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)].