Abstract

The data presented here and elsewhere (36, 37) implicate an active metabolite of certain allyl-containing barbiturates and their derivatives in the destruction of cytochrome P-450 heme. Since epoxides are reactive intermediates in the oxidative metabolism of certain olefins and aromatic compounds (30), metabolic conversion of the allyl group of these compounds to an epoxide may be involved in the breakdown of cytochrome P-450 heme to the so-called green pigments. Foreman and Maynert (38) have demonstrated the formation of an epoxide of secobarbital in vitro and Doedens (39) has tentatively identified AIA epoxide in the urine of rats administered 200 mg of AIA per kg. The important pharmacological and toxicological implications of the formation of reactive epoxide intermediates in the metabolism of a wide variety of compounds have recently been discussed (40-43). Epoxide intermediates in the oxidation of bromobenzene and polycyclic hydrocarbons have been implicated in hepatotoxicity (43-45) and chemical carcinogenesis (40-42); however, these compounds did not cause the destruction of cytochrome P-450 (personal communication, J. Gillette). The possible toxicological significance of the breakdown of cytochrome P-450 is unknown.