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Suppression of Choline-deficient Diet-induced Hepatocyte Membrane Lipid Peroxidation in Rats by the Peroxisome Proliferators 4-Chloro-6-(2,3-xylidino)-2-pyrimidinylthio(N-ß-hydroxyethyl)acetamide and Di(2-ethylhexyl)phthalate¹

Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261

Many hypolipidemic peroxisome proliferators have been shown to induce liver tumors in rats after long-term feeding. In short-term assays, however, some of them prevent the development of -glutamyl transpeptidase-positive foci, the putative preneoplastic lesions, in the liver of carcinogen-initiated rats and inhibit the promoting effect of a cholinedeficient (CD) diet on these lesions. The CD diet-induced lipid peroxidation in the liver has been implicated as one of the underlying mechanisms of the promoting effect. In the present study, the effects of 4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio(N-ß-hydroxyethyl)acetamide (BR931) and di(2-ethylhexyl)phthalate (DEHP) on CD diet-induced liver membrane lipid peroxidation were investigated by determining the extents of conjugated diene formation. No evidence of lipid peroxidation was detected in the microsomal lipids of the liver after administration of BR931 or DEHP at concentrations of 0.16% and 1%, respectively, for 1, 2, and 4 wk. When added to a CD diet, both BR931 and DEHP effectively protected against the diet-induced lipid peroxidation. There was an increase in cellular glutathione levels after 4 wk and an increase in catalase activity after 2 wk in the liver of rats fed BR931 or DEHP. The levels of activity of the glutathione peroxidases and glutathione-s-transferase were significantly reduced. The results suggest that, in the acute stage, hypolipidemic peroxisome proliferator-induced effects of excess production of H₂O₂ and potential lipid peroxidation are balanced by stimulation of some cellular detoxifying systems. The inhibition of lipid peroxidation by hypolipidemic peroxisome proliferators may account for their inhibitory effects on the CD diet-induced promotion of preneoplastic foci.

¹ This work was supported by grants from the NIH (CA26556 and CA40062), Department of Health and Human Services.

² To whom requests for reprints should be addressed.

Received 1/14/86. Revised 4/ 8/86. Accepted 4/ 8/86.

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