Role of active oxygen species in the photodestruction of microsomal cytochrome P-450 and associated monooxygenases by hematoporphyrin derivative in rats.
The cytochrome P-450 in hepatic microsomes prepared from rats pretreated with hematoporphyrin derivative was shown to be rapidly destroyed in the presence of long-wave ultraviolet light. The photocatalytic destruction of the heme-protein was dependent on both the dose of ultraviolet light and of hematoporphyrin derivative administered to the animals. The destructive reaction was accompanied by increased formation of cytochrome P-420, loss of microsomal heme content, and diminished catalytic activity of cytochrome P-450-dependent monooxygenases such as aryl hydrocarbon hydroxylase and 7-ethoxycoumarin O-deethylase. The specificity of the effect on cytochrome P-450 was confirmed by the observation that other heme-containing moieties such as myoglobin and cytochrome c were not susceptible to photocatalytic destruction. The destruction of cytochrome P-450 was a photodynamic process requiring oxygen since quenchers of singlet oxygen, including 2,5-dimethylfuran, histidine, and beta-carotene, each substantially diminished the reaction. Scavengers of superoxide anion such as superoxide dismutase and of H2O2 such as catalase did not protect against photodestruction of cytochrome P-450, whereas inhibitors of the hydroxyl radical, including benzoate, mannitol, and ethyl alcohol, did afford protection. These results indicate that lipid-rich microsomal membranes and the heme-protein cytochrome P-450 embedded therein are potential targets of injury in cells exposed to hematoporphyrin derivative photosensitization.
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Dixit
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Mukhtar
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Bickers
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D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003574:Cytochrome c Group / Q000378:metabolism; D017324:Hematoporphyrin Derivative; D006415:Hematoporphyrins / Q000494:pharmacology*; D006418:Heme / Q000378:metabolism; D006427:Hemin / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000494:pharmacology; D006878:Hydroxides / Q000494:pharmacology; D017665:Hydroxyl Radical; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D009211:Myoglobin / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D010105:Oxygenases / Q000378:metabolism; D010782:Photolysis; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013481:Superoxides / Q000494:pharmacology; D014466:Ultraviolet Rays
D003574:Cytochrome c Group; D006415:Hematoporphyrins; D006878:Hydroxides; D009211:Myoglobin; D011838:Radiation-Sensitizing Agents; D013481:Superoxides; D017665:Hydroxyl Radical; D006418:Heme; D017324:Hematoporphyrin Derivative; D006427:Hemin; D003577:Cytochrome P-450 Enzyme System; D006861:Hydrogen Peroxide; D010105:Oxygenases; D010100:Oxygen