(±)-Pantoprazole sodium, [(±)-PAN·Na], is a proton pump inhibitor that is administered as a racemate. The protective effects of (-)-PAN·Na, (+)-PAN·Na and (±)-PAN·Na on various experimental ulcers in animals were compared. (-)-PAN·Na inhibited gastric lesions induced by water-immersion stress, aspirin, ethanol, and reserpine in a dose-dependent manner. The dose that inhibited 50% of lesions (ID50) were 2.72 ± 1.03, 1.60 ± 0.64, 4.12 ± 2.18, and 2.77 ± 0.86 mg/kg, respectively. The ID50 values of (+)-PAN·Na and (±)-PAN·Na were 1.7, 2.6, 1.8, 2.7 and 1.5, 1.7, 1.6, 1.9 times higher, respectively, than that of (-)-PAN·Na. Primary culture of rat gastric epithelial cells was investigated as an in vitro model for comparing the cell protective effects among the three agents. Exposed to the three drugs at the concentrations of 2.5 × 10-1-2.5 × 10-5 mg/ml, cultured cells were treated with either pH 3.5 medium or 3.5 mM indomethacin. Cytoprotection was evaluated by MTT. (-)-PAN·Na, (+)-PAN·Na and (±)-PAN·Na provided significant cytoprotective effects when the cells were pretreated with the drugs prior to exposure to 3.5 mM indomethacin, whereas, when they were treated concurrently, no significant cytoprotective effects were found. In pH 3.5 medium-induced damage, the three drugs had marked protective effects on gastric cells, however, when the concentration of drugs was high (0.25 mg/ml), only (+)-PAN·Na had significant cytoprotection. We concluded that the cytoprotective mechanisms of (-)-PAN·Na and (+)-PAN·Na are different. The results of in vitro experiments were not in complete accordance with the in vivo results, suggesting that the effects of the three drugs on ulcer inhibition are mainly due to the effects of acid inhibition rather than cytoprotection.
Size-fractionated air-borne particles and gaseous samples were collected using Andersen low pressure impactor with polyurethane foam at Tokyo. Dioxin concentrations of these particles and gaseous substances were measured with high resolution gas chromatograph/high resolution mass spectrometer (HRGC/HRMS). Particle diameter distribution has two peaks, one around 0.7 μm and the other around 5 μm both in summer and winter. But, dioxin has a peak at around the particle diameter of 0.52 μm. And, It was observed that smaller particle was the higher weight concentration of dioxins in the particle except in the case of tetrachlorodibenzofurans (TeCDFs). From these results, it was recognized that 75% or more of toxic dioxin component was contained in particles of 1 μm or smaller.
We developed a simple and rapid analytical method for determining the residues of emamectin benzoate, milbemectin, abamectin, ivermectin and emamectin metabolites in tomato, Japanese Radish and Japanese tea by liquid chromatography/mass spectrometer (LC/MS) with electrospray ionization (ESI). A sample extracted with acetone was simply cleaned up using only a Sep-Pak C18, and then directly measured by LC/MS (ESI). Several LC/MS measurement conditions were studied that included the mobile phase, solvent for sample solution, range of calibration and standard deviation of the measurement. Detecting target macrocyclic lactone chemicals with methanol as the mobile phase was more sensitive than acetonitrile, especially, milbemectin. The detection limits of these chemicals were 0.1 to 0.5 ng/ml (10 μl injection), and they were similar or more sensitive to the previous fluorescence detection method. For the measurement of these chemicals in tomato, Japanese radish and tea by LC/MS (ESI), ion suppression was always observed. To compensate for such an effect, we used a matrix-matched calibration. This compensation method is effective for obtaining accurate values. The recoveries by the developed method were in an acceptable range for the screening method and 90.1-120.9% except for milbemectin and abamectin from tea leaves that had interfering peaks.
In vitro binding assays are useful in the initial screening of endocrine disrupting chemicals. Such assays should be applied to the estrogen receptors (ER) of not only humans but also wildlife. As a system for birds is yet to established, we expressed the ligand binding domain (LBD) of quail ERα and ERβ as a fusion protein with glutathione S-transferase and using these proteins, developed two systems (a competitive enzyme immunoassay and a fluorescence polarization assay) for assaying the capacity to bind ERs in vitro. Moreover, 20 test chemicals selected by Ministry of the Environment of Japan were evaluated in terms of binding ability. Both systems worked well, the competitive enzyme immunoassay proving especially powerful, since it needs no special equipment. This system is applicable to other species including fish, amphibians and reptiles when information on the LBD of ER is available.
Polychlorinated biphenyls (PCBs) are molecules structurally related to dioxins and were widely used in the past in industrial applications. Their chemical stability and high lipophilicity make them persistent pollutants and dangerous occupational contaminants. Our previous results showed that “low concentrations” of PCBs (≤ 10 μg/ml, using the commercial mixture Aroclor 1254) inhibit in vitro hormonal induced myogenic differentiation. Here we extend the notion of PCBs as inhibitors of myogenic differentiation induced by lower serum medium. Aroclor 1254 treatment of myogenic cells, induced to differentiate in low serum medium, inhibits (at concentrations ≤ 10 μg/ml) the extent of fusion and the size of the myotubes as well as the accumulation of sarcomeric myosin. We also investigated whether the cell mortality observed at Aroclor 1254 concentrations ≥ 10 μg/ml is due to necrosis or to apoptosis. Using different approaches, we observed that Aroclor 1254 causes necrosis but not apoptosis of myogenic cells in a dose-dependent manner. In addition, we report that Aroclor 1254 induces release of the intracellular enzymes lactate dehydrogenase (LDH) and creatine kinase (CK) in a dose-dependent manner. These results may explain the CK serum elevation observed in patients exposed to high doses of PCBs.
We have examined the protective effect of Sargassum polycystum (Phaeophyceae) alcoholic extract against a single dose of acetaminophen (intraperitoneally, 800 mg/kg body wt in saline solution) induced hepatic oxidative stress in experimental rats. The levels of serum glutamate oxaloacetate transaminase, pyruvate transaminase, lactate dehydrogenase, alkaline phosphatase, bilirubin, creatinine and blood urea were determined. The activities of glutathione, vitamins (C & E) and the levels of lipid peroxides in the liver homogenate were also determined. The acetaminophen induction resulted a significant elevation in the levels of serum marker enzymes, bilirubin, and creatinine with decreased blood urea. The activities of hepatic glutathione and vitamins (C & E) were also significantly depleted with increased lipid peroxides in acetaminophen intoxicated rats. The oral pre-treatment with alcoholic extract of Sargassum polycystum (200 mg/kg body wt/day for a period of 15 days) showed hepatoprotective nature against acetaminophen induced biochemical changes in the serum and liver tissue. The animals pre-treated with Sargassum polycystum extract alone, did not show any toxicity in the liver tissue, which was confirmed by histