title: Effects of Doxorubicin and Fenofibrate on the activities of NADH oxidase and citrate synthase in mice.
abstract: Doxorubicin (Dox) has widely been used as an anticancer drug, but its use is limited by serious toxicity to the heart, kidney and liver. Mitochondrial dysfunction is one of the potential mechanisms of toxicity but not fully understood. Fenofibrate, one of the peroxisome proliferator-activated receptor-alpha (PPARα) ligands, is involved in lipid metabolism which takes place primarily in the mitochondria, so mitochondrial function may be affected by fenofibrate. Therefore, we investigated the effects of DOX and fenofibrate on activities of both mitochondrial citrate synthase and NADH oxidase, which are marker enzymes in the tricarboxylic acid (TCA) cycle and a measure of the complex I-III-IV activity in electron transport chain, respectively. Dox (15 mg/kg) and/or fenofibrate (100 mg/kg/day) were administered to mice for 3 or 14 days, and the activities of citrate synthase and NADH oxidase were measured. Our study showed that Dox significantly inhibits the activity of citrate synthase while fenofibrate induces the activity. Similar to citrate synthase, NADH oxidase activity was also induced by fenofibrate except in spleen but inhibited by Dox except in the heart and liver. Furthermore, fenofibrate not only protects citrate synthase activity from Dox-induced toxicity in the ventricle but also significantly rescues NADH oxidase activity in the kidney. These results reveal the actions of fenofibrate and Dox on the mitochondria, and the underlying mechanism may be related to the toxicity of Dox, which has clinical implications in the side effects of Dox treatment by modulation of mitochondrial function.
authors.affiliation: Department of Biochemistry & Molecular Biology, School of Basic Medical Sciences, Zhengzhou University, Henan, China.
authors.forename: Chun-Xia
authors.initials: CX
authors.lastname: Yao
authors.forename: Wen-Yan
authors.initials: WY
authors.lastname: Li
authors.forename: Shu-Feng
authors.initials: SF
authors.lastname: Zhang
authors.forename: Shan-Feng
authors.initials: SF
authors.lastname: Zhang
authors.forename: Hai-Feng
authors.initials: HF
authors.lastname: Zhang
authors.forename: Ming-Xi
authors.initials: MX
authors.lastname: Zang
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000633:toxicity*; D002950:Citrate (si)-Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002952:Citric Acid Cycle; D004317:Doxorubicin / Q000008:administration & dosage / Q000633:toxicity*; D011345:Fenofibrate / Q000008:administration & dosage / Q000494:pharmacology*; D008024:Ligands; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009928:Organ Specificity; D047493:PPAR alpha / Q000378:metabolism; D020011:Protective Agents / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D000903:Antibiotics, Antineoplastic; D008024:Ligands; D009097:Multienzyme Complexes; D047493:PPAR alpha; D020011:Protective Agents; D004317:Doxorubicin; C023107:NADH oxidase; D009247:NADH, NADPH Oxidoreductases; D002950:Citrate (si)-Synthase; D011345:Fenofibrate