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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

Department of Medicine, University of Manitoba, and Manitoba Institute of Cell Biology, 100 Olivia St., Winnipeg, Manitoba, Canada R3E OV9

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 P-450 and NADPH-cytochrome c reductase 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 reductase 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 Murphy-Sturm lymphosarcoma and transplantation i.m. of Walker 256 carcinosarcoma caused similar alterations in hepatic microsomal function. Splenic microsomal electron transport system function, drug metabolism, and heme oxygenase did not demonstrate 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 lymphosarcoma-bearing rats, due to decreased hepatic microsomal electron transport system function. Hepatic cytochrome P-450 content is reduced, primarily due to decreased cytochrome P-450 synthesis. The resultant increase in size of the hepatic free heme pool may cause substrate-mediated induction of hepatic heme oxygenase in Murphy-Sturm lymphosarcoma-bearing rats.

¹ Supported by grants from the Medical Research Council of Canada and the National Cancer Institute of Canada.

² To whom requests for reprints should be addressed.

Received 12/ 2/81. Accepted 6/ 8/82.