Grant: Operating Grant

There are considerable compounds from environmental and dietary sources that humans have to cope with every day. Glucuronidation, mediated by UDP-glucuronosyltransferase (UGT) is the prevailing conjugative pathway for both xenobiotics, including drugs, and endogenous compounds. This process is involved in their inactivation and elimination from the body and is particularly active in liver, but also in other excretory organs, such as kidney, small intestine, and colon. Understanding the mechanisms for regulation of these enzymes has importance implications for safe and effective drug therapy as well as for carcinogenesis. Our recent research has led to the discovery of a new regulatory mechanism of the UGT pathway involving nine novel proteins produced by alternative splicing. This discovery clearly represents a new paradigm for the regulation of drug-metabolizing enzymes. Our goal is now to demonstrate the pharmacological and toxicological relevance of this new mechanism through various functional studies. We will use complementary approaches to study human tissues involved in drug metabolism as well as cellular models that will be exposed to drugs and carcinogens. We will use complementary approaches to study human tissues involved in drug metabolism as well as cellular models that will be exposed to drugs and carcinogens. This emerging project is highly focused and its clinical relevance is likely to be substantial because of the importance of this metabolic pathway for drugs, carcinogens and hormones.