Hypolipidemic agents alter hepatic mitochondrial respiration in vitro

The direct effects of three different classes of structurally diverse hypolipidemic agents on respiration were studied in mitochondria isolated from donor Sprague-Dawley rats. Two classes of peroxisome proliferators (i.e. plasticizers and hypolipidemic hormones and drugs) and one class of peroxisome inhibitors (i.e. anti-psychotic drugs) were studied. The phthalate ester plasticizers dibutylphthalate, ethylhexanoic acid and di(2-ethylhexyl) adipate, the hypolipidemic hormones or drugs dehydro-epiandrosterone (DHEA), thyroxine (T4), triiodothyronine (T3), gemfibrozil, clofibrate and naphthoflavone, and the anti-psychotic drugs chlorpromazine, thioridazine and fluphenazine were studied. As the dose of the plasticizer dibutylphthalate increased from 8 to 200 mumol/l, there was a decrease (P < 0.05) in state 3 (+ADP) respiration and in the respiratory control ratio for both substrates tested. The anti-psychotic drug chlorpromazine decreased state 3 malate + pyruvate-supported respiration and increased state 3 succinate-supported respiration. As the concentration of all three anti-psychotic drugs increased, there was a linear increase in state 4 respiration (-ADP) and a decrease in the respiratory control ratio for both substrates tested. As the dose of the hypolipidemic agents DHEA, gemfibrozil and T4 increased, there was a linear reduction in state 3 malate + pyruvate-supported respiration. However, when succinate was used as the substrate to support respiration, only the thyroid hormones significantly decreased state 3 respiration. Gemfibrozil, T4 and T3 increased state 4 respiration, regardless of the substrate used. As the dose of clofibrate, gemfibrozil, and the thyroid hormones increased, there was a linear reduction in the respiratory control ratio for both substrates tested.(ABSTRACT TRUNCATED AT 250 WORDS)