Acute toxicity of penicillic acid and its interaction with pentobarbital and other compounds.

Abstract Penicillic acid (PA), a carcinogenic mycotoxin, can cause generalized hepatic necrosis in the mouse and cytotoxicity in cultured cells, including hepatocytes. Acute toxicity of PA in the mouse was increased by pentobarbital and 3-methylcholanthrene (3MC) pretreatment but decreased by SKF-525A. Cysteine, when given 5 min before but not 20 min after PA administration, protected the mouse against PA toxicity, while diethyl maleate pretreatment increased PA toxicity in the mouse. PA potentiated pentobarbital-induced narcosis in a dose- and time-dependent manner but had no effect on induction time. PA potentiated hypothermia, depressed body weight gain, decreased the liver/body weight ratio, and prolonged the pentobarbital half-life in blood and brain, but had no effect on the brain pentobarbital level upon awakening. PA competitively inhibited in vitro pentobarbital metabolism. These results suggest that PA may be biotransformed into an active metabolite(s) and that glutathione (GSH) may be involved in the detoxification of PA. Inhibition of drug-metabolizing enzymes by PA may account for the enhancement of pentobarbital-induced narcosis.