Peroxisomal proliferators inhibit acyl CoA synthetase and stimulate protein kinase C in vivo.
The mechanism by which hypolipidemic drugs and industrial plasticizers cause hepatic tumors in rodents remains unknown. It is known, however, that protein kinase C is elevated during hepatic cell turnover, and sustained cellular replication is correlated with an increased incidence of hepatic tumors. Therefore, several peroxisomal proliferators varying in their tumorigenic potency in chronic feeding studies were examined for their ability to increase protein kinase C activity. Intragastric administration of (4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio)acetic acid (Wy-14,643; 100 mg/kg) increased protein kinase C activity threefold in 5 hr and fivefold in 10 hr. Perfluorooctanoate also increased protein kinase C activity significantly in microsomes at 5 hr. Wy-14,643 and perfluorooctanoate also diminished acyl CoA synthetase activity significantly, with Wy-14,643 exhibiting competitive type kinetics. Other peroxisomal proliferators were examined [e.g., ciprofibrate, clofibrate, 2-ethylhexanol, valproate, and di(ethylhexyl)phthalate (DEHP)] and collectively an inverse relationship between their ability to stimulate protein kinase C activity and inhibit acyl CoA synthetase was observed (r = -0.80). All chemicals examined had no direct effect on protein kinase C activity in vitro. Interestingly, those compounds which are more potent as hepatocarcinogens (e.g., Wy-14,643) in long-term feeding studies decreased acyl CoA synthetase and elevated protein kinase C activity to a greater extent than their weaker counterparts (e.g., DEHP). It is proposed that inhibition of acyl CoA synthetase by peroxisomal proliferators elevates free fatty acids which stimulate protein kinase C activity and ultimately promote tumor formation.
Bojes
H K
HK
Department of Pharmacology, University of North Carolina at Chapel Hill 27599-7365.
Thurman
R G
RG
D042962:Acyl-CoA Oxidase; D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D002374:Catalase / Q000032:analysis; D002455:Cell Division / Q000187:drug effects; D003066:Coenzyme A Ligases / Q000037:antagonists & inhibitors*; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D008297:Male; D008830:Microbodies / Q000187:drug effects* / Q000201:enzymology; D008862:Microsomes, Liver / Q000201:enzymology; D010088:Oxidoreductases / Q000032:analysis; D011493:Protein Kinase C / Q000187:drug effects*; D011743:Pyrimidines / Q000633:toxicity; D051381:Rats; D011916:Rats, Inbred F344; D012097:Repressor Proteins; D029701:Saccharomyces cerevisiae Proteins; D000098859:Long-Chain-Fatty-Acid-CoA Ligase
D002273:Carcinogens; D011743:Pyrimidines; D012097:Repressor Proteins; D029701:Saccharomyces cerevisiae Proteins; C006253:pirinixic acid; D010088:Oxidoreductases; D002374:Catalase; D042962:Acyl-CoA Oxidase; D011493:Protein Kinase C; D003066:Coenzyme A Ligases; C090799:FAA2 protein, S cerevisiae; D000098859:Long-Chain-Fatty-Acid-CoA Ligase