Grant: Operating Grant

Every day, humans have to cope with a large number of compounds from environmental and dietary sources, many of which being detrimental to human health. Glucuronidation is mediated by UDP-glucuronosyltransferases (UGT). It is the prevailing mechanism to inactivate potentially harmful molecules such as drugs and food carcinogens as well as endogenous molecules such as hormones and facilitate their elimination from the body. This process is particularly active in the liver, but also in other excretory organs, such as kidney, small intestine, and colon. Understanding how the activity of UGT proteins is controlled has important implications for safe and effective drug therapy as well as for carcinogenesis. We have recently discovered a new regulatory mechanism of detoxification by UGTs. We have found nine new UGT proteins in human cells and demonstrated that they interfere with glucuronidation activity. In addition, our research has further revealed that these new proteins could control cellular fitness and contribute to the development and progression of cancer. This discovery clearly represents a new paradigm for the regulation and function of drug-metabolizing enzymes. Our goal is now to study how the new UGT proteins regulate the inactivation of drugs, toxic molecules and hormones and to understand their contribution in regulating cell metabolism. We will use complementary approaches to study human tissues involved in drug metabolism as well as cellular models that will be exposed to drugs, hormones and carcinogens. The findings generated from these studies are likely to have an important pharmacological and clinical impact because UGT protein activity is directly related to the elimination of toxic compounds and drugs, thereby modulating not only the effectiveness of drug treatment and side-effects, but also the development and progression of cancer.