Cumene hydroperoxide-dependent oxidation of NNN'N'-tetramethyl-p-phenylenediamine and 7-ethoxycoumarin by cytochrome P-450. Comparison between the haemoproteins from liver and olfactory tissue.
The interaction of cytochromes P-450 of the liver and olfactory epithelium of male hamsters with cumene hydroperoxide (CHP) has been characterized with regard to the ability of CHP to (1) support 7-ethoxycoumarin-O-de-ethylase (ECOD) activity, (2) support the oxidation of NNN'N'-tetramethyl-p-phenylenediamme (peroxidase activity) and (3) cause inactivation of cytochrome P-450. In the liver, CHP was found to support both ECOD and peroxidase activities while causing only minimal inactivation of cytochrome P-450. In contrast, in the olfactory epithelium CHP was virtually unable to support ECOD activity, peroxidase activity was 4-fold greater than in the liver, and extensive inactivation of cytochrome P-450 occurred. The reasons for these differences have been investigated with particular reference to the mode of cytochrome P-450-catalysed decomposition of CHP, that is, via homolytic or heterolytic cleavage of the hydroperoxide dioxygen bond. In both tissues, cumenol (2-phenylpropan-2-ol) was the major product of CHP decomposition detected. The radical scavenger nitrosobenzene inhibited cumenol formation by 84% in the olfactory epithelium, but by only 38% in the liver. This may indicate that dioxygen-bond scission occurs predominantly homolytically in the nasal tissue, whereas there is a balance between homolysis and heterolysis in the liver. It is suggested that the inability of CHP to support ECOD activity in the olfactory epithelium and the extensive inactivation of cytochrome P-450 that it causes both stem from decomposition of the hydroperoxide occurring homolytically rather than heterolytically in this tissue.
Reed
C J
CJ
MRC Toxicology Unit, MRC Laboratories, Carshalton, Surrey, U.K.
De Matteis
F
F
D015660:7-Alkoxycoumarin O-Dealkylase / Q000378:metabolism; D000818:Animals; D001555:Benzene Derivatives / Q000378:metabolism*; D003374:Coumarins / Q000378:metabolism*; D006224:Cricetinae; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology*; D008297:Male; D008647:Mesocricetus; D008862:Microsomes, Liver / Q000378:metabolism; D009831:Olfactory Mucosa / Q000378:metabolism; D010655:Phenylenediamines / Q000378:metabolism*; D013772:Tetramethylphenylenediamine / Q000378:metabolism*
D001555:Benzene Derivatives; D003374:Coumarins; D065607:Cytochrome P-450 Enzyme Inhibitors; D010655:Phenylenediamines; C017299:7-ethoxycoumarin; D003577:Cytochrome P-450 Enzyme System; D015660:7-Alkoxycoumarin O-Dealkylase; D013772:Tetramethylphenylenediamine; C007164:cumene hydroperoxide