The nongenotoxic hepatocarcinogen Wy-14,643 is an uncoupler of oxidative phosphorylation in vivo.
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.
Keller
B J
BJ
Department of Pharmacology, University of North Carolina, Chapel Hill 27599-7365.
Bradford
B U
BU
Marsman
D S
DS
Cattley
R C
RC
Popp
J A
JA
Bojes
H K
HK
Thurman
R G
RG
D042962:Acyl-CoA Oxidase; D000255:Adenosine Triphosphate / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D002273:Carcinogens / Q000008:administration & dosage / Q000633:toxicity*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008830:Microbodies / Q000187:drug effects / Q000201:enzymology; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism; D010085:Oxidative Phosphorylation / Q000187:drug effects*; D010088:Oxidoreductases / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects; D011743:Pyrimidines / Q000008:administration & dosage / Q000633:toxicity*; D051381:Rats; D011916:Rats, Inbred F344; D014475:Uncoupling Agents / Q000633:toxicity*; D014508:Urea / Q000378:metabolism
D002273:Carcinogens; D011743:Pyrimidines; D014475:Uncoupling Agents; C006253:pirinixic acid; D000255:Adenosine Triphosphate; D014508:Urea; D010088:Oxidoreductases; D042962:Acyl-CoA Oxidase