The Nongenotoxic Hepatocarcinogen Wy-14,643 Is an Uncoupler of Oxidative Phosphorylation in Vivo
| Autor: | Blair U. Bradford, Ronald G. Thurman, Heidi K. Bojes, Barbara J. Keller, Daniel S. Marsman, James A. Popp, Russell C. Cattley |
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| Rok vydání: | 1993 |
| Předmět: |
Male
medicine.medical_specialty Uncoupling Agents Mitochondria Liver Oxidative phosphorylation Biology Toxicology Microbodies Oxidative Phosphorylation chemistry.chemical_compound Adenosine Triphosphate Oxygen Consumption In vivo Internal medicine medicine Animals Urea Acyl-CoA oxidase Pharmacology Analysis of Variance Oxidase test Peroxisome Rats Inbred F344 Rats Pyrimidines Endocrinology Liver chemistry Toxicity Carcinogens Acyl-CoA Oxidase Oxidoreductases Adenosine triphosphate |
| Zdroj: | Toxicology and Applied Pharmacology. 119:52-58 |
| ISSN: | 0041-008X |
| Popis: | Wy-14,643 is a potent nongenotoxic hepatic carcinogen and peroxisome proliferator in rodents; however, the mechanism by which it causes tumors remains unknown. In previous work it was demonstrated that Wy-14,643 caused a dose-dependent uncoupling of oxidative phosphorylation (half-maximal effect = 100 microM) in isolated mitochondria (Keller et al., 1992, Biochim. Biophys. Acta, 1162, 237-244); therefore, the purpose of this study was to determine if uncoupling occurred in vivo under conditions which lead ultimately to tumors. Rats were fed Wy-14,643 (0.1%) in ground laboratory chow for 1, 21, 75, and 105 days. As expected, activity of the peroxisomal marker enzyme, acyl-CoA oxidase, was increased about eightfold in liver homogenates during the first 3 weeks of treatment, confirming the induction of peroxisomes. Basal rates of oxygen uptake by the perfused liver were increased significantly by Wy-14,643 treatment at all time points studied, consistent with the hypothesis that oxidative phosphorylation was uncoupled. Basal rates of oxygen uptake of about 130 mumol/g/hr were increased by over 20 mumol/g/hr in rats fed Wy-14,643 in their diet for 10 weeks. Concomitantly, rates of urea synthesis from ammonia, a process highly dependent on ATP supply, were reduced significantly in the perfused liver from 104 mumol/g/hr in control livers to 13 mumol/g/hr in livers from rats treated with Wy-14,643 for 75 days. Taken together, these data indicate that energy supply is disrupted in vivo due to uncoupling of oxidative phosphorylation by Wy-14,643. |
| Databáze: | OpenAIRE |
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