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)
Department of Food, Nutrition, and Food Service Management, University of North Carolina at Greensboro 27412, USA.
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D000244:Adenosine Diphosphate / Q000378:metabolism; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D008830:Microbodies / Q000187:drug effects; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects*; D010766:Phosphorylation; D010968:Plasticizers / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D014150:Antipsychotic Agents; D000960:Hypolipidemic Agents; D010968:Plasticizers; D000244:Adenosine Diphosphate