Pro-oxidant effect of dehydroepiandrosterone in rats is mediated by PPAR activation.
DHEA-treatment exerts a dual effect, prooxidant or antioxidant, depending on the dosage and, therefore, on the tissue concentration reached. In agreement with previous studies showing a prooxidant effect of DHEA, here we show that pharmacological doses of DHEA produce increased H(2)O(2) levels and a marked reduction of GSH content in rat liver. DHEA, also increases both catalase (by 30%) and cytochrome-C-reductase (by 30%) activities in the liver cytosol. The effectiveness of the state of increased oxidative stress is also documented by changes in fatty acid pattern of the microsomal membranes. Moreover, DHEA, at high doses, enhances beta-oxidation, as demonstrated by an increase of acyl-CoA-oxidase activity and of cytochrome P450 4A content, confirming that it acts as a PPARs inducer. Both PPARs induction and proxidant effects completely disappear when DHEA is administered at lower doses. Seven days treatment (4 or 10 mg) is unable to affect either levels of proxidant species and of antioxidant molecules, or cytochrome P450 4A content and beta-oxidation. Prolonged DHEA treatment (4 mg/day) for three weeks not only is unable to affect PPARs activation and beta-oxidation, but it also exerts a protective effect against ADP/Fe(2+) induced lipid peroxidation. This latter result confirms the antioxidant effects of DHEA at low doses, as already previously documented.
Mastrocola
Raffaella
R
Department of Experimental Medicine and Oncology, General Pathology Section, Corso Raffaello 30, University of Turin, 10125 Turin, Italy.
Aragno
Manuela
M
Betteto
Silvia
S
Brignardello
Enrico
E
Catalano
Maria G
MG
Danni
Oliviero
O
Boccuzzi
Giuseppe
G
D000284:Administration, Oral; D000818:Animals; D002374:Catalase / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D003687:Dehydroepiandrosterone / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005227:Fatty Acids / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000032:analysis; D015227:Lipid Peroxidation / Q000187:drug effects*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism; D016877:Oxidants / Q000008:administration & dosage / Q000494:pharmacology*; D010084:Oxidation-Reduction; D010088:Oxidoreductases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D017392:Thiobarbituric Acid Reactive Substances / Q000032:analysis; D014157:Transcription Factors / Q000378:metabolism*
D005227:Fatty Acids; D016877:Oxidants; D018160:Receptors, Cytoplasmic and Nuclear; D017392:Thiobarbituric Acid Reactive Substances; D014157:Transcription Factors; D003687:Dehydroepiandrosterone; D006861:Hydrogen Peroxide; D010088:Oxidoreductases; D002374:Catalase; C028427:palmitoyl CoA oxidase; D009251:NADPH-Ferrihemoprotein Reductase; D005978:Glutathione