The relationship of the cyclic nucleotide system to inhibition of hepatic drug metabolism in Walker 256 carcinoma-bearing rats.
The hepatic cyclic nucleotide system and hepatic monooxygenase activity were examined in male rats following intramuscular or subcutaneous Walker 256 carcinosarcoma transplantation. Twelve days of continuous s.c. tumor growth significantly increased hepatic cyclic AMP levels, while levels of cyclic GMP, cytochrome P-450, cytochrome b-5, and p-chloro-N-methylaniline metabolism were significantly decreased. Whole blood from 6 day i.m. tumor-bearing rats incubated with liver slices obtained from non-tumor-bearing rats produced significantly elevated hepatic cyclic AMP levels concurrent with significantly depressed hepatic p-chloro-N-methylaniline metabolism. The chronological monitoring of tumor growth demonstrated a close temporal relationship between decreased cyclic AMP-dependent protein kinase activity, microsomal metabolism of p-chloro-N-methylaniline, and the mixed-function oxidase system. Significant changes in these hepatic enzyme systems occurred as early as 17 hours following tumor transplantation. At this same time, sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis revealed the appearance of a 184,000 molecular weight protein in hepatic tissue from all tumor-bearing rats. These studies are compatible with the proposal that the hepatic cyclic AMP system may modulate toxohormone effects on hepatic drug biotransformation.
D000818:Animals; D002279:Carcinoma 256, Walker / Q000378:metabolism*; D000242:Cyclic AMP / Q000502:physiology*; D006152:Cyclic GMP / Q000502:physiology*; D008099:Liver / Q000378:metabolism*; D008297:Male; D006899:Mixed Function Oxygenases / Q000378:metabolism; D009368:Neoplasm Transplantation; D051381:Rats; D014184:Transplantation, Homologous
D000242:Cyclic AMP; D006899:Mixed Function Oxygenases; D006152:Cyclic GMP