title: Raloxifene affects fatty acid oxidation in livers from ovariectomized rats by acting as a pro-oxidant agent.
abstract: Estrogen deficiency accelerates the development of several disorders including visceral obesity and hepatic steatosis. The predisposing factors can be exacerbated by drugs that affect hepatic lipid metabolism. The aim of the present work was to determine if raloxifene, a selective estrogen receptor modulator (SERM) used extensively by postmenopausal women, affects hepatic fatty acid oxidation pathways. Fatty acids oxidation was measured in the livers, mitochondria and peroxisomes of ovariectomized (OVX) rats. Mitochondrial and peroxisomal β-oxidation was inhibited by raloxifene at a concentration range of 2.5-25 μM. In perfused livers, raloxifene reduced the ketogenesis from endogenous and exogenous fatty acids and increased the β-hydroxybutyrate/acetoacetate ratio. An increase in ¹⁴CO₂ production without a parallel increase in the oxygen consumption indicated that raloxifene caused a diversion of NADH from the mitochondrial respiratory chain to another oxidative reaction. It was found that raloxifene has a strong ability to react with H₂O₂ in the presence of peroxidase. It is likely that the generation of phenoxyl radical derivatives of raloxifene in intact livers led to the co-oxidation of NADH and a shift of the cellular redox state to an oxidised condition. This change can perturb other important liver metabolic processes dependent on cellular NADH/NAD⁺ ratio.
authors.affiliation: Laboratory of Biological Oxidations, Department of Biochemistry, University of Maringá, 87020900 Maringá, Brazil.
authors.forename: E R
authors.initials: ER
authors.lastname: Martins-Maciel
authors.forename: L B
authors.initials: LB
authors.lastname: Campos
authors.forename: C L
authors.initials: CL
authors.lastname: Salgueiro-Pagadigorria
authors.forename: A
authors.initials: A
authors.lastname: Bracht
authors.forename: E L
authors.initials: EL
authors.lastname: Ishii-Iwamoto
mesh_terms: D000214:Acyl Coenzyme A / Q000378:metabolism; D042962:Acyl-CoA Oxidase / Q000378:metabolism; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology / Q000378:metabolism* / Q000503:physiopathology; D018450:Disease Progression; D015914:Estrogen Replacement Therapy / Q000009:adverse effects; D005227:Fatty Acids / Q000378:metabolism*; D005234:Fatty Liver / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D006861:Hydrogen Peroxide / Q000737:chemistry; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008930:Mitochondria, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D010052:Ovariectomy / Q000009:adverse effects; D016877:Oxidants / Q000009:adverse effects* / Q000737:chemistry; D010084:Oxidation-Reduction; D009195:Peroxidase / Q000378:metabolism; D020675:Peroxisomes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D020849:Raloxifene Hydrochloride / Q000009:adverse effects* / Q000737:chemistry; D051381:Rats; D020845:Selective Estrogen Receptor Modulators / Q000009:adverse effects* / Q000737:chemistry
chemical_list: D000214:Acyl Coenzyme A; D005227:Fatty Acids; D016877:Oxidants; D020845:Selective Estrogen Receptor Modulators; D020849:Raloxifene Hydrochloride; D006861:Hydrogen Peroxide; D009195:Peroxidase; D042962:Acyl-CoA Oxidase