the in vitro glucuronidation and oxidation, respectively, of salicylic acid using heterologously expressed enzymes.  Then we will investigate the effect of UGT1A6 and CYP2C9 genotypes on the metabolism of aspirin in humans.  These results will help us to further evaluate these enzymes as critical players in the metabolism of aspirin and identify individuals who may have an increased benefit from aspirin use.