Protective effect of dietary selenium supplementation on delayed cardiotoxicity of adriamycin in rat: is PHGPX but not GPX involved?

The involvement of Se enzymes in the protection against the oxidative stress induced by adriamycin (ADR) in rat heart has been studied in animals fed for 10 weeks at three different levels of Se content (low = 0.02 ppm; normal = 0.5 ppm; high = 1.0 ppm) and receiving a weekly injection of 3 mg/kg ADR for 4 weeks. ECG (QaT duration) and contractility of isolated atria were measured. The high-Se diet showed a significant protection on both parameters. To assess the hypothesis that an increase of specific activity of antioxidant Se enzymes may account for the cardioprotective effect of selenium, glutathione peroxidase (GPX), and phospholipid hydroperoxide glutathione peroxidase (PHGPX) were tested. The assays were performed on ventricles isolated from treated rats. At the end of the experimental period, GPX (cytosolic enzyme) did not show any significant difference between controls and ADR-treated at any level of Se content, thus excluding its involvement in the cardioprotection observed in high-Se ADR-treated animals. PHGPX, which is present both in cytosol and in the cell membrane, showed a trend to increase its activity in the presence of ADR treatment only in the membrane fraction; however, the statistical significance was reached only in the low-Se group (+100%). This observation suggests that membrane PHGPX might be involved in the cellular mechanism of adaptation of the heart to the toxic effects of ADR; however, the behavior of these enzymes does not seem to account for the significant protection of selenium supplementation both on ECG and on contractile indices of ADR cardiotoxicity.(ABSTRACT TRUNCATED AT 250 WORDS)

The spin trap alpha-phenyl-tert-butyl nitrone protects against myelotoxicity and cardiotoxicity of adriamycin while preserving the cytotoxic activity.

The possibility of preventing the myelo- and cardiotoxicity of adriamycin (ADR), was explored in in vivo experiments in the rat. Assuming that free radicals play a key role in the ADR organotoxicity, a new anti-radical approach was set up by administering a spin trapping compound (PBN) which is taken up by the cells and specifically interacts with radicals. ADR was given i.v., 3 mg/kg every 3rd day for 3 times. PBN was continuously administered throughout the persistence time of ADR in myocardium (15 days). Serial ECG and leukocyte counting were performed during 10 weeks, then hearts were isolated and Langendorff-perfused; functional parameters (heart rate, contractility, coronary flow) were evaluated. PBN improved ECG and prevented the myelotoxicity, while functional parameters were not significantly different from those of control. Cytotoxicity was evaluated in vitro in 3 different human tumour cell lines; PBN did not modify the cytotoxicity of ADR, thus excluding a free radical involvement in this activity. The present results suggest that a proper administration schedule of spin traps might be a promising approach for improving the therapeutic index of ADR.

The hydrophilic spin trap, 5,5-dimethyl-1-pyrroline-1-oxide, does not protect the rat heart from reperfusion injury.

The role and site of free radical generation in myocardial ischemia/reperfusion injury were investigated using the hydrophilic spin trapping agent, 5,5-dimethyl-1-pyrroline-1-oxide (DMPO). DMPO (40 mM) proved ineffective in preserving the contractile performance and energy metabolism of Langendorff-perfused rat hearts following ischemia and reperfusion. This result, which is in contrast with the cardioprotection observed with hydrophobic spin traps, suggests that free radicals are generated intracellularly under these conditions.

Intestinal absorption of manganese: an in vitro study.

Our work on isolated rat intestine aimed at studying the hypothesis that the intestinal transport of manganese was carrier-mediated and, consequently, subjected to saturation. Our results confirm this hypothesis, assessing the concentration of carrier saturation for manganese at 0.5 mM. As this concentration, which may determine self-limitation in the intestinal absorption of this metal, is much higher than the maximal allowed concentration of the EEC Standard (50 mg/l), food and water should be carefully monitored for their manganese content in order to avoid reaching toxic concentrations in blood and tissues.

Cardiotoxicity induced by doxorubicin in vivo: protective activity of the spin trap alpha-phenyl-tert-butyl nitrone.

The role of free radical generation in the development of the acute cardiotoxicity induced by doxorubicin (DXR) in the rat and the protective activity of anti-radical drugs were investigated in in vivo experiments by evaluating the body weight curve, ECG, contractile performance and coronary flow up to 10 days after DXR. A lipophilic spin trap (alpha-phenyl-tert-butyl nitrone, PBN) was continuously administered at a dose of 0.65 mg/kg every hour for 2 weeks by an intraperitoneal osmotic pump. DXR was administered i.v. at a dose of 9 mg/kg 3 days after beginning the PBN infusion. DXR impaired ECG and body weight gain after 3 days (partly reversible at later times), while contractility and coronary flow were significantly impaired throughout the experimental time. PBN was shown to prevent the DXR-induced alterations of contractility and coronary flow, while ECG was non-significantly improved. The body weight curve was not affected. Since the dose of PBN used does not produce pharmacological effects, the protective activity in rats receiving DXR indicates that free radicals may play a causal role in the acute cardiotoxicity in vivo. The use of suitable spin traps and administration schedules seems to be an interesting approach for the prevention of radical-dependent pathologies.