S.K. Hasan

Evidence for the involvement of hydroxyl radicals in nickel mediated enhancement of lipid peroxidation: Implications for nickel carcinogenesis

The administration of nickel to rats resulted in enhanced hepatic lipid peroxidation, levels of glutathione and iron with a concomitant decrease in glutathione peroxidase activity. These effects were dose dependent. Enhanced lipid peroxidation was found to be inhibited by the exogenous addition of ethylenediamine tetraacetic acid (EDTA), benzoate and ethanol while catalase and superoxide dismutase were ineffective in this regard. Our data strongly suggest the involvement of hydroxyl radicals in the nickel mediated enhancement of lipid peroxidation which may have their implications in the carcinogenicity of nickel compounds.

Evidence for the involvement of nitric oxide in cisplatin-induced toxicity in rats.

Cisplatin treatment of rats results into a significant increase in the activity of Ca2+-independent nitric oxide synthase (NOS) in kidneys and liver. Significant enhancement of lipid peroxidation in gastric mucosa, kidneys and liver was also observed. The administration of NG-nitro-l-arginine methyl ester, an inhibitor of NOS, markedly reduced renal and gastrointestinal toxicity, and also decreased the content of blood urea nitrogen, serum creatinine, and incidence of diarrhoea along with a significant inhibition in lipid peroxidation in the target organs. The present report, while demonstrating the beneficial effect of the blockade of NO pathways during cisplatin chemotherapy, may be helpful in developing strategies for combating some of the toxic side-effects of the drug.

Green tea polyphenols and tannic acid act as potent inhibitors of phorbol ester-induced nitric oxide generation in rat hepatocytes independent of their antioxidant properties.

The deleterious effects of excessive release of nitric oxide (NO) have been implicated in the tissue damage and inflammation. In this study, the effect of various flavonoids and other oxidant scavenging chemical agents have been studied for their ability to inhibit 12-O-tetradecanoyl phorbol 13-acetate (TPA)-induced NO generation in rat hepatocyte. Hepatocytes activated with TPA (25-200 nM) released NO in a concentration- and time-dependent manner. Green tea polyphenols (GTP) and tannic acid (TA) were most effective in inhibiting TPA-induced NO generation (90%). These agents were also effective in inhibiting NO formation when added 2 h following TPA addition. The other oxidant scavengers, such as L-histidine, sodium azide, vitamin E and sodium benzoate, were not found to be effective even up to 1.0 mM concentration. These results suggest that TA and GTP are potent inhibitors of NOS activity and the inhibition of TPA-induced NO generation by these polyphenols is independent of their antioxidant activity. It is tempting to speculate that these agents could be utilized in the pharmacological manipulations of NO-dependent pathophysiological responses.

Arsenicism in India: Dermal Lesions and Hair Levels

Objective: One million people in 8 districts of West Bengal are exposed to high levels of arsenic in drinking water. Two hundred thousand individuals reportedly show arsenic-related symptoms. The clinical manifestations mainly pertain to dermal lesions characterized by diffuse pigmentation superimposed by 2-1 0-mm macules of depigmentation, which are clinically labeled as a rain-drop pattern of pigmentation and/or keratinization of the palms of the hands and the soles of the feet. We confirmed that there is chronic arsenic exposure. We analyzed arsenic levels in hair because objective, biological, etiological evidence is unavailable. Design. We contacted all of the available cases in one of the affected villages, and they were asked to volunteer for the study. We eventually selected only those cases who had (1) skin lesions that evidenced the raindrop pattern of pigmentation and/or keratinization of the palms of the hands and soles of the feet and (2) other family members who had evidence of arsenicrelated problems. Setting. The study was conducted in a small village of Domkal block of Distt Murshidabad in West Bengal. Protocol. Each subject was interviewed about personal, social, and clinical details, and he or she was examined clinically. A sample of hair was obtained from the occiputonuchal region of the head, close to the root, from each subject. The samples, which measured 5-1 5 cm and weighed 0.5-1 .O gm, were stored in labeled paper bags. The hair samples were washed, weighed, cold digested, and analyzed with atomic absorption spectrophotometry. Participants. Of the 19 persons selected, only 7 males and 1 female agreed to participate. Two of the males were excluded because they had recently shaved off their scalp hair. The study, therefore, included 5 males and 1 female. The mean age of the subjects was 31.5 yr (range = 25-47 yr). One of the subjects was an occasional smoker, and none were addicted to any toxicants. All were engaged in agricultural activities, and some were also involved in other supplemental occupations ( e g , carpentry, tea wending, construction work, household work). Results. A rain-drop pattern of pigmentation was present on the trunk and upper arms or thighs of all the subjects. Two of the subjects had keratinization of the palms, and 1 had keratinization of the feet. One of the subjects complained of tingling and numbness in his arms. There was no evidence of occupational exposure to arsenic compounds among any of the study subjects. The levels of arsenic in hair of these subjects ranged between 2.57 pg/gm and 8.85 pg/gm (mean = 5.55 pg/gm, median = 5.68 pg/gm). The subject with the highest level of arsenic in hair had resided continuously in the same area (i.e., without any break), whereas other subjects of the same village gave a history (i.e., during the past 4 yr) of nonresidence in the area that ranged from 5 mo to 1 yr. Conclusion. The cases of dermatoses studied revealed high levels of arsenic in hair, compared with normal values of 0.08-0.2 pg/gm in hair reported among healthy, unexposed subjects. On the basis of existing reports and the present study, we can conclude that the cases of dermatoses reported from West Bengal are initial clinical manifestations of long-term arsenic intake. Investigators are instituting engineering and other measures to provide safe drinking water, but public-health measures for the prevention of additional exposures and for the prevention of a worsening clinical picture require identification of affected individuals. Investigators could use hair arsenic levels to determine risk for debilitating arsenicism.

