Grant: Operating Grant

Cytochrome P450s are key enzymes in the modification of drugs and other foreign small molecules within the body. They form an essential part of a system that modifies an extraordinary diversity of substances. The normal biological role of cytochrome P450s is believed to be one of detoxication. However, in the case of certain foreign small molecules, the immediate product is a chemically reactive form, capable of combining with and damaging cellular target molecules, such as proteins and DNA. One consequence of the formation of such reactive intermediates may be cellular toxicity or adverse drug reactions. Another may be to cause mutations in cellular DNA and yet another may be to cause cancer. Thus cytochrome P450s are implicated in reactions leading both to detoxication and to toxicity. Much remains to be learned at the molecular level concerning how the levels of the different cytochrome P450s present in humans and in experimental animals are regulated. The major objective of the present project is to analyze the regulation of specific P450 genes in mouse and rat liver. This work will provide an indication as to how cytochrome P450 genes are regulated and how they vary from one individual to another. It may also contribute to an understanding of why there is interindividual variation in drug metabolism in humans and perhaps suggest reasons why individuals might vary in their susceptibility to cancer.