Inhibition of lipopolysaccharide-induced liver injury in rats treated with a hepatic drug-metabolizing enzyme inducer p,p'-DDT

摘要

? 2014 Elsevier GmbH. ? 2014 Elsevier GmbH. Hepatocellular hypertrophy in association with drug-metabolizing enzyme induction is considered to be an adaptive change associated with drug metabolism. To improve our understanding of liver hypertrophy, we determined the effect of a single ip injection of either lipopolysaccharide (LPS) or vehicle in male F344 rats with hepatocellular hypertrophy induced by oral delivery of p,. p'-DDT for 2 weeks. The rats were sacrificed 3. h or 24. h after LPS or vehicle injection. LPS induced a focal hepatocellular necrosis in rats fed the control diet. When rats pre-treated with p,. p'-DDT were injected with LPS, necrotic foci surrounded by ballooned hepatocytes were observed in the liver. The change was consistent with reduced LPS-mediated increases in plasma hepatic biomarkers, neutrophil influx, and apoptosis, and also associated with hepatic mRNA levels of TNF-α, CYPs, and NOS2. By contrast, when combined with p,. p'-DDT and LPS, faint hepatocellular fatty change was extended, together with a synergistic increase in total blood cholesterol. These results suggest that hepatocytes exposed to p, p'-DDT are protected from the cell-lethal toxic effects of an exogenous stimulus, resulting in cell ballooning rather than necrosis in association with reduced inflammation and apoptosis, but compromised by an adverse effect on lipid metabolism. Hepatocellular hypertrophy in association with drug-metabolizing enzyme induction is considered to be an adaptive change associated with drug metabolism. To improve our understanding of liver hypertrophy, we determined the effect of a single ip injection of either lipopolysaccharide (LPS) or vehicle in male F344 rats with hepatocellular hypertrophy induced by oral delivery of p,. p'-DDT for 2 weeks. The rats were sacrificed 3. h or 24. h after LPS or vehicle injection. LPS induced a focal hepatocellular necrosis in rats fed the control diet. When rats pre-treated with p,. p'-DDT were injected with LPS, necrotic foci surrounded by ballooned hepatocytes were observed in the liver. The change was consistent with reduced LPS-mediated increases in plasma hepatic biomarkers, neutrophil influx, and apoptosis, and also associated with hepatic mRNA levels of TNF-α, CYPs, and NOS2. By contrast, when combined with p,. p'-DDT and LPS, faint hepatocellular fatty change was extended, together with a synergistic increase in total blood cholesterol. These results suggest that hepatocytes exposed to p, p'-DDT are protected from the cell-lethal toxic effects of an exogenous stimulus, resulting in cell ballooning rather than necrosis in association with reduced inflammation and apoptosis, but compromised by an adverse effect on lipid metabolism.