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Biochemical pharmacology

Microsomal metabolism of N,N-diethylacetamide and N,N-dimethylacetamide and their effects on drug-metabolizing enzymes of rat liver.


PMID 8080444

Abstract

This study was undertaken to investigate: (1) the effect of N,N-diethylacetamide (DEAC) and N,N-dimethylacetamide (DMAC) administration to rats on drug-metabolizing enzymes in the liver; (2) the in vitro dealkylation of DEAC and DMAC by hepatic microsomes from rats treated with various P450 inducers and purified P450 (2B1 and 2E1). DEAC administration at doses of 100-300 mg/kg i.p. for 3 days mostly induced P450 2B1/2-associated hepatic microsomal monooxygenase activities (pentoxyresorufin O-depenthylase and the 16 beta-testosterone hydroxylase) and its own dealkylation (DEAC deethylase activity). P4502E1-linked monooxygenase activities, such as aniline and p-nitrophenol hydroxylases, were not affected. DEAC treatment increased the amount of P4502B1/2 in microsomes in a dose-dependent manner, but depressed the amount of P-4502C11 as assayed by western blotting. DMAC treatment did not alter any microsomal monooxygenases or phase II enzymatic activity. The oxidative metabolism of DEAC and DMAC with control and induced microsomes resulted in the dealkylation of these solvents, giving rise to acetaldehyde and formaldehyde, respectively. The kinetic parameters for these N-dealkylations were investigated. It was found that phenobarbital-, dexamethasone- and DEAC-induced microsomes deethylated DEAC with a Vmax approximately 3-fold of control-, ethanol- or beta-naphtoflavone-induced microsomes, although with a similar affinity; ethanol- or acetone-induced microsomes demethylated DMAC with a Vmax higher than that of control microsomes. In a reconstituted system, the purified P4502B1 dealkylated DEAC, but not DMAC, at the rate of 6.2 nmol/min/nmol P450, whereas purified P4502E1 dealkylated DMAC, but not DEAC, at the rate of 7.9 nmol/min/nmol P450. Oxidation of DEAC and DMAC were markedly inhibited in microsomes from DEAC-treated rats by anti-P4502B1 IgG and in microsomes from acetone-treated rats by anti-P4502E1 IgG, respectively. These results indicate that DMAC and DEAC are predominantly oxidated by different P450 isozymes and that only DEAC, when administered to rat, is capable of altering the expression of the hepatic P450 system. This latter feature could be related to the higher toxicity reported for DEAC.

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137529
N,N-Diethylacetamide, 97%
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