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 mumol/kg] to control 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 vacuoles around the periportal area. Electron microscopy showed an increased number of vacuoles and autophagosomes containing organelle-like material. 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, respectively. 5-Aminolevulinic acid dehydrase decreased 25% from controls, and metal chelatase activities decreased to 25% of the PB-treated group. Injection of As(III) alone resulted in a mild increase in lipid-containing vacuoles around the periportal zone, a moderate loss of glycogen in midzonal areas, and, by electron microscopy, a dilatation of the bile canaliculi and an increase of the number of myelin-like structures. CYP450 content and the O-dealkylation of ethoxy- and pentoxyresorufin and N-demethylation of benzphetamine all decreased between 30 and 50%. These results demonstrate the greater susceptibility of the liver to injury following PB with compounds not requiring metabolic activation. The metabolic basis of these changes are unclear but may result from an increased demand for metabolic energy due to PB induction and decreased adenosine triphosphate synthesis caused by arsenic.