Changes in the rat liver drug metabolizing system during a short thiobenzamide feeding cycle.
The changes in the hepatic drug metabolizing enzymes induced by the liver tumor promoter thiobenzamide (TB) were investigated. Feeding of TB to rats at a promoting regimen (1 g/kg of diet for 2 weeks) resulted in a significant decrease in the amount of liver microsomal cytochrome P-450 and of total heme. Also, the activity of cytochrome P-450 dependent monooxygenases (aminopyrine demethylase, arylhydrocarbonmonooxygenase and ethoxycoumarindeethylase) and FAD-containing monoxygenase (N,N-dimethylaniline N-oxidase and TB S-oxidase) were depressed. By contrast, phase II enzymes such as epoxide hydrase, UDP-glucuronyl transferase and GSH-transferase were significantly induced. This overall change in the drug metabolizing system was associated with tolerance of the liver towards a high necrogenic dose of TB itself as well as with an increase of mitoses and apoptosis of the hepatocytes. The findings suggest a possible relationship between this TB-induced adaptive response and the promoting activity of the compound on liver carcinogenesis.
Chieli
E
E
Istituto di Patologia Generale dell'Universita' di Pisa, Scuola Medica, Italy.
Saviozzi
M
M
Malvaldi
G
G
D000220:Adaptation, Biological / Q000187:drug effects; D000577:Amides / Q000633:toxicity*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D008938:Mitosis / Q000187:drug effects; D006899:Mixed Function Oxygenases / Q000378:metabolism; D009245:NADH Dehydrogenase / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D013854:Thioamides / Q000633:toxicity*
D000577:Amides; D013854:Thioamides; C015539:thiobenzamide; D004247:DNA; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D009245:NADH Dehydrogenase