Grant: CIHR Fellowship

At present, it is estimated that there are 300,000 carriers of hepatitis C virus (HCV) in Canada, while worldwide there are around 170 million carriers who are at risk of developing serious liver diseases if left untreated. Despite years of research and development, we only have 2 drugs available to patients. This slow progress is partly due to deleterious drug-induced adverse effects and toxicities that are not observed in healthy non infected individuals. For example, the clinical development of a potent anti-HCV drug, has been recently halted since it induced sudden cardiac death in HCV patients but not in healthy volunteers that were tested previously. Following that three additional drug candidates were halted due to similar toxicities. In this regard, the elimination of an administered drug is one of the most important physiological functions of the liver through drug metabolizing enzymes and elimination transporters. Thus, the expression and function of the drug metabolizing enzymes and transporters is an important determinant of the physiological turnover of an administered drug. Therefore, the study of interactions between HCV and detoxifying enzymes, which are required for the elimination of drugs from host body, will result in a better understanding of the drug induced toxicities in HCV patients. In this project we will study the effect of HCV infection on the expression and activity of drug metabolizing enzymes and transporters in liver and the subsequent capacity to detoxify and eliminate drugs. Furthermore, we will try to identify the mechanism(s) behind these toxicities.The findings of these studies will help us better understand the mechanism of drug induced toxicities in HCV patients, and provide strategies to prevent it. This will promote the development of safer anti-HCV drugs.