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 (PPARa) 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. Doxorubicin (Dox), an anthracycline anticancer drug, is effectively and frequently used to treat a variety of tumour malignancies [1,2]. Unfortunately, its clinical use is limited by its serious toxicity to the heart, brain, kidney and liver. Over the past years, a great deal has been learnt about the mechanisms of its toxicity; for example, previous studies showed that Dox not only inhibits both DNA and RNA synthesis but also targets key cellular enzymes such as topoisomerases I and II [3], which results in DNA damage, G1 and G2 growth arrest, and induction of apoptosis. Accumulating evidence shows that Dox can cause mitochondrial dysfunction [4-6] but its precise mechanisms remain unknown.Mitochondria functions as primary energy providers to relentlessly produce enough ATP to sustain life processes through oxidative phosphorylation, which is tightly coupled to the tricarboxylic acid (TCA) cycle [7,8]. Citrate synthase and NADH oxidase, which are mitochondrial marker enzyme in the TCA cycle and a measure of the complex I-III-IV activity in electron transport chain, respectively [9], are key markers of mitochondrial function [10,11]. Most notably, complexes I (NADH: ubiquinone oxidoreductase), the first electron transport complexes, was shown to be inactivated by Dox through a superoxide-dependent mechanism [12]. These studies by Kotamraju et al. have provided compelling suggestions for establishing D...

Fenofibrate unexpectedly induces cardiac hypertrophy in mice lacking MuRF1

“…Because fenofibrate can affect cardiac mitochondrial respiration [28–30], we next investigated mitochondria number and ultrastructure in MuRF1−/− hearts after fenofibrate treatment (Fig. 3).…”

Cardiac cytochrome c and cardiolipin depletion during anthracycline-induced chronic depression of mitochondrial function

“…Our starting hypothesis was based on DOX effects on respiratory complexes and mitochondrial carriers (Cheneval et al, 1983;Davies and Doroshow, 1986;Nicolay and de Kruijff, 1987;Oliveira and Wallace, 2006;Yao et al, 2011). We had anticipated that OXPHOS enzymatic reserves were lower in the heart or, alternatively, that OXPHOS in heart mitochondria was dependent in one particular respiratory complex, more so than liver or kidney.…”

“…Additionally, DOX has been reported to interfere with Complex III and IV (Nicolay and de Kruijff, 1987), the phosphate carrier (Cheneval et al, 1983) and the adenine nucleotide translocator (ANT) (Oliveira and Wallace, 2006), among other mitochondrial proteins. Although most of the studies report effects in heart or cardiac-like models, some of DOX effects are shared among other tissues (Nicolay and de Kruijff, 1987;Santos et al, 2002;Yao et al, 2011). Still, DOX-induced toxicity preferentially occurs in the heart.…”

Ameliorative effect of naringin against doxorubicin-induced acute cardiac toxicity in rats

“…One of the well-known mechanisms of Dox is the inhibition of macromolecular biosynthesis by DNA intercalation (Momparler et al, 1976) as well as its cytotoxic action is manifested by the inhibition of topoisomerse II (Bodley et al, 1989). Also, few earlier reported studies demonstrated the role of Dox in escalating free radical production which leads to cytotoxicity in various organs like heart, brain, liver, and kidney (Tacar et al, 2013;Yao et al, 2011). In the current study, we evaluated the potential effect of NR to ameliorate the Dox-induced acute cardiac toxicity in rats.…”