Benzene modulation of liver cell structure and heme-cytochrome P-450 metabolism

Rats were treated with subcutaneous benzene, 440 mg/kg, for 3 and 14 days (acute and chronic exposure). Their hepatic cell heme and drug metabolizing enzymes as well as cell morphology by electron microscopy were examined. Electron micrographs of hepatocytes from the benzene-treated rats showed disruption of the mitochondrial membranes and mitochondrial structure. The activity of the rate-limiting enzyme of heme synthesis, delta-aminolevulinic acid synthase was increased 1.5-2-fold in both acutely and chronically exposed animals. In the acutely exposed animals, there was a 50% inhibition of the second enzyme of heme synthesis, delta-aminolevulinic acid dehydratase, while in the chronically exposed there was 70% inhibition. The rate-limiting enzyme of heme degradation, heme oxygenase, was increased more than twofold in both sets of animals. Cytochrome P-450 content was increased 77% in the acutely treated and 35% in the chronic. Associated with this increase in cytochrome P-450 content, there was a twofold increase in both arylhydrocarbon hydroxylase and aminopyrine-N-demethylase activities after acute exposure. During chronic exposure, however, there was a return to normal of the aminopyrine-N-demethylase activity and a decline in arylhydrocarbon hydroxylase induction to 1.25 times control. Results from this study indicate that benzene exposure produces adverse effects on mitochondria and heme metabolism. The precise relationships of these disturbances to benzene toxicity are not clear; however the possible role of heme oxygenase and degree of cytochrome P-450 induction are considered. Finally, the alterations of arylhydrocarbon hydroxylase and aminopyrine-N-demethylase activities point to a potential mechanism of differential toxicity from metabolites of benzene.