Metabolic activation of 2-methylfuran by rat microsomal systems
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.
- Research Organization:
- National Cancer Institute, Bethesda, MD
- OSTI ID:
- 6291166
- Journal Information:
- Toxicol. Appl. Pharmacol.; (United States), Vol. 3
- Country of Publication:
- United States
- Language:
- English
Similar Records
Metabolism and binding of cyclophosphamide and its metabolite acrolein to rat hepatic microsomal cytochrome P-450
Effect of mixed function oxidase induction and inhibition on salicylate-induced nephrotoxicity in male rats
Related Subjects
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