Alterations in Hepatic and Splenic Microsomal Electron Transport System Components, Drug Metabolism, Heme Oxygenase Activity, and Cytochrome P-450 Turnover in Murphy-Sturm Lymphosarcoma-bearing Rats1

Hepatic and splenic microsomal electron transport system function, microsomal heme oxygenase activity, and microsomal drug metabolism have been examined in male Wistar rats bearing Murphy-Sturm lymphosarcoma 2 to 15 days following i.m. tumor transplantation. Hepatic microsomal cytochrome P450 and NADPH-cytochrome c reducÃ-ase activity decreased significantly [cytochrome P-450 nadir was 0.49 ± .07 (S.E.) nmol/mg at 10 days as compared with 1.21 ±0.10 for control (p < 0.001); NADPH-cytochrome c reducÃ-ase nadir was 38.7 ±3.5 nmol/min/mg at 10 days as compared with 75.3 ±4.1 for control (p < 0.001)], and hepatic microsomal oxidative drug metabolism was also significantly diminished [benzo(a)pyrene hydroxylase nadir was 0.35 ±0.09 nmol/min/mg at 10 days as compared with 1.28 ±0.36 for control (p < 0.05); aminopyrine demethylase nadir was 0.60 ±0.27 nmol/ hr/mg at 10 days as compared with 2.85 ±1.40 for control (p < 0.01 )]. Conversely, hepatic microsomal heme oxygenase activity was significantly increased (peak was 0.092 ±0.008 nmol/min/mg at 10 days as compared with 0.038 ±0.014 for control (p < 0.001)]. Transplantation i.v. or i.p. of MurphySturm lymphosarcoma and transplantation i.m. of Walker 256 carcinosarcoma caused similar alterations in hepatic micro somal function. Splenic microsomal electron transport system function, drug metabolism, and heme oxygenase did not dem onstrate these changes, nor could they be wholly reproduced in liver or spleen by transplantation of irradiated tumor cells or 105,000 x g Murphy-Sturm lymphosarcoma cell supernatant. Using double-label isotope techniques, the relative rates of hepatic cytochrome P-450 synthesis and degradation were both found to be significantly decreased in Murphy-Sturm lymphosarcoma-bearing rats as compared with control rats. These results suggest that the capacity for hepatic microsomal oxidative drug metabolism is reduced in Murphy-Sturm lym phosarcoma-bearing rats, due to decreased hepatic micro somal electron transport system function. Hepatic cytochrome P-450 content is reduced, primarily due to decreased cyto chrome P-450 synthesis. The resultant increase in size of the hepatic free heme pool may cause substrate-mediated induc tion of hepatic heme oxygenase in Murphy-Sturm lymphosar coma-bearing rats.