Grant: Operating Grant

UGTs are a very broad and divers group of enzymes found in the internal membranes of cells that mediate our defense against the toxic effects of small molecules such as carcinogens, therapeutic drugs and hormones. Unless modified by the addition of a sugar group by UGT enzymes, these compounds will accumulate in the body to toxic levels. Evidence shows large interindividual variability in UGT enzymes that has clinically relevant implications in defining drug response and toxicity as well as influencing cancer risk and progression. Research in the Guillemette lab focuses on investigating novel mechanisms are at the origin of this variability, how these enzymes are controlled in the cell and how this impact our ability to eliminate drugs and regulate hormone levels. Our goals are to unravel the genetic and epigenetic basis of individual differences of UGT-dependant drug metabolism and therapeutic outcome. We also expand investigations to determine how mRNA splicing contributes to create variability while expanding the number of human UGTs. We will pursue our prospective clinical study to determine the relationship between patient's genetic profile for UGTs and the therapeutic response to the anticancer drug irinotecan. Research design will also include cell culture models and study of human tissue banks of drug metabolizing tissues. This proposal unites many innovative aspects while using a multiple approach from bench to a clinical investigation. Our effort is primarily focused on few specific drugs but will have a huge impact on a number of widely used therapeutics also processed through this critical metabolic pathway. Furthermore, this work may provide novel strategies to help reduce the risk of cancer and prevent its progression.