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Reductive-oxygenation mechanism of metabolism of carbon tetrachloride to phosgene by cytochrome P-450

LR Pohl, RD Schulick, RJ Highet and JW George

The mechanism of metabolism of carbon tetrachloride (CCl4) to phosgene (COCl2) in rat liver microsomes was investigated. When the oxygen dependency of the reaction was studied, it was found that the rate of the reaction increased as the oxygen concentration in the reaction atmosphere was decreased from 100% to 5%. Decreasing the oxygen concentration below 5% caused a decrease in the rate of the reaction. The reaction was not inhibited by superoxide dismutase or catalase nor was it supported by cumene hydroperoxide. A reconstituted form of cytochrome P-450 from phenobarbital-pretreated rats metabolized CCl4 to COCl2. These results are consistent with a mechanism we call reductive oxygenation. The first step of the reaction is the cytochrome P-450- dependent reductive dechlorination of CCl4 to trichloromethyl radical (CCl3.). This intermediate is trapped by oxygen to form trichloromethylperoxyl radical (CCl3OO.), which decomposes to COCl2 and possibly an electrophilic form of chlorine.

Volume 25, Issue 2, pp. 318-321, 03/01/1984
Copyright © 1984 by American Society for Pharmacology and Experimental Therapeutics






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