Inhalation anesthetics and cytochrome P-450-dependent reactions in rat liver microsomes.
The activities of liver microsomal enzymes were studied in preparations from unanesthetized rats and rats anesthetized for one hour with nitrous oxide, diethyl ether, halothane or chloroform. Most of the enzymes studied were cytochrome P-450-dependent oxygenases that hydroxylate endogenous substrates. The other microsomal enzymes, assayed for comparison, included the cytochrome P-450-dependent aminopyrine demethylase, glucose-6-phosphatase, a dehydrogenase, and NADPH-cytochrome P-450 reductase. No anesthetic was associated with a significant change in activity of any enzyme studied. In rats pretreated with phenobarbital no anesthetic except chloroform changed enzymic activity. All hydroxylations were inhibited markedly by chloroform, as were a microsomal dehydrogenation, hydrolysis of glucose-6-phosphate, and NADPH-cytochrome P-450 reductase activity. Administration of alpha-tocopherol did not prevent the inhibition associated with chloroform in phenobarbital-induced animals. It is concluded that cytochrome P-450-dependent hydroxylations involved in metabolic processes normally proceeding in the endoplasmic reticulum of the liver are not permanently affected by the anesthetics used in this study. The inhibitory effect of chloroform after pretreatment with phenobarbital is unspecific and affects a large number of different microsomal enzymes. Evidence that mechanisms other than lipid peroxidation may be responsible for the toxic effects of chloroform in the liver is presented.
D000633:Aminopyrine N-Demethylase / Q000378:metabolism; D000769:Anesthesia, Inhalation; D000777:Anesthetics / Q000494:pharmacology*; D000818:Animals; D002725:Chloroform / Q000494:pharmacology; D002790:Cholesterol 7-alpha-Hydroxylase / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005019:Ethyl Ethers / Q000494:pharmacology*; D005952:Glucose-6-Phosphatase / Q000378:metabolism; D006221:Halothane / Q000494:pharmacology; D006865:Hydrogenation; D006868:Hydrolysis; D006900:Hydroxylation; D006913:Hydroxysteroid Dehydrogenases / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D009609:Nitrous Oxide / Q000494:pharmacology*; D051381:Rats; D013250:Steroid Hydroxylases / Q000378:metabolism
D000777:Anesthetics; D005019:Ethyl Ethers; D002725:Chloroform; D003577:Cytochrome P-450 Enzyme System; D006913:Hydroxysteroid Dehydrogenases; D013250:Steroid Hydroxylases; D002790:Cholesterol 7-alpha-Hydroxylase; D000633:Aminopyrine N-Demethylase; D005952:Glucose-6-Phosphatase; D009609:Nitrous Oxide; D006221:Halothane