The allylisopropylacetamide and novonal prosthetic heme adducts.
Administration of 2-isopropyl-4-pentenamide (AIA) and 2,2-diethyl-4-pentenamide (novonal) to phenobarbital-pretreated rats gives rise to abnormal porphyrins derived from the prosthetic heme group of inactivated cytochrome P-450. The abnormal porphyrins, identified by NMR and other spectroscopic methods, are N-alkylated protoporphyrin IX derivatives in which the N-alkyl moiety is derived from the parent drug by addition of a hydroxyl group to the internal carbon and of a porphyrin nitrogen to the terminal carbon of the pi-bond. A secondary reaction of the hydroxyl with the amide group converts the N-alkyl moiety into a lactone. The indicated alkylation-lactonization sequence is supported by the fact that the AIA adduct formed under an atmosphere of 18O2 incorporates one labeled oxygen atom. The regiochemistry of heme alkylation is consistent with a previously postulated active site topology [J. Biol. Chem. 258:4202-4207 (1983)].
D000081:Acetamides / Q000494:pharmacology*; D000502:Allylisopropylacetamide / Q000494:pharmacology*; D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006418:Heme / Q000031:analogs & derivatives*; D008099:Liver / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
D000081:Acetamides; D000502:Allylisopropylacetamide; D006418:Heme; C016019:diethylallylacetamide; D003577:Cytochrome P-450 Enzyme System; D010634:Phenobarbital