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.
D000171:Acrolein / Q000031:analogs & derivatives / Q000378:metabolism*; D000447:Aldehydes / Q000378:metabolism*; D000818:Animals; D001711:Biotransformation; D002250:Carbon Radioisotopes; D065607:Cytochrome P-450 Enzyme Inhibitors; D005663:Furans / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology; D007700:Kinetics; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000378:metabolism; D010634:Phenobarbital / Q000494:pharmacology; D010882:Piperonyl Butoxide / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains
D000447:Aldehydes; D002250:Carbon Radioisotopes; D065607:Cytochrome P-450 Enzyme Inhibitors; D005663:Furans; D007093:Imidazoles; C046803:N-octyl imidazole; C029060:2-methylfuran; C046802:acetylacrolein; D000171:Acrolein; D006899:Mixed Function Oxygenases; D010882:Piperonyl Butoxide; D010634:Phenobarbital