Induction of Hepatic Glutathione S-Transferase and UDP-Glucuronosyltransferase Activities by Ketamine in Rats

BackgroundKetamine has been shown to induce rat cytochrome P-450 in a way similar to phenobarbital. However, whether ketamine is able to induce glutathione S-transferase (GST) and UDP-glucuronosyltransferase (UGT), two major phase II drug-metabolizing enzymes, remains unclear. The present study aimed to investigate the effect of ketamine on GST and UGT activities in rats.MethodsIn a dose-response study, male adult Wistar rats were treated with 10, 20, 40 or 80 mg/kg ketamine intraperitoneally twice daily for 4 days. Livers were removed 1 day after ketamine treatment and hepatic GST and UGT activities were determined. In a reversibility study, rats were treated with 80 mg/kg ketamine intraperitoneally twice daily for 4 days and killed 1, 2, 3 or 4 days after the last dose of ketamine. Livers were removed and hepatic GST and UGT activities were determined.ResultsThe results of the dose-response study showed that treatment of rats with 10, 20, 40, or 80 mg/kg ketamine produced 19%, 20%, 18%, and 25% increases respectively in the catalytic activity of hepatic cytosolic GST, and 41%, 41%, 35%, and 38% increases respectively in the catalytic activity of microsomal UGT. The results of the reversibility study showed that the GST activities of the rats killed 1, 2, 3, or 4 days after ketamine treatment were 62%, 88%, 46% and 65% higher than the activity of the control group. The UGT activities of the rats killed 1, 2, 3, or 4 days after ketamine treatment were 56%, 53%, 54% and 72% higher than the activity of the control group.ConclusionKetamine is able to induce the activities of hepatic GST and UGT in rats. The induced GST and UGT activities persist for at least 4 days after cessation of ketamine. The results suggest the possibility of interactions of drugs related to phase II enzyme induction in chronic ketamine users.