Abstract

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.