Hepatic drug metabolizing enzyme induction and serum triacylglycerol elevation in rats treated with chlordiazepoxide, griseofulvin, rifampicin and phenytoin.
Five days intraperitoneal administration of rats with chlordiazepoxide (0.4 mg/kg), griseofulvin (7 mg/kg), rifampicin (8. 6 mg/kg), phenytoin (4.3 mg/kg) and phenobarbitone (1.4 mg/kg; an established inducer of microsomal enzymes) caused a significant increase in serum triacylglycerol (P<0.001) and the activities of aniline hydroxylase, aminopyrine N-demethylase and p-nitroanisole O-demethylase (P<0.001). Aniline hydroxylase, aminopyrine N-demethylase and p-nitroanisole O-demethylase activities were increased 1.48-, 1.15- and 1.47-fold, respectively, in chlordiazepoxide-treated rats, 1.65-, 1.20- and 1.38-fold in griseofulvin-treated rats, 1.74-, 1.36- and 1.44-fold in rifampicin-treated rats, 1.56-, 1.29- and 1.62-fold in phenytoin-treated rats and 2.26-, 1.72- and 1.93-fold in phenobarbitone-treated rats. Chlordiazepoxide, griseofulvin, rifampicin, phenytoin and phenobarbitone increased the activity of cytosolic phosphatidate phosphohydrolase by 52, 58, 67, 73 and 82%, respectively, while the drugs elicited 50, 60, 60, 73 and 87% increases in the activity of the microsomal phosphatidate phosphohydrolase. Similarly, chlordiazepoxide, griseofulvin, rifampicin, phenytoin and phenobarbitone elicited 2.4-, 2.39-, 2.34-, 1.69- and 3.75-fold increases in serum triacylglycerol concentrations. The correlations between serum triacylglycerol concentrations and the activities of aniline hydroxylase, aminopyrine N-demethylase and p-nitroanisole O-demethylase were significant in all treatment groups (r=0.83, r=0.92 and r=0.87, respectively, n=30, P<0.001). Our results suggest that induction of hepatic enzymes by the administered drugs may lead to hypertriglyceridaemia as an adverse effect, possibly by inducing the activity of regulatory enzymes in the biosynthesis of triglyceride.
Farombi
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Drug Metabolism and Toxicology Unit, Department of Biochemistry, College of Medicine, University of Ibadan, Ibadan, Nigeria. library@kdl.ui.edu.ng
Akinloye
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Akinmoladun
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Emerole
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D000633:Aminopyrine N-Demethylase / Q000187:drug effects / Q000378:metabolism; D000815:Aniline Hydroxylase / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002707:Chlordiazepoxide / Q000494:pharmacology*; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006118:Griseofulvin / Q000494:pharmacology*; D008658:Inactivation, Metabolic; D008099:Liver / Q000033:anatomy & histology / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D010090:Oxidoreductases, O-Demethylating / Q000187:drug effects / Q000378:metabolism; D010672:Phenytoin / Q000494:pharmacology*; D010711:Phosphatidate Phosphatase / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012293:Rifampin / Q000494:pharmacology*; D014280:Triglycerides / Q000097:blood*
D004791:Enzyme Inhibitors; D014280:Triglycerides; D006118:Griseofulvin; D010672:Phenytoin; D002707:Chlordiazepoxide; C026048:4-nitroanisole O-demethylase; D010090:Oxidoreductases, O-Demethylating; D000815:Aniline Hydroxylase; D000633:Aminopyrine N-Demethylase; D010711:Phosphatidate Phosphatase; D012293:Rifampin