Cytochrome P450 CYP3A Regulation in Humanized Transgenic Mice

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The study of the regulation of human genes is inherently difficult. It is difficult or impossible to gain access to many body tissues in either healthy or sick individuals to examine coordinated gene function (or dysfunction). For this reason, it is often the case that we have a much better understanding of gene function in species such as rats and mice, the most common animal environments for biomedical research. However, findings in animals often fail to meaningfully mirror what occurs in man. To progress our understanding of human genes we need to develop models that more faithfully reproduce the human situation in an environment that is amenable to both manipulation and close examination, such as the novel 'humanised' mouse models described in this application. This application deals with the regulation genes that control liver enzymes belonging to the human cytochrome P450 3A (CYP3A) subfamily. These enzymes are present in several tissues including liver, gut, lung and breast. They form the main disposal pathway for foreign chemicals such as drugs, environmental pollutants and some cancer causing chemicals. In addition they are involved in the breakdown of several important internally produced substances, such as steroid hormones. Altered formation of CYP3A enzymes can have a dramatic impact on the action of many important drugs and may predispose to some forms of cancer. In this project, we will insert the genes for all four human CYP3A enzymes into mice. We expect that these 'humanised' mouse models will effectively enable the human situation to be studied in a convenient animal model and allow detailed studies to be performed. A knowledge of the mechanisms involved in CYP3A enzyme formation is of particular importance to the fields of drug and steroid metabolism (both in health and in disease states), liver diseases and foetal pharmacology. In addition, these models will provide a new and useful tool for drug development.