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.

Mechanistic approach for the toxic effects of perfluorooctanoic acid on isolated rat liver and brain mitochondria.

BACKGROUND: Perfluorooctanoic acid (PFOA) is one of the most widely used perfluoroalkanes as surfactants, lubricants and processing aids in the production of polymers, which has also been detected in the environment, wildlife and human body. Animal studies indicated that PFOA caused a wide array of toxic effects including liver and brain dysfunction, carcinogenicity and reproductive and developmental toxicity. Based on the established role of mitochondria-mediated pathways in the observed toxic effects of many drugs and chemicals, in this study, the potential toxic effects of PFOA on mitochondria isolated from rat liver and brain have been investigated. METHOD: Mitochondria were isolated by differential centrifugation method and incubated with different concentrations of PFOA (0.5-1.5 mM). The effects of PFOA were assessed on a series of mitochondrial parameters including reactive oxygen species (ROS) formation, activities of mitochondrial complexes I/II/III, reduced glutathione (GSH) content, adenosine triphosphate (ATP) level, membrane potential, lipid peroxidation (LPO), mitochondrial swelling and cytochrome c release. RESULTS: The data on liver mitochondria indicated that PFOA-induced ROS elevation in both mitochondrial complexes I and III, mitochondrial membrane potential collapse, swelling, cytochrome c release and decreased ATP level which induces apoptosis or necrosis. On brain mitochondria, PFOA showed fairly similar effects on the above-mentioned parameters. However, different results were obtained when the effect of PFOA was assessed on LPO and complex II activity. CONCLUSIONS: Due to the fact that PFOA had toxic effects on the mitochondria isolated, it could be suggested that mitochondrial toxicity could be a plausible mechanism for the toxic effects of this fluorochemical on liver and brain function.

Effect of n6-cyclopentyladenosine on ouabain-induced toxicity in isolated Guinea pig atria.

ABSTRACT The effect of N6-cyclopentyladenosine (CPA), an A(1)-selective adenosine agonist, was studied on ouabain-induced toxicity in spontaneously beating isolated guinea pig atria. CPA (2-16 nM) produced a dose-dependent decrease in the force of contractions (34%-51%) and in the rate of contractions (22%-48%). CPA significantly increased the time of onset of arrhythmia (toxicity) induced by ouabain (1.2 muM) when it was administered 10 min before ouabain was added in organ bath. Ouabain (1.2 muM) alone produced arrhythmia at 7 min and either asystole or standstill at 22 min. CPA (8 nM) increased the time required to produce arrhythmia to 27.5 min and prolonged beating atria to more than 63 min and prevented the occurrence of asystole. These findings indicated that CPA produces direct cardiac action, probably due the inhibition of cardiac Na(+) and Ca(2+) channels. Moreover, our results suggest that CPA may reduce the membrane conduction through inhibition of ionic channels, which decrease ouabain-induced toxicity.

The prevalence and antibiotic resistance of Shigella sp. recovered from patients admitted to Bouali Hospital, Tehran, Iran during 1999-2001.

The present study was conducted to determine the prevalence of serotypes and antibiotic resistance in Shigella spp. isolated from patients admitted to Bouali hospital, Tehran, Iran during 1999 to 2001. All cases of shigellosis that were diagnosed according to their clinical pictures and microbial cultures were included in current study. Patients' age ranged from 12 to 89 years. Overall, 52 patients (56%) and 41(44%) were males and female, respectively. From a total of 90 Shigella isolates, 40 strains were identified as S. sonnei (45%), 26 as S. flexneri (27.9%), 3 as S. boydii (3%) and 21 as S. dysenteriae (24%). More than 95% of the isolates were susceptible to ciprofloxacin, ceftriaxone and ceftizoxim, 70% to nalidixic acid and less than 50% to co-trimoxazole, tetracycline, ampicillin and fourazolodon.

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.