Application of Chemical Cytochrome P-450 Model System to Studies on Drug Metabolism.

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Cytochrome P-450 plays an important role in metabolizing biomolecules and xenobiotics, and the mechanism of its catalytic activities has been the subject of extensive investigation. Recently many attempts have been made to reproduce the reactivity in chemical systems with a simple metalloporphyrin. We have achieved the synthesis of many effective P-450 mimics and clarified their functions with the aim of developing artificial enzymes having high similarity to the native P-450 system for investigation of drug metabolism.Here we present the results of our studies for three years.(1) The stable iron porphyrin ligated by alkyl thiolate showed enormously accelerated heterolytic O-O bond cleavage of peracids even in hydrophobic solvents. The heterolytic cleavage gives Fe^<5+>-oxenoid type active species which is thought to be a strong oxidant.(2) Modified cytochrome c, immobilized cytochrome c and microperoxidase-11, catalyzed some P-450-like substrate oxidations. The reaction mechanisms of these N- and S-oxidations were similar to those of P-450itself.(3) Ru-porphyrin/2,6-disubstituted pyridine N-oxide system was developed for olefin epoxidation. In the presence of acid, this system effectively catalyzed a oxidation of unactivated alkane and turn over number of the catalyst was 18800.(4) Many P-450 model systems were tested for ability to metabolize various drugs compared with the native P-450 system and coupling reactions of aniline derivatives, beta-oxo formation of piperidine derivatives, and oxidative decarboxylation of phenylacetic acid derivatives were found to be new P-450 dependent metabolic pathways. These results clearly show that P-450 model is useful for identification of minor/new/unstable metabolites.