Inactivation of cytochrome P-450 by 2-isopropyl-4-pentenamide and other xenobiotics leads to heme-derived protein adducts.
When cytochrome P-450 in phenobarbital-induced rat liver microsomes was destroyed by 2-isopropyl-4-pentenamide (AIA) in vitro, 50% of the degraded heme was recovered as heme-derived products irreversibly bound to microsomal proteins. In contrast, less than 50% of the degraded heme was accounted for as N-alkylated porphyrins. Furthermore, 64% of the irreversibly bound products was bound specifically to a 54-kD form of cytochrome P-450. Several other compounds which have been reported to destroy cytochrome P-450 by forming N-alkylated porphyrins also produced heme-derived protein adducts. These findings indicate that the formation of heme-derived protein adducts may represent an important pathway for the irreversible degradation of cytochrome P-450 by many xenobiotics.
D000081:Acetamides / Q000494:pharmacology*; D000502:Allylisopropylacetamide / Q000494:pharmacology*; D000818:Animals; D065607:Cytochrome P-450 Enzyme Inhibitors; D006418:Heme / Q000032:analysis*; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D009249:NADP / Q000378:metabolism; D011166:Porphyrins / Q000032:analysis; D011485:Protein Binding; D011506:Proteins / Q000032:analysis*; D051381:Rats; D011919:Rats, Inbred Strains
D000081:Acetamides; D065607:Cytochrome P-450 Enzyme Inhibitors; D011166:Porphyrins; D011506:Proteins; D000502:Allylisopropylacetamide; D006418:Heme; D009249:NADP