Section on Genetic Disorders of Drug Metabolism

Head: Ida S. Owens

This section studies the biochemical and molecular genetics of human UDP-glucuronosyltransferase family A (encoded by the UGT1 locus) as it relates to both health and disease states. Since uncovering and decribing the novel mutligenic UGT1 locus that encodes nine UDP-glucuronosyltransferases including the bilirubin metabolizing one, we have established the genetic and molecular basis of the lethal hyperbilirubinemia, Crigler-Najjar (CN) type I, and the less deleterious CN II disease, and the mild Gilbertýs syndrome. Further, we have developed a model as to how the gastrointestinal (GI) distribution of a subset of these enzymes functions as a chemical defense against diet-associated chemicals. We continue to characterize their substrate selections/efficacies and to study the regulation of the bilirubin and the other isoforms as these factors relate to chemical toxicities, carcinogenesis, mutagenesis, therapeutic drug interactions, and teratogenesis. Models for transient-down regulation of these GI-distributed enzymes versus efficacy of chemical uptake and resulting tissue damage are investigated. Further, polymorphic genes among these isozymes represented in the population and their differential effects on drug metabolism are also studied.

Resources

• Employee Listing
• E-Mail the Lab: owens@helix.nih.gov