Molecular Pharmacology, Vol 18, 602-605, Copyright © 1980 by the American Society for Pharmacology and Experimental Therapeutics

Destruction of Cytochrome P-450 by Olefins: N-Alkylation of Prosthetic Heme

¹ Department of Pharmaceutical Chemistry, School of Pharmacy, and Liver Center, University of California, San Francisco, California 94143

Destruction of phenobarbital-inducible cytochrome P-450 during metabolism of 4-ethyl-1-hexene and ethylene results in accumulation of abnormal hepatic porphyrins. Field desorption mass spectrometric analysis of these "green" porphyrins has shown that they are 1:1:1 stoichiometric adducts of protoporphyrin IX (isolated as the dimethyl ester), the olefin in question, and an oxygen atom. The electronic absorption spectra of the adducts, as both free bases and zinc complexes, are virtually superimposable with the corresponding spectra of the dimethyl ester (DME) of synthetic N-methylprotoporphyrin IX. The zinc complexes of both N-methylprotoporphyrin IX (DME) and the 4-ethyl-1-hexene adduct exhibit mass spectrometric molecular ions attributable to the porphyrin plus zinc plus a chloride ion, although evidence for thermal generation of protoporphyrin IX (DME) from both of these porphyrins in the mass spectrometer is provided. These results establish that N-alkylation of prosthetic heme during attempted metabolism of olefinic bonds is the cause of cytochrome P-450 destruction. They also suggest that N-(2-hydroxyethyl)protoporphyrin IX (dimethyl ester) is the probable structure of the ethylene adduct.

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ACKNOWLEDGMENTS We are grateful to Prof. A. Burlingame and his staff for facilitating our use of the Biomedical Mass Spectrometry Resource.