Abstract
Microspectrophotometry has been used to evaluate the distribution of some selectively inducible species of microsomal cytochrome P-450 in the rat liver lobule. Centrilobular increases in cytochrome P-450 concentration evoked by pretreatment with phenobarbitone or isosafrole contrasted markedly with the periportal induction produced by 3-methylcholanthrene. Lobular and lobar variations in drug-metabolising enzyme activity were measured, and their significance is discussed. Some oxygen-containing heterocyclic compounds were evaluated for their acute toxicity in rats. Several furans and methylenedioxyphenyls produced a classical hepatotoxic response, with fatty degeneration and necrosis. Benzofuran administration resulted in a clinical and ultrastructural picture of intrahepatic cholestasis, but without demonstrable stagnation of bile flow. Renal toxicity followed pretreatment with benzofuran or safrole, and diminution of splenic erythropoiesis occurred after the injection of various furans or methylenedioxyphenyls. Benzofuran, dibenzofuran and trans-stilbene oxide were potent inducers of hepatic microsomal epoxide hydrolase activity, corresponding with an increase in a polypeptide band of 48000 MW upon SDS gel electrophoresis. These compounds also induced a band of about 52000 MW. Pretreatment with furan or benzofuran caused a loss of microsomal cytochrome P-450, the latter with a concomitant increase in haem oxygenase activity. Dibenzofuran induced haem oxygenase, but did not lower cytochrome P-450 concentrations. Many of the effects of benzofuran were potentiated by pretreatment with inducers of cytochrome P-450. Administration of trans-stilbene oxide or methylenedioxyphenyls increased hepatic cytochrome P-450 levels; the latter also increased a polypeptide band of 53000 MW on gel electrophoresis. Possible mechanisms of toxicity of some oxygen heterocycles, particularly benzofuran, are discussed in the light of the interrelationship of these endoplasmic reticulum protein changes. Tritiated benzofuran was excreted by the rat in considerable quantities in both urine and faeces. Radioactivity was detected in several tissues, and was retained in the spleen one week after pretreatment. Chromatographic analysis suggests that a major route of benzofuran metabolism may involve cleavage of the furan ring.