Induction of rat hepatic cytochrome P-450 by ketamine and ITS toxicological implications
Journal
Journal of Toxicology and Environmental Health - Part A
Journal Volume
68
Journal Issue
17-18
Pages
1581-1597
Date Issued
2005
Author(s)
Abstract
Ketamine is a common intravenous anesthetic and a frequent drug of abuse, alone or in combination with cocaine. However, the pharmacokinetic effects of ketamine have not been fully investigated. This study determined the effects of ketamine on cytochrome P-450 (P-450)-dependent catalytic activities, protein levels, and hepatotoxicity using male Wistar rats treated with 10, 20, 40, or 80 mg/kg ketamine intraperitoneally twice daily for 4 d. Treatment with ketamine produced a dose-dependent increase of pentoxyresorufin O-dealkylation activity of liver microsomes. Treatment with 80 mg/kg ketamine resulted in 14-, 3-, and 2-fold rise in O-dealkylation of pentoxyresorufin, ethoxyresorufin, and methoxyresorufin of rat liver microsomes, respectively. The treatment produced 31% and 86% increases in 7-ethoxycoumarin O-deethylation and erythromycin N-demethylation, respectively. In addition, aniline hydroxylation activity was elevated by 62%. Protein blot analysis of liver microsomal proteins revealed that 80 mg/kg ketamine induced P-450 1A, 2B, 2E1, and 3A proteins by 2-, 13-, 2-, and 2-fold, respectively. In reversibility study, ketamine-induced pentoxyresorufin O-dealkylation, 7-ethoxycoumarin O-deethylation, erythromycin N-demethylation, and methoxyresorufin O-demethylation activities of liver microsomes prepared from rats 4 d after ketamine treatment were 75%, 48%, 29%, and 38% lower than the respective activities of liver microsomes prepared from rats 1 d after treatment. Protein blot analysis showed that ketamine-induced P-450 2B1/2 proteins also decreased in a time-dependent manner in 4 d. In hepatotoxicity study, treatment of rats with 1 ml/kg CCl4 produced a 7-fold increase in serum alanine aminotransferase activity level and a 17-fold rise in ratspretreated with 80 mg/kg ketamine for 4 d. Treatment of ICR mice with 120 mg/ kg cocaine produced a 17% mortality, whereas the same dose of cocaine produced a 50% mortality in mice pretreated with ketamine. Treatment of mice with 100 mg/kg cocaine produced a 76-fold increase in serum alanine aminotransferase activity level and a 260-fold rise in mice pretreated with 80 mg/kg ketamine for 4 d. The present study shows that ketamine induces the expression of multiple forms of P-450 in rat liver microsomes and increases CCl4-induced liver toxicity and cocaine-mediated acute toxicity. Other potential pharmacological or toxicological events related to ketamine use need to be further explored. Copyright? Taylor & Francis Inc.
SDGs
Other Subjects
7 ethoxycoumarin deethylase; alanine aminotransferase; carbon tetrachloride; cocaine; cytochrome P450; ketamine; liver protein; pentoxyresorufin dealkylase; unspecific monooxygenase; anesthetic agent; carbon tetrachloride; cocaine; cytochrome b5; cytochrome P450; ketamine; reduced nicotinamide adenine dinucleotide phosphate ferrihemoprotein reductase; animal cell; animal experiment; article; chemical reaction kinetics; controlled study; dose response; drug effect; enzyme activity; liver microsome; liver toxicity; male; nonhuman; priority journal; protein blotting; protein folding; protein induction; rat; animal; biosynthesis; drug potentiation; enzymology; Institute for Cancer Research mouse; liver; metabolism; mortality; mouse; pathology; weight reduction; Wistar rat; Animalia; Rattus norvegicus; Anesthetics, Dissociative; Animals; Carbon Tetrachloride; Cocaine; Cytochrome P-450 Enzyme System; Cytochromes b5; Drug Synergism; Ketamine; Liver; Male; Mice; Mice, Inbred ICR; Microsomes, Liver; Mortality; NADPH-Ferrihemoprotein Reductase; Rats; Rats, Wistar; Weight Loss
Type
journal article