The Effects of CCl4 and U-27267 on Cytochrome P0450 and Mixed-Function-Oxidase Activities in Male ICR Mice
Reynolds, Michael A.
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The hepatotoxic effects of carbon tetrachloride (CCl4) a known hepatotoxin, on mouse liver cytochrome P-450 concentration, aniline hydroxylase and benzphetamine demethylase activities were investigated.. Acute CCl4 treatment caused a marked decrease in cytochrome P-4S0 concentration, as well as, decreased microsomal enzyme activities. Substantially increased blood serum glutamic pyruvic transaminase (SGPT) levels were reflective of the extent of hepatic injury. Serum alkaline phosphatase activity increased slightly while serum cholesterol levels showed no treatment effect. Using CCl4-induced hepatotoxicity as a positive control and model of hepatotoxic attack, the effects of U-27267 (3,4,S-Tribromo-N-N-a-trimethyl-pyrazole-l-acetamide) on cytochrome P-4S0, aniline hydroxylase and benzphetamine demethylase activities were investigated. Subacute U-27267 treatment produced a significant dose-related increase in cytochrome P-450 concentration and associated microsomal enzyme activities. SGPT levels showed only a slight increase in comparison to the SGPT levels after CCl4 treatment. The results of this study indicate that there is no direct relationship between the hepatotoxicity of a compound and its action on cytochrome P-450 and associated microsomal enzyme activities. As an inducer of microsomal enzyme activity, it was concluded that the mechanism of U-27267-hepatotoxicity is different than that of CCl4-induced hepatic injury and that comparison of U-27267 with other hepatotoxic agents would be useful.