Alterations in microsomal drug metabolism and heme oxygenase activity in isolated hepatic parenchymal and sinusoidal cells in Murphy-Sturm lymphosarcoma-bearing rats.

Previous studies have demonstrated that Murphy-Sturm lymphosarcoma-bearing rats have significantly decreased hepatic microsomal cytochrome P-450 and NADPH-cytochrome c reductase activity, a consequent decreased capacity for oxidative microsomal drug metabolism, and increased microsomal heme oxygenase activity. Splenic microsomes obtained from tumor-bearing rats did not display similar changes. To define the cellular locus of these changes, preparations of hepatic parenchymal and hepatic sinusoidal cells were obtained from control and Murphy-Sturm lymphosarcoma-bearing rats and examined for alterations in microsomal parameters of drug metabolism and heme oxygenase. In hepatic parenchymal cell populations, heme oxygenase activity was significantly increased in tumor-bearing rats (0.046 nmol/mg/min vs. 0.019 nmol/mg/min, control, p less than 0.01) while other microsomal parameters were all significantly decreased in activity (cytochrome P-450, 0.25 nmol/mg vs 0.70 nmol/mg, control, p less than 0.001; NADPH-cytochrome c reductase, 24.4 nmol/mg/min vs 42.6 nmol/mg/min, control, p less than 0.005; benzo(a) pyrene hydroxylase, 0.230 nmol/mg/min vs. 0.518 nmol/mg/min, control, p less than 0.001). These results are similar to those obtained with microsomes from whole liver. Conversely, while hepatic sinusoidal cell preparations also demonstrated increased heme oxygenase activity (0.134 nmol/mg/min vs 0.079 nmol/mg/min, control, p less than 0.01), all other hepatic sinusoidal cell microsomal parameters were not appreciably altered in tumor-bearing animals. The results indicate that the major effect of the tumor-bearing state on hepatic microsomal heme and drug metabolism is on the parenchymal cell, and not the sinusoidal cell population.