Mechanism of induction of hepatic microsomal drug metabolizing enzymes by a series of barbiturates.
The inducing effect of certain barbiturates (secobarbitone, thiopentone, pentobarbitone, allobarbitone, phenobarbitone and barbitone) on the levels of the hepatic microsomal drug-metabolizing enzymes has been studied in the rat both in vivo and in vitro. The extent of induction was related to the plasma half-lives of the barbiturates; compounds with low rates of metabolism and long half-lives were the most potent inducing agents. The latter (phenobarbitone, pentobarbitone and allobarbitone) were shown by spectral technique to interact with cytochrome P-450 suggesting that their mechanism of enzyme induction was 'substrate induction' in type. Barbiturates containing an allyl group (secobarbitone and allobarbitone) had a weaker inducing effect than expected, possibly due to their destruction of cytochrome P-450. Despite its short plasma half-life of 0-5 h thiopentone was a relatively potent inducer probably due to its metabolism to pentobarbitone, which has a much longer plasma half-life (1-3 h). Barbitone is an effective inducer of the drug-metabolizing enzymes, yet does not interact spectrally with cytochrome P-450; this is in accord with the observations that although there are increases in NADPH-cytochrome c reductase and cytochrome b5, following administration of barbitone there is no increase in cytochrome P-450. Barbiturate pretreatment does not affect the activities of glucose-6-phosphatase, glucose-6-phosphate dehydrogenase or 6-phosphogluconate dehydrogenase.
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D001463:Barbiturates / Q000097:blood / Q000378:metabolism / Q000494:pharmacology*; D001713:Biphenyl Compounds; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects*; D005037:Ethylmorphine-N-Demethylase / Q000378:metabolism; D005952:Glucose-6-Phosphatase / Q000378:metabolism; D005954:Glucosephosphate Dehydrogenase / Q000378:metabolism; D006207:Half-Life; D006591:Hexobarbital / Q000494:pharmacology; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism; D009579:Nitrobenzoates; D010088:Oxidoreductases / Q000378:metabolism; D010734:Phosphogluconate Dehydrogenase / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D012890:Sleep / Q000187:drug effects
D001463:Barbiturates; D001713:Biphenyl Compounds; D009579:Nitrobenzoates; D003577:Cytochrome P-450 Enzyme System; D006591:Hexobarbital; D010088:Oxidoreductases; D010734:Phosphogluconate Dehydrogenase; D005954:Glucosephosphate Dehydrogenase; D001189:Aryl Hydrocarbon Hydroxylases; D005037:Ethylmorphine-N-Demethylase; D009251:NADPH-Ferrihemoprotein Reductase; D005952:Glucose-6-Phosphatase