Inorganic arsenic is clearly a toxicant and carcinogen in humans. In mammals, including humans, inorganic arsenic often undergo methylation, forming compounds such as pentavalent dimethyarsinic acid (DMAsV). Recent evidence indicates that DMAsV is a complete carcinogen in rodents while evidence for inorganic arsenic as a carcinogen in rodents remains unclear. Thus, we studied the molecular mechanisms of the in vitro cytolethality of DMAsV compared to that of the trivalent inorganic arsenic, sodium arsenite, using rat liver TRL 1215 cells. Arsenite was very cytotoxic in these cells; its lethal concentration in vitro in 50% of a population (LC50) was 20 μM after a 48-hr exposure. With arsenite, most dead cells showed histological and biochemical evidence of necrosis. The arsenite cytolethality markedly increased when cellular reduced glutathione (GSH) was depleted with the glutathione synthase inhibitor, L-buthionine-[S,R]-sulfoximine (BSO). In contrast, DMAsV was nearly three orders of magnitude less cytotoxic (LC50 = 1.5 mM) although evidence showed the predominating form of death was apoptosis. Surprisingly, GSH depletion actually decreased the DMAsV-induced apoptosis. It is suggested that DMAsV requires intracellular GSH to induce apoptosis. Ethacrynic acid (EA), an inhibitor of glutathione S-transferase that catalyzes GSH-substrate conjugation, and aminooxyacetic acid (AOAA), an inhibitor of β-lyase which catalyzes the final breakdown of GSH-substrate conjugates, were also effective in suppressing the DMAsV-induced apoptosis. These findings indicate that DMAsV was likely conjugated in some form with cellular GSH, and this conjugate induced apoptosis during subsequent metabolic reactions. Because apoptosis is a process by which organisms eliminate abnormal cells, the arsenic biomethylation in the human body may essentially a detoxicating event.
The hydrocarbon method for the detection of irradiated foods is now recognized as the international technique. This method is based on radiolysis of fatty acids in food to give hydrocarbons. In order to expand this technique's application, ten foods (butter, cheese, chicken, pork, beef, tuna, dry shrimp, avocado, papaya, and mango) were irradiated in the range from 0.5 to 10 kGy and the hydrocarbons in them were detected. Recoveries of the hydrocarbons from most foods were acceptable (38-128%). Some hydrocarbons were found in non-irradiated foods, particularly, in butter, cheese, tuna, and shrimp. Seven irradiated foods, butter, cheese, chicken, beef, pork, tuna, dry shrimp, and avocado were detectable at their practical doses by measuring the appropriate marker hydrocarbons. In most case, marker hydrocarbon will be 1,7-hexadecadiene. However, the marker hydrocarbons produced only in irradiated foods varied from food to food; therefore, it is necessary to check a specific irradiated food for marker hydrocarbons. On the other hand, two irradiated foods (papaya and mango which were irradiated at their practical doses) were difficult to distinguish from non-irradiated foods using this method.
An assay of platelet monoamine oxidase type-B (MAO-B) activity has been explored in the search for a reliable method of discriminating selegiline (SG) use from methamphetamine (MA) abuse. MAO-B activity was measured by fluorimetry of 4-hydroxyquinoline (4HOQ) produced by oxidative deamination of kynuramine, the substrate for MAO-B. MA and most of its related compounds including its precursors produced no platelet MAO-B inhibition in vitro even at their lethal levels, though SG, its specific metabolites selegiline N-oxide (SGO) and N-desmethylselegiline (DM-SG), as well as its enantiomer d-deprenyl exhibited high platelet MAO-B inhibitory potency. In vivo, remarkable inhibition of MAO-B occurred even within an hour after drug administration, and the inhibition apparently lasted approximately 6-8 days after both 2.5 and 7.5 mg oral doses of SG hydrochloride. The present study suggests that the decrease of platelet MAO-B activity would be a significant marker to discriminate SG use from MA abuse, even a week after drug use.
The in vitro effects of various chemicals, such as styrene dimers, styrene trimers, alkylphenols, phthalate esters, phytoestrogens, and organotin compounds, on the production of interferon-gamma (IFN-γ), a type 1 helper T-cells (Th1) specific cytokine, and interleukin-4 (IL-4), a type 2 helper T-cells (Th2) specific cytokine, which are secreted from anti CD3-stimulated mouse spleen cells, were examined. These chemicals suspected of having an endocrine disruptor function and to which humans may become exposed via ingestion through food, food containers, and food packaging. It was found the organotin compounds bis(tributyltin) oxide, tributyltin chloride, and dibutyltin dichloride at concentrations which did not elicit any cytotoxicity inhibited secretion of the Th1 and Th2 specific cytokines IFN-γ and IL-4 at concentrations (0.01-0.03, 0.07-0.1, and 0.096-0.132 μM for IC50, respectively) that were much lower than those of the other chemicals. However, these butyltin compounds exhibited similar degrees of inhibitory effects on IFN-γ and IL-4 secretion and did not selectively inhibit the secretion of one or the other cytokine. However, diphenyltin dichloride and phenyltin trichloride enhanced the secretion of IL-4 at the comparatively low concentrations of 0.3 μM and 1.0 μM, respectively, although these compounds significantly inhibited IFN-γ secretion at the same concentrations. In addition, 4-t-pentylphenol enhanced IL-4 secretion although it inhibited IFN-γ secretion at the comparatively high concentration of 30 μM. It was also found that some styrene trimers, phthalate esters and flavonoids as well as the alkyl phenols octylphenols and nonylphenol among others, inhibited the secretion of both cytokines at comparatively high concentrations (< 30 μM).
