Regulation of cytochrome P450 metabolism in rats receiving total parenteral nutrition

Total parenteral nutrition (TPN) provides adequate nutritional support to patients who are unable to eat. Because TPN is administered intravenously, it bypasses the gastrointestinal tract. This circumvention is associated with a physiological alteration in gastrointestinal structure and function along with a depression of hepatic drug metabolizing enzymes. The goal of this dissertation was to identify possible mechanisms for regulating TPN-associated hepatic cytochrome P450 (CYP) enzyme depression. This was accomplished through the testing of the following two hypotheses: (1) depression of hepatic drug metabolism can be reversed through the normalization of gut function with glutamine, and (2) hepatic CYP enzymes retain their ability to be regulated by exogenous substances (phenobarbital or dexamethasone) during TPN administration. All studies were carried out using a chronically catheterized male Sprague Dawley rat model. Phenobarbital or dexamethasone was administered to the appropriate rats only on the last three days prior to sacrifice, while supplementation of TPN with glutamine occurred every day. After one-week of TPN administration, the rats were sacrificed and liver microsomes made. Formation rates of 4- and 1′-hydroxymidazolam (50 μM) and Vmax for hydroxytestosterone metabolites in the hepatic microsomes were used as CYP2B, CYP2C, and CYP3A probes. Results showed that supplementation of TPN with glutamine, which has been shown to prevent the TPN-associated gastrointestinal disorders, caused a two-fold improvement (p \u3c 0.05) in hepatic CYP activity when compared to TPN fed controls. However, the rats\u27 activity levels were still significantly depressed (p \u3c 0.05) when compared to chow-fed controls. This lack of CYP activity restoration was not a result of the TPN administration preventing CYP enzyme induction. When phenobarbital or dexamethasone was administered to TPN and chow-fed animals, both groups had similar patterns of induction and suppression of hepatic CYP enzymes. These studies imply that glutamine has some direct affects on hepatic CYP enzyme regulation, the intestine may play a role in regulating hepatic CYP enzymes, and that hepatic CYP enzymes retain their ability to become modulated by exogenous substances during TPN administration