Cytochrome P-450ac is an enzyme existing is human, rat and other animal species, and is inducible by fasting, diabetes, ketogenic diets, as well as chemicals such as acetone, alcohols, pyrazole, and isoniazid. It is a key enzyme in the metabolism of acetone, N-nitrosodimethylamine, ethers, alkanes, CCl4, enflurane, and other xenobiotics. In the past few years, our laboratory has made major contributions to the understanding of this enzyme. Our long term objective is to understand the detailed molecular mechanisms of the regulation of this important enzyme, the structural basis for its catalytic activity, and its roles in the metabolism of drugs and environmental chemicals.
The specific aims of this project are as follows: 1. To elucidate the mechanisms of the regulation of P-450ac by examining the roles of acetone, other ketone bodies, and hormones in the induction of this enzyme in the rat liver. 2. To characterize the molecular events in the regulation of P-450ac by measuring transcriptional and translational activities as well as the stabilities of mRNA and protein. 3. To investigate the sex-related differences and hormonal regulation of P-450ac in the mouse kidney at the physiological, biochemical, and molecular biological levels. 4. To understand the active site dynamics and catalytic functions of P-450ac by examining the structural characteristics of its substrates, by deriving structural information from the amino acid sequence, by modifying specific amino acid residues in the active site with a site-directed mutagenesis approach, and by studying the metabolism and toxicity of environmental chemicals. The project is expected to provide important new information concerning the regulation of P-450ac as well as its roles in the metabolism of drugs and toxic chemicals. This basic information should be very useful in our understanding of environmental toxicology, chemical carcinogenesis, and drug-nutrient interaction.
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