Carbon tetrachloride and 2-isopropyl-4-pentenamide-induced inactivation of cytochrome P-450 leads to heme-derived protein adducts.
When CCl4 was incubated with rat liver microsomes from phenobarbital-treated rats in an aerobic or anaerobic atmosphere, over 69% of the heme moiety of cytochrome P-450 was destroyed. At least 45% of the degraded heme under both reaction conditions was accounted for as heme-derived products irreversibly bound to microsomal proteins. Furthermore, 33% of the irreversibly bound products were bound specifically to a 54-kDa form of cytochrome P-450. A structurally different compound, 2-isopropyl-4-pentenamide, also destroyed the heme moiety of cytochrome P-450 and produced heme-derived adducts of microsomal proteins that accounted for 28% of the destroyed heme. These results represent a novel mechanism for the destruction of cytochromes P-450 by xenobiotics.
D000081:Acetamides / Q000494:pharmacology*; D000502:Allylisopropylacetamide / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites; D002251:Carbon Tetrachloride / Q000494:pharmacology*; D065607:Cytochrome P-450 Enzyme Inhibitors; D004586:Electrophoresis / Q000379:methods; D006418:Heme / Q000378:metabolism*; D007120:Immunochemistry; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism*; D051381:Rats
D000081:Acetamides; D065607:Cytochrome P-450 Enzyme Inhibitors; D011506:Proteins; D000502:Allylisopropylacetamide; D006418:Heme; D002251:Carbon Tetrachloride