Assessing the Metabolic and Toxic Effects of Anticonvulsant Doses of Polyunsaturated Fatty Acids on the Liver in Rats

Abstract

Polyunsaturated fatty acids (PUFA), at high doses, have been demonstrated to possess anticonvulsant properties in animal seizure models. Little is known, however, about the possible metabolic or adverse effects of PUFA at these high, anticonvulsant doses. The goal of the present study was to assess the metabolic and potential adverse effects of high-dose PUFA administration to rats. Adult male rats received a fatty acid mixture containing α-linolenic and linoleic acid in a 1 to 4 ratio, intraperitoneally, for 3 wk. After sacrifice, livers were isolated and analyzed for fatty acid composition and for mRNA expression of HMG-CoA lyase, catalase, and glutathione S-transferases A1 and A4, markers for ketosis, antioxidant defense, and phase II xenobiotic metabolism, respectively. Chronic administration of the PUFA mixture decreased hepatic levels of total lipids—and several fatty acids within total lipids—without altering mRNA expression of HMG-CoA lyase, a metabolic marker of ketosis. The PUFA mixture did not affect mRNA expression of catalase or glutathione S-transferases A1 and A4, which are involved in antioxidant defense and phase II xenobiotic metabolism. These findings suggest that PUFA, given for 3 wk at anticonvulsant doses, result in significant changes in liver lipid metabolism, but do not alter measured genetic markers of liver toxicity.

Funding for this study was provided by the Canadian Institutes of Health Research (CIHR) to W. M. Burnham, the CIHR New Investigator Award to J. P. McPherson, and the CIHR doctoral research award to A. Y. Taha.