ENHANCED ARSENITE-INDUCED HEPATIC MORPHOLOGICAL AND BIOCHEMICAL-CHANGES IN PHENOBARBITAL-PRETREATED RATS

Changes in liver morphology and biochemistry have been assessed 16 hr after a sc injection of sodium arsenite [As(III), 75 mu mol/ kg] to co ntrol and phenobarbital (PB)-pretreated (80 mg/kg, ip daily for 3 days ) adult male Wistar rats. As(III) administration to PB-pretreated rats [PB + As(III)] caused hydropic degeneration, total loss of glycogen, necrosis in some centrilobular zones, and an increase in lipid vacuole s around the periportal area. Electron microscopy showed an increased number of vacuoles and autophagosomes containing organelle-like materi al. There was a 30% decrease in total hepatic cytochrome P-450 (CYP450 ). O-dealkylation of ethoxy- and pentoxyresorufin and N-demethylation of benzphetamine decreased to 42, 32, and 30% of control values, respe ctively. 5-Aminolevulinic acid dehydrase decreased 25% from control, a nd metal chelatase activities decreased to 25% of the PR-treated group . Injection of As(III) alone resulted in a mild increase in lipid-cont aining vacuoles around the periportal zone, a moderate loss of glycoge n in midzonal areas, and, by electron microscopy, a dilatation of the bile canaliculi and an increase of the number of myelin-like structure s. CYP450 content and the O-dealkylation of ethoxy- and pentoxyresoruf in and N-demethylation of benzphetamine all decreased between 30 and 5 0%. These results demonstrate the greater susceptibility of the liver to injury following PB with compounds not requiring metabolic activati on. The metabolic basis of these changes are unclear but may result fr om an increased demand for metabolic energy due to PB induction and de creased adenosine triphosphate synthesis caused by arsenic.