New mechanistic approach of inorganic palladium toxicity: impairment in mitochondrial electron transfer.

Human activities have increased the levels of palladium (Pd) that are progressively accumulating in the environment. The growing evidence of Pd toxicity has become the focus of serious concern for the environment, organisms and humans, with little data on the mechanism of Pd toxicity. Recent studies have suggested that mitochondria have a key role in Pd toxicity via mitochondrial membrane potential collapse and depletion of the cellular glutathione (GSH) level. Therefore, it was decided to determine the mechanistic toxicity of Pd towards isolated mitochondria via new and reliable methods. Isolated liver and kidney mitochondria were obtained by differential ultracentrifugation and incubated with different concentrations of Pd (100-400 µM). Our results showed that Pd induced mitochondrial dysfunction via an increase in mitochondrial ROS production and membrane potential collapse, which correlated to cytochrome c release. Also, increased disturbance in oxidative phosphorylation was also shown by the increase in ADP/ATP ratio in Pd-treated mitochondria, which indicates mitochondrial dysfunction in isolated liver and kidney mitochondria. Our results suggest that Pd-induced toxicity is the result of a disruptive effect on the mitochondrial respiratory chain, increasing the chance of cell death signaling. In addition, it is supposed that kidney tissue is more susceptible to Pd exposure than liver tissue.

Effects of long-term exposure to hydrogen sulfide on human red blood cells.

BACKGROUND: Hydrogen sulfide (H2S) exhibits both physiological and toxicological roles in the biological systems. Acute exposure to high levels of H2S is life threatening while long-term exposure to ambient levels of H2S elicits human health effects. OBJECTIVE: To study the harmful effects of long-term exposure to low levels of H2S on human blood cells. METHODS: 110 adult workers from Iran who were occupationally exposed to 0-90 ppb H2S for 1-30 years were studied. The participants aged between 18 and 60 years and were exposed directly or indirectly to sulfur compounds (exposed group). The origin of H2S was natural gas processing plants. A control group consisting of 110 males who were not in contact with H2S was also studied. For all participants, hematological profile including total hemoglobin and red blood cell count and sulfhemoglobin, methemoglobin levels were measured. RESULTS: Among all parameters evaluated in this study the mean methemoglobin and sulfhemoglobin levels were significantly higher among workers who were exposed to sulfur compounds than the control group. Major differences throughout the study period for sulfhemoglobinemia among exposed groups were observed. CONCLUSION: Long-term exposure to even low levels of H2S in workplaces may have potential harmful effects on human health.

Alternative electron acceptors: Proposed mechanism of paraquat mitochondrial toxicity.

Paraquat (PQ) is a relatively safe and effective herbicide used all over the world. PQ is very toxic to all living organisms; and many cases of acute poisoning and death have been reported over the past decade. The main suggested potential mechanism for PQ toxicity is the production of superoxide radicals from the metabolism of the PQ by microsomal enzyme systems, and by inducing mitochondrial toxicity. Mitochondria are considered to be a major source of reactive oxygen species in cells and according to this hypothesis, PQ, through suitable oxidation and reduction processes, is able to participate in the redox system in mitochondria. The potential ability of PQ to accept electrons from complex (I, II, III, IV) leads to rapid reaction with molecular oxygen to yield superoxide anion which can lead to the formation of more toxic reactive oxygen species, e.g., hydroxyl radical, often taken as the main toxicant. Lipid peroxidation due to PQ has been implicated in a number of deleterious effects such as increased membrane rigidity, osmotic fragility, decreased mitochondrial components, reduced mitochondrial survival and lipid fluidity. The biological effect of reactive oxygen species (ROS) is controlled by a wide spectrum of enzymatic and non-enzymatic defense mechanisms such as superoxide dismutas (SOD), catalase (CAT) and glutathione. According to this hypothesis, the chemical cascades lead to the reduction of PQ, which reacts quite rapidly with molecular oxygen to yield superoxide anion. The generation of free radicals and lipid peroxidation are the main factors that lead to mitochondrial damage.

Captopril ameliorates toxicity induced by paraquat in mitochondria isolated from the rat liver.

The aim of the present study was to show the abilities of captopril as a thiol ACEi (angiotensin converting enzyme inhibitor), on mitochondria toxicity due to paraquat. Mitochondrial isolation from rat liver was divided into 4 groups. Group 1 was considered as control, group 2 received paraquat (5 mM), group 3 received captopril (0.08 mM) and group 4 received paraquat (5 mM)+captopril (0.08 mM). Lipid peroxidation, catalase activity, GSH (reduced glutathione) and GSSG (oxidized glutathione) concentrations were determined in isolated rat liver mitochondria. Simultaneous treatment of mitochondria with captopril (0.08 mM)+paraquat (5 mM) significantly ameliorate the mitochondria toxicity induced by paraquat (5 mM) alone. The results confirm antioxidant effect of captopril. This effect appears to be attributable to the Sulfhydryl Groups (SH) in the compound which may be due to captopril abilities to scavenge reactive oxygen species. The results indicate that captopril may prevent oxidative stress induced by paraquat.

Using Janus green B to study paraquat toxicity in rat liver mitochondria: role of ACE inhibitors (thiol and nonthiol ACEi).

Janus green B (JG-B) dye is used for vital staining of mitochondria and its reduction and oxidation shows the electron transfer chain alteration. The defect in electron transfer chain of mitochondria by paraquat is linked to free radical formation. In this present study we compared the abilities of different angiotensin-converting enzyme inhibitors, captopril (a thiol ACEi), enalapril, and lisinopril (two nonthiol ACEi) on mitochondria toxicity due to paraquat. The rat liver mitochondria were first isolated by centrifuge (at 4 degrees C at a speed of 7,000 g) in a mixture of 0.25 M saccharose solution and 0.05 M Tris buffer. Various concentrations of paraquat (1, 5, 10 mM), enalapril (0.25, 0.5, 1 mM), lisinopril (0.01, 0.05, 0.1 mM), and captopril (0.08, 0.1, 1 mM) on the mitochondria isolated from the liver with respect to time were investigated. Paraquat at a concentration of 5 mM was determined to be significantly different compared to control values (P<0.05) and captopril at a concentration of 0.08 mM, lisinopril (0.01 mM), and enalapril (0.25 mM) were found not to be significantly different from controls as found by spectroscopy at wavelength of 607 nm. Simultaneous treatment of mitochondria with captopril (0.08 mM) and paraquat (5 mM) significantly ameliorates the mitochondria toxicity of paraquat (5 mM) alone (P<0.05). Our results show that captopril is a more effective antioxidant than the nonthiol ACEi. Lisinopril (0.01 mM) and enalapril (0.25 mM) did not significantly change the mitochondrial toxicity by paraquat (5 mM) (P>0.05). The antioxidative action of captopril appears to be attributable to the sulfahydryl group (SH) in the compound. This effect may be due to captopril's abilities to scavenge reactive oxygen species.