Project 171323

Glucuronosyltransferase (UGT) enzymes are responsible for the glucuronidation metabolic pathway and play an essential role in the elimination and detoxification of a large diversity of drugs from all classes, accounting for ~35% of drug conjugation. In human, UGT super-family is subdivided in two families (UGT1 and UGT2) and are encoded by highly polymorphic loci. This proposal aims to pursue and further expand our previous findings concerning the relationship between genetic variations in a UGT gene and response to an anticancer drug. The proposed study will generate important information regarding patients treated in Canada and this has never been tested before and are necessary to establish the value of prospective genotyping with anticancer drug therapy by health care providers in Canada. On the other hand, while most pharmacogenomic studies solely focus on DNA sequence variations, we propose to study the regulation of UGT activity by epigenomic (e.g. CpG methylation and histone deacetylation) and post-transcriptional (e.g. mRNA splicing) events. We believe that the study of classical single nucleotide polymorphisms (SNPs) to epigenomic and new splicing events is critical for a better understanding underlying interindividual variations in xeno- and endobiotic glucuronidation by human UGT enzymes and to fully appreciate their in vivo significance, particularly in drug response. We intend to highlight those new mechanisms that create diversity and variability in this important metabolic pathway. This proposal unites many innovative aspects while using a multiple approach from bench to a clinical investigation.

investigating the pharmacogenomics of human UGT enzymes, including the impact of genetic variations, epigenomics, and mRNA splicing on anticancer drug response