Disulfiram metabolism as a requirement for the inhibition of rat liver mitochondrial low Km aldehyde dehydrogenase.
Biochem Pharmacol. 1991 Sep 12; 42(7):1361-6.BP

Abstract

In humans and animals, disulfiram produces a disulfiram-ethanol reaction after an ethanol challenge, the basis of which is the inhibition of liver aldehyde dehydrogenase (ALDH). Disulfiram and the metabolites diethyldithiocarbamate (DDTC), diethyldithiocarbamate-methyl ester (DDTC-Me), and S-methyl-N,N-diethylthiolcarbamate (DETC-Me) were studied in order to determine the role of bioactivation in disulfiram's action as an inhibitor of rat liver mitochondrial low Km ALDH (RLM low Km ALDH). In in vitro studies, disulfiram and DDTC (0.01 to 2.0 mM) both inhibited RLM low Km ALDH in a concentration-dependent manner. The addition of rat liver microsomes to the mitochondrial incubation did not further increase disulfiram-induced RLM low Km ALDH inhibition. However, DDTC-induced RLM low Km ALDH inhibition was increased further, but only at DDTC concentrations less than 0.05 mM. DDTC-Me and DETC-Me (2.0 mM) similarly exhibited an increased RLM low Km ALDH inhibition after the addition of liver microsomes. In in vivo studies, disulfiram (75 mg/kg), DDTC (114 mg/kg), DDTC-Me (41.2 mg/kg) or DETC-Me (18.6 mg/kg) administered i.p. to female rats inhibited RLM low Km ALDH. Inhibition of drug metabolism by pretreatment of rats with the cytochrome P450 inhibitor N-octylimidazole (NOI) (20 mg/kg, i.p.) prior to either disulfiram, DDTC, DDTC-Me or DETC-Me administration blocked the inhibition of RLM low Km ALDH. The in vitro and in vivo data support the conclusion that bioactivation of disulfiram to a reactive chemical species is required for RLM low Km ALDH inhibition and a disulfiram-ethanol reaction.

Authors+Show Affiliations

Yourick JJ

Department of Pharmacology and Toxicology, University of Kansas, Lawrence 66045.

Faiman MD

No affiliation info available

MeSH

Aldehyde DehydrogenaseAnimalsCytochrome P-450 Enzyme SystemDisulfiramDitiocarbDose-Response Relationship, DrugFemaleImidazolesKineticsMitochondria, LiverRatsRats, Inbred Strains

Pub Type(s)

Journal Article

Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

1656985

Citation

Yourick, J J., and M D. Faiman. "Disulfiram Metabolism as a Requirement for the Inhibition of Rat Liver Mitochondrial Low Km Aldehyde Dehydrogenase." Biochemical Pharmacology, vol. 42, no. 7, 1991, pp. 1361-6.

Yourick JJ, Faiman MD. Disulfiram metabolism as a requirement for the inhibition of rat liver mitochondrial low Km aldehyde dehydrogenase. Biochem Pharmacol. 1991;42(7):1361-6.

Yourick, J. J., & Faiman, M. D. (1991). Disulfiram metabolism as a requirement for the inhibition of rat liver mitochondrial low Km aldehyde dehydrogenase. Biochemical Pharmacology, 42(7), 1361-6.

Yourick JJ, Faiman MD. Disulfiram Metabolism as a Requirement for the Inhibition of Rat Liver Mitochondrial Low Km Aldehyde Dehydrogenase. Biochem Pharmacol. 1991 Sep 12;42(7):1361-6. PubMed PMID: 1656985.

* Article titles in AMA citation format should be in sentence-case

TY - JOUR T1 - Disulfiram metabolism as a requirement for the inhibition of rat liver mitochondrial low Km aldehyde dehydrogenase. AU - Yourick,J J, AU - Faiman,M D, PY - 1991/9/12/pubmed PY - 1991/9/12/medline PY - 1991/9/12/entrez SP - 1361 EP - 6 JF - Biochemical pharmacology JO - Biochem Pharmacol VL - 42 IS - 7 N2 - In humans and animals, disulfiram produces a disulfiram-ethanol reaction after an ethanol challenge, the basis of which is the inhibition of liver aldehyde dehydrogenase (ALDH). Disulfiram and the metabolites diethyldithiocarbamate (DDTC), diethyldithiocarbamate-methyl ester (DDTC-Me), and S-methyl-N,N-diethylthiolcarbamate (DETC-Me) were studied in order to determine the role of bioactivation in disulfiram's action as an inhibitor of rat liver mitochondrial low Km ALDH (RLM low Km ALDH). In in vitro studies, disulfiram and DDTC (0.01 to 2.0 mM) both inhibited RLM low Km ALDH in a concentration-dependent manner. The addition of rat liver microsomes to the mitochondrial incubation did not further increase disulfiram-induced RLM low Km ALDH inhibition. However, DDTC-induced RLM low Km ALDH inhibition was increased further, but only at DDTC concentrations less than 0.05 mM. DDTC-Me and DETC-Me (2.0 mM) similarly exhibited an increased RLM low Km ALDH inhibition after the addition of liver microsomes. In in vivo studies, disulfiram (75 mg/kg), DDTC (114 mg/kg), DDTC-Me (41.2 mg/kg) or DETC-Me (18.6 mg/kg) administered i.p. to female rats inhibited RLM low Km ALDH. Inhibition of drug metabolism by pretreatment of rats with the cytochrome P450 inhibitor N-octylimidazole (NOI) (20 mg/kg, i.p.) prior to either disulfiram, DDTC, DDTC-Me or DETC-Me administration blocked the inhibition of RLM low Km ALDH. The in vitro and in vivo data support the conclusion that bioactivation of disulfiram to a reactive chemical species is required for RLM low Km ALDH inhibition and a disulfiram-ethanol reaction. SN - 0006-2952 UR - https://www.unboundmedicine.com/medline/citation/1656985/Disulfiram_metabolism_as_a_requirement_for_the_inhibition_of_rat_liver_mitochondrial_low_Km_aldehyde_dehydrogenase_ DB - PRIME DP - Unbound Medicine ER -

Tags

Disulfiram metabolism as a requirement for the inhibition of rat liver mitochondrial low Km aldehyde dehydrogenase.Biochem Pharmacol. 1991 Sep 12; 42(7):1361-6.BP