Evaluation of Hepatic Mixed Function Oxidase (MFO) Systems After Administration of Allylisopropylacetamide CC14 CS2 or Polyriboinosinic Acid · Polyribocytidylic Acid to Mice

Abstract

Almost all drugs and environmental xenobiotics are metabolized by hepatic cytochrome P-450-dependent mixed function oxidase (MFO) systems. When administered to animals, most of these chemicals either induce or have little or no effect on MFO systems, but a few produce marked losses. Allylisopropylacetamide (AIA), CCl4, CS2 and polyriboinosinic acid·polyribocytidylic acid (poly rI·rC) are prototypes of xenobiotics which destroy MFO systems by different mechanisms. With the exception of poly rI·rC, these agents are believed to produce their effect via “suicidal” reactions, i.e., only after they have been converted by cytochrome P-450 to reactive metabolites (reviewed by De Matteis 1978). The metabolites of AIA, and those of many other compounds that possess terminal olefin groups, destroy cytochrome P-450 by reacting with its heme to form green pigments (De Matteis 1971). Cytochrome P-450 destroys itself by converting CS2 to a product which combines covalently with apocytochrome P-450 (Bond and De Matteis 1969; Catignani and Neal 1975; Dalvi et al. 1975; De Matteis 1978). CCl4 is believed by many to exert its toxic effect through the cytochrome P-450-mediated formation of free radical intermediates (Hrycay and O’Brien 1971), but there is less agreement as to the mechanism involved. Lipid peroxidation of the microsomal membrane is a major consequence of CCl4 intoxication (reviewed by De Matteis 1978). Destruction of cytochrome P-450 probably occurs both indirectly as a result of disruption of the membrane and more directly by the hydroperoxides produced by lipid peroxidation. The mechanism of action of poly rI·rC and other interferon inducing agents is not well understood.KeywordsMicrosomal CytochromeMixed Function OxidaseDemethylase ActivityAniline HydroxylaseMixed Function Oxidase SystemThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.