The effect of triethylene tetramine upon the selective removal of nickel (II), iron (II), manganese (II) and tin (II) in rats

Abstract The distribution of Nickel-63, Iron-59, Manganese-54 and Tin-113 in plasma was studied in rats which received single intravenous (i.v.) injection of aqueous solutions of their salts alone, and in rats which also received single intramuscular (im) injection of triethylene tetramine (TETA). TETA was extremely effective in reducing the plasma concentration of Nickel-63 followed by that of Iron-59, Manganese-54 and Tin-113.

Removal of nickel by chelating drugs from the organs of nickel poisoned rats

Abstract The chelating drugs namely ethylenediamine tetraacetic acid (EDTA), 1,2,cyclohexylenediamine tetraacetic acid (CDTA), hydroxyethylenediamine triacetic acid (HEDTA) diethylenetriamine pentaacetic acid (DTPA), and triethylenetetraamine hexaacetic acid (TTHA), were examined for the mobilization of nickel from body organs of sham operated and partially hepatectomized rats in early nickel poisoning. These chelating drugs successfully reduced the body burden of nickel from both the nickel treated experimental groups. EDTA was relatively more effective in reducing the hepatic content of nickel while CDTA and HEDTA were more effective in reducing its renal content. These drugs also reduced nickel burden in heart and lung to variable degrees. The over all efficacy of the chelating drugs are in the order: EDTA > CDTA > HEDTA > TTHA > DTPA

The distribution of manganese-54 in fetal, young and adult rats

The distribution of 54Mn in various organs of pregnant rats and of their 19-day-old fetuses and in non-pregnant female rats of various ages has been studied 18 h after an i.v. injection of 54MnCl2. The results indicate that early neonates are more susceptible to manganese (Mn) than the growing rats. The localization of 54Mn in liver and brain of the embryo was highly significant.

Pharmacokinetics and metabolic disposition of nickel in poisoned rats — Effect of chelating drugs

Abstract The kinetics of mobilization of hepatic and renal nickel by lipophilic drugs namely cyclam and TETA and hydrophilic drugs namely EDTA, CDTA, DTPA and HEDTA was studied at 16, 24, and 72 hrs in rats treated with nickel (II) chloride. Both the types of drugs although having comparable stability constants for nickel exhibit a marked difference in their efficacy and behaviour. The former type of drugs reduced the renal nickel while increasedits hepatic content. The latter ones reduced both renal and hepatic contents. A mathematical correlation established in the form of linear regression equations between % mobilization of nickel, stability constants and time duration revealed a positive and significant correlation between all the three parameters. These equations also revealed the highest order of efficacy of drugs at the shortest time investigated.

Effect of nitrilotriacetic acid (NTA) on the distribution of manganese-54 in rats

The effect of single dose of NTA on the removal of radio-manganese in various organs and in plasma has been studied in rats which received single i.v. injection of54Mn(II). The lowered value of radio-manganese in NTA treated rats as compared to control animal indicates that NTA binds rapidly and forms stable and diffusible complex resulting in the fast excretion of the injected54Mn(II).

Toxicokinetics of nickel in glutathione depleted rats

Abstract The toxicokinetics of nickel was studied in normal and glutathione depleted rats. The depletion of glutathione resulted in an increased retention of 63nickel in plasma and in body organs with concomitant decrease in 63nickel elimination in urine. In both the groups, kidney was the major site of accumulation of 63nickel followed by lung, heart, spleen and liver. The injected nickel was mainly eliminated via urine. The time course elimination of 63nickel followed first order kinetics and the correlation between the time and plasma/or tissue nickel concentration was statistically significant. Our results suggest that depletion of glutathione may increase the toxicity of nickel by altering its toxicokinetics.