The Nongenotoxic Hepatocarcinogen Wy-14,643 Is an Uncoupler of Oxidative Phosphorylation in Vivo

• Published in: Toxicology and applied pharmacology Vol. 119; no. 1; pp. 52 - 58
• Main Authors: Keller, B.J., Bradford, B.U., Marsman, D.S., Cattley, R.C., Popp, J.A., Bojes, H.K., Thurman, R.G.
• Format: Journal Article
• Language: English
• Published: San Diego, CA Elsevier Inc 01.03.1993; Elsevier
• Subjects: Acyl-CoA Oxidase; Adenosine Triphosphate - metabolism; Analysis of Variance; Animals; Biological and medical sciences; Carcinogenesis, carcinogens and anticarcinogens; Carcinogens - administration & dosage; Carcinogens - toxicity; Chemical agents; Liver - drug effects; Liver - metabolism; Male; Medical sciences; Microbodies - drug effects; Microbodies - enzymology; Mitochondria, Liver - drug effects; Mitochondria, Liver - metabolism; Oxidative Phosphorylation - drug effects; Oxidoreductases - metabolism; Oxygen Consumption - drug effects; Pyrimidines - administration & dosage; Pyrimidines - toxicity; Rats; Rats, Inbred F344; Tumors; Uncoupling Agents - toxicity; Urea - metabolism; Carcinogen; Vertebrata; Chronic; Mammalia; Oxidative phosphorylation; Rat; Toxicity; Animal; Rodentia; Epigenetics; Mechanism of action; Peroxisome proliferator
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1006/taap.1993.1043

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 μM) 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 peroxtsomes. 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 μmol/g/hr were increased by over 20 μmol/gIhr 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 μmol/g/hr in control livers to 13 μmol/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.