Hepatic cholesterol metabolism as a function of carbon disulfide concentration and treatment with phenobarbital

Male F344 rats were exposed to carbon disulfide (CS2) at 0, 30, 75, 150, 300, or 600 ppm for 6 hr by inhalation in the presence or absence of 0.1% phenobarbital (PB) in the drinking water starting 5 days before exposure to CS2. Exposure to 600 ppm CS2 only resulted in a decrease in hepatic cholesterol synthesis and an increase in the liver-to-body-weight ratio (relative liver weight); however, it caused no histopathological damage and had little or no consistent effect on the concentration of hepatic cholesterol or on hepatic water content. Treatment with PB alone resulted in increases in the concentration of hepatic cholesterol and relative liver weight. Exposure to 300 ppm CS2 + PB or to 600 ppm CS2 + PB resulted in a decrease in hepatic cholesterol synthesis and increases in the concentration of hepatic cholesterol, relative liver weight, hepatic water content, and histopathological damage. A concentration-response relationship was demonstrated between exposure to CS2 only and decreased hepatic cholesterol synthesis. A concentration-response relationship also was demonstrated between exposure to CS2 in rats that had been treated with PB and decreased hepatic cholesterol synthesis, increased hepatic cholesterol concentration, increased relative liver weight, increased hepatic water content, and histopathological damage. Treatment with PB lowered the concentration of CS2 required to alter hepatic cholesterol metabolism. The reported observations are consistent with the theory that oxidative metabolism is involved in the expression of CS2-mediated alterations of hepatic cholesterol metabolism.