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Title: Metabolic activation of 2-methylfuran by rat microsomal systems

Abstract

2-Methylfuran (2-MF), a constituent of cigarette smoke and coffee, causes necrosis of liver, lungs, and kidneys in rodents. 2-MF is metabolically activated by mixed-function oxidases to acetylacrolein, a reactive metabolite that binds covalently to microsomal protein. The hepatic microsomal metabolism of 2-MF to reactive metabolite required the presence of NADPH and oxygen and was dependent on incubation time and substrate concentration. The microsomal metabolism of 2-MF was inducible by pretreatment of rats with phenobarbital and was inhibited by piperonyl butoxide and N-octyl imidazole, which indicates that the metabolism of 2-MF may be mediated by cytochrome P-450. Acetylacrolein was a potent inhibitor of mixed-function oxidase and completely inhibited the microsomal metabolism of 2-MF, indicating that 2-MF is a suicide substrate for the enzyme. The sulfhydryl nucleophile cysteine was a better trapping agent of the reactive metabolite of 2-MF than N-acetylcysteine or glutathione. Lysine decreased the covalent binding of 2-MF metabolites, presumably by reacting with the aldehyde group of acetylacrolein. In addition, in the presence of NADPH, 2-MF was bioactivated by both pulmonary and renal cortical microsomes to reactive metabolites that were covalently bound to microsomal proteins.

Authors:
;
Publication Date:
Research Org.:
National Cancer Institute, Bethesda, MD
OSTI Identifier:
6291166
Resource Type:
Journal Article
Journal Name:
Toxicol. Appl. Pharmacol.; (United States)
Additional Journal Information:
Journal Volume: 3
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; CARBON 14 COMPOUNDS; METABOLIC ACTIVATION; FURANS; MIXED-FUNCTION OXIDASES; BIOCHEMICAL REACTION KINETICS; ACROLEIN; ALDEHYDES; ENZYME INHIBITORS; IMIDAZOLES; MICROSOMES; PHENOBARBITAL; RATS; ANESTHETICS; ANIMALS; ANTICONVULSANTS; AZINES; AZOLES; BARBITURATES; CELL CONSTITUENTS; CENTRAL NERVOUS SYSTEM DEPRESSANTS; DRUGS; ENZYMES; HETEROCYCLIC COMPOUNDS; HYPNOTICS AND SEDATIVES; KINETICS; LABELLED COMPOUNDS; MAMMALS; ORGANIC COMPOUNDS; ORGANIC NITROGEN COMPOUNDS; ORGANIC OXYGEN COMPOUNDS; ORGANOIDS; OXIDOREDUCTASES; OXYGENASES; PYRIMIDINES; REACTION KINETICS; RODENTS; VERTEBRATES; 550201* - Biochemistry- Tracer Techniques

Citation Formats

Ravindranath, V, and Boyd, M R. Metabolic activation of 2-methylfuran by rat microsomal systems. United States: N. p., 1985. Web. doi:10.1016/0041-008X(85)90242-X.
Ravindranath, V, & Boyd, M R. Metabolic activation of 2-methylfuran by rat microsomal systems. United States. https://doi.org/10.1016/0041-008X(85)90242-X
Ravindranath, V, and Boyd, M R. 1985. "Metabolic activation of 2-methylfuran by rat microsomal systems". United States. https://doi.org/10.1016/0041-008X(85)90242-X.
@article{osti_6291166,
title = {Metabolic activation of 2-methylfuran by rat microsomal systems},
author = {Ravindranath, V and Boyd, M R},
abstractNote = {2-Methylfuran (2-MF), a constituent of cigarette smoke and coffee, causes necrosis of liver, lungs, and kidneys in rodents. 2-MF is metabolically activated by mixed-function oxidases to acetylacrolein, a reactive metabolite that binds covalently to microsomal protein. The hepatic microsomal metabolism of 2-MF to reactive metabolite required the presence of NADPH and oxygen and was dependent on incubation time and substrate concentration. The microsomal metabolism of 2-MF was inducible by pretreatment of rats with phenobarbital and was inhibited by piperonyl butoxide and N-octyl imidazole, which indicates that the metabolism of 2-MF may be mediated by cytochrome P-450. Acetylacrolein was a potent inhibitor of mixed-function oxidase and completely inhibited the microsomal metabolism of 2-MF, indicating that 2-MF is a suicide substrate for the enzyme. The sulfhydryl nucleophile cysteine was a better trapping agent of the reactive metabolite of 2-MF than N-acetylcysteine or glutathione. Lysine decreased the covalent binding of 2-MF metabolites, presumably by reacting with the aldehyde group of acetylacrolein. In addition, in the presence of NADPH, 2-MF was bioactivated by both pulmonary and renal cortical microsomes to reactive metabolites that were covalently bound to microsomal proteins.},
doi = {10.1016/0041-008X(85)90242-X},
url = {https://www.osti.gov/biblio/6291166}, journal = {Toxicol. Appl. Pharmacol.; (United States)},
number = ,
volume = 3,
place = {United States},
year = {Wed May 01 00:00:00 EDT 1985},
month = {Wed May 01 00:00:00 EDT 1985}
}