PT - JOURNAL ARTICLE AU - C. S. PITCHUMONI AU - R. J. STENGER AU - W. S. ROSENTHAL AU - E. A. JOHNSON TI - EFFECTS OF 3,4-BENZPYRENE PRETREATMENT ON THE HEPATOTOXICITY OF CARBON TETRACHLORIDE IN RATS DP - 1972 May 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 227--233 VI - 181 IP - 2 4099 - http://jpet.aspetjournals.org/content/181/2/227.short 4100 - http://jpet.aspetjournals.org/content/181/2/227.full SO - J Pharmacol Exp Ther1972 May 01; 181 AB - Enhancement of carbon tetrachloride (CCl4) hepatotoxicity by pretreatment with phenobarbital has been Postulated to be related to Proliferation of hepatie smooth endoplasmic reticulum and the associated increase of hepatic microsomal cytochmrome P-450. To evaluate the relative contribution of these changes, CCl4 hepatotoxicity after 3,4-benzpyrene pretreatment was studied since this "narrow spectrum" hepatic enzyme inducer does not cause overt proliferation of the smooth endoplasmic reticulum but does elicit an increase in a related heme compound, viz., cytochrome P-448. Male rats Weighing 60 to 8O g were treated with a single i.p. injection of benzpyrene (25-mg/kg. dissolved in olive oil). Controls received olive oil alone. Twenty-four hours later, augmented hepatic drug-metabolizing enzme activity in benzpyrene treated rats was reflected in vivo by a reductiois in zoxazolamine-induced paralysis time and resistance to a lethal dose of zoxazolamine and in vitro by increased hepatic microsomal cytochrome P-448. Electron microscopy revealed no overt proliferation of hepatic smooth endoplasmic reticulum in such benzpyrene-treated animals. Identical benzpyrene-treated and control rats then were challenged with an i.p. injection of CCL4 (0.125 to 0.25 ml). Subsequently, animals were sacrificed at intervals and light microscopic study indicated that benzpyrene-CC14-treated rats consistently displayed more extensive hepatic necrosis than olive oil-CCl4-treated controls. In addition, at a dose of 0.2 ml of CCI4, there was a 66% mortality in benzpyrene pretreated animals, compared to 15% in controls. When the dose of CCL4 was reduced to 0.166 ml. mortality in the benzpyrene-pretreated rats was 30%, with no deaths in the olive oil-CC14-treated controls. These results indicate that overt proliferation of the hepatic smooth endoplasmic reticulum is not a prerequisite for the enhancement of CCL4 hepatotoxicity by drug pretreatment. It was considered likely that the observed enhancement was related to the metabolic changes effected by benzpyrene administration. © 1972 by The Williams & Wilkins Co.