UV stabilizers used in food contact plastics were tested for their estrogenic activity by the yeast two-hybrid assay. Among 11 kinds of UV stabilizers, 2-hydroxy- 4-methoxybenzophenone and 2,2′-dihydroxy-4-methoxybenzophenone displayed estrogenic activity, while salicylate, benzoate and benzotriazole derivatives and a benzophenone derivative had no activity. Therefore, benzophenone and 19 kinds of hydroxylated derivatives were further studied. Of these, 15 chemicals showed estrogenic activity. The strongest activity was by 2,4-dihydroxybenzophenone, 4-hydroxy-4′-chlorobenzophenone, 4-hydroxybenzophenone and 2,3,4-trihydroxybenzophenone. Their activities were stronger than that of bisphenol A which was recognized as a potential endocrine disruptor. The following structure-activity relationships of benzophenones were obtained. The activity of the benzophenones with a hydroxyl group at the 3 or 4-position was positive and rather strong, though that of other benzophenones without a hydroxyl group at the 3 or 4-position was negative or weakly positive. The effect of the hydroxyl group in the phenol moiety were in order of 4- > 3- >> 2-position. A hydroxyl group added at the 2-position of the 4-hydroxylated benzene ring enhanced the activity. On the other hand, a hydroxyl group added to the benzene ring of the hydrophobic moiety reduced the binding, while the chloro group enhanced it. Some of these relationships might possibly hold for other estrogenic chemicals that possess two benzene rings.
We previously reported1,2) that volcanic ash soil from Mt. Aso may affect the quality of water in the regions where volcanic ash from the present crater in Naka-dake have been deposited, and that adsorption of pesticides (Environmental standards and items requiring observation according to the Fundamentals of Environment Act) by volcanic ash soil from Mt. Aso may be affected by the water-solubility of chemicals and the kinds and number of hydrophilic functional groups at the molecular level of chemicals. The present study using "simulated weathering" (treatment with humic acid) demonstrated that the pesticides that the absorption efficiency improved by treated humic acid treated were 2,2-dichlorovinyldimethylphosphate (DDVP), 2-sec-butylphenyl methylcarbamate (BPMC), O,O-dimethyl O-4-nitro-m-tolyl phosphorothioate (MEP), Bebthiocarb, Isoxathion, 4-nitrophenyl 2,4,6-trichlorophenyl ether (CNP), and deteriorated adversely in Propyzamide, Diazinon.
The association of chronic cigarette smoking and abstention with oxidative DNA damage was studied. The serum level of an oxidative DNA damage marker, 8-hydroxy-2′-deoxyguanosine (8-OHdG), was measured in 20 healthy male smokers and 8 healthy male non-smokers. The 8-OHdG level was significantly higher in the smokers than in the non-smokers (0.22 ± 0.05 vs. 0.07 ± 0.02 ng/ml, p < 0.001). Ten of 20 smokers abstained from smoking for 4 weeks. Their 8-OHdG levels were significantly reduced by the smoking abstention (0.27 ± 0.05 to 0.14 ± 0.02 ng/ml, p < 0.001). The remaining 10 not only abstained from smoking, but also received 2g /day of oral vitamin C. Their 8-OHdG levels were also significantly reduced (0.27 ± 0.05 to 0.13 ± 0.02 ng/ml, p < 0.001). However, there was no significant difference in the serial changes in 8-OHdG level between the smoking abstention group and the smoking abstention with vitamin C supplementation group. These results suggest that chronic cigarette smoking enhanced oxidative DNA damage, but the damage was repaired by smoking abstention, and that vitamin C supplementation might not enhance the repair. In light of the DNA damage, smoking abstention should be encouraged.
Large amounts of various pesticides have been used in farms, rice paddies and gardens. However, few studies on the pesticides in rainwater have been conducted in Japan. Thus, rainwater samples were collected from August 2001 until July 2002 at Isogo Ward of Yokohama, and 51 kinds of pesticides in the 51 samples were investigated. Although sampling point was not located in the agricultural area, dichlorvos (0.33-0.05 μg/l), chlorothalonil (0.27-0.05 μg/l), fenitrothion (0.24-0.05 μg/l), molinate (0.12-0.05 μg/l), diazinon (0.07-0.05 μg/l), and malathion (0.05 μg/l) were detected. Dichlorvos was the most frequently detected (65% of samples) and its highest concentration in rainwater (0.33 μg/l) was found on May 7, 2002. Chlorothalonil was the second most frequently detected (33% of samples) and its highest concentration in rainwater (0.27 μg/l) was found on May 26, 2002.
We observed glucose metabolism and insulin secretion in healthy young men after intake of large amounts of sugar. Ten subjects, with the randomized cross-over design, ingested sucrose or maltose solution hourly from 10:00 to 13:00 (75 g in 225 ml water per time). Plasma concentrations of glucose, insulin and c-peptide were measured in fasting, at 30 min after each intake and at 2 hr after last intake. Plasma glucose concentration increased after the first intake and decreased to the fasting level from the second intake. Plasma insulin and c-peptide concentrations increased from the first intake and retained throughout following intakes. Plasma concentrations of glucose, insulin and c-peptide were higher in maltose group than in sucrose group and the significant differences were observed after the last intake. In the present study, glucose concentration maintained in the normal range after intake of large amounts of disaccharide and insulin secretion responded well to this repeated intake of disaccharide, however, maltose tended to induce insulin resistance compared with sucrose.
Methoxychlor (MXC), a chlorinated hydrocarbon pesticide, adversely affects the hormonal system in animals by producing metabolites with estrogenic activity. When methoxychlor was administrated to male rats for 7 days, CYP2C11 as well as its 2B1/2 and 3A1 was induced in the liver. In addition, an in vitro study using recombinant CYPs and HPLC analysis showed that only the CYP2C11 subfamily converted MXC into hormonally active metabolites, such as demethylated derivatives, not 2B1 and 3A1. These findings suggest that MXC accelerates the conversion of itself into hormonally active metabolites, leading to disruption of the endocrine system.
The effects of sex hormones on the level of rat organic anion transporter 3 (rOAT3) protein and its localization were studied in rat kidney. Western blot analysis detected both minor 100-kDa and major 69-kDa proteins in the crude plasma membrane fraction of the kidney. The sum of the levels of both proteins in male rats was not different from that in castrated rats, testosterone-treated rats that had been castrated or female rats. In ovariectomized female rats, the level of these proteins was 3-4 times higher than that in other groups. Treatment of ovariectomized female rats with estradiol reduced rOAT3 to a normal level. Immunohistochemical analysis indicated that rOAT3 was expressed in the renal cortex and outer medulla, where this protein localized in the basolateral membrane of tubules. The immunological localization of rOAT3 was similar in the 6 experimental groups. These results suggest that the cellular level of rOAT3 protein is regulated, at least in part, by estradiol in rat kidney.
Toxicological and metabolic interactions of selenium (Se) with arsenic (As) have been reported in many experimental studies. However, for human populations, possible interactions between As and Se and their toxicological significance have not been established. In this study, we have examined the relationship between Se and As in spot urine samples collected from the inhabitants of two rural communities of northeast Bangladesh. The urinary As (UAs) and Se (USe) concentrations were determined by hydride generation atomic absorption spectrometry (HGAAS). Negative correlation between UAs and USe was found in both males and females. Considering the exposure condition in these communities, it is unlikely that the correlation reflected the correlation between the intakes of these elements. This result suggests that As exposure from drinking water or food may change Se metabolism in humans. Possible toxicological significance of the interaction is discussed.
In a previous study, we demonstrated the existence of casein kinase II-like ectokinase activity on rat basophilic leukemia 2H3 (RBL-2H3) cells (Immunol. Let. 68, 369, 1999), and to determine the role of ectokinase in the degranulation of RBL-2H3 cells, in this study we investigated the effect of casein kinase II substrate peptide on the degranulation by the cells. Casein kinase II peptide (RRRDDDSDDD) dose-dependently (IC50 = 50 μM) inhibited β-hexosaminidase release by IgE-sensitized antigen-stimulated RBL-2H3 cells, whereas casein kinase II peptide analogue (RRRDDDADDD) only partially inhibited β-hexosaminidase release by antigen-stimulated RBL-2H3 cells. Preincubation of RBL-2H3 cells with 200 μM of casein kinase II peptide significantly inhibited external 130 kDa protein phosphorylation, and casein kinase II peptide inhibited the sustained increase in cytosolic calcium ion concentration in response to antigen stimulation. Our findings suggest that casein kinase II acts as an ectokinase in RBL-2H3 cells and that casein kinase II peptide acts as a competitor for phosphorylation of ectoprotein, which involves degranulation and a transmembrane influx of Ca2+ by IgE receptor cross-linking. Another casein kinase II inhibitor, GT copolymer, also inhibited the degranulation of antigen-stimulated RBL-2H3 cells. Thus, the modulator of casein kinase II activity seems to be a good tool for the inhibitor of signal transduction in RBL-2H3 cells.
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