The effects of nutritional modifications on the metabolism of xenobiotics such as environmental chemicals have been extensively studied and widely discussed. However, the mechanisms by which dietary nutrients regulate the induction of hepatic drug metabolizing enzymes are not known. This research proposal is intended to elucidate the mechanisms by which lipid nutrition regulates the induction of specific P-450 isozymes (P450s) and glutathione S-transferase (GST) with the following specific aims: 1. To study the effects of dietary polyunsaturated fatty acids (PUFA) on the induction of specific P-450s (P-450b, P- 450ac, and P-450c) by inducers such as phenobarbital (PB), acetone, and 3-methylcholanthrene, respectively, by determining selected enzyme activities and by quantitating these P-450s immunochemically. 2. To determine whether dietary PUFA modulate the induction of P-450 at the levels of transcription, translation, or membrane incorporation of the P-450 molecule. 3. To study the effects of dietary PUFA on the induction of hepatic GST by PB and to compare these results to those obtained with the P-450b. The results will elucidate the basic mechanisms by which dietary PUFA regulate the induction of specific P-450s and GST. The studies are important in understanding the role of dietary PUFA on the metabolic activation of xenobiotics to genotoxic metabolites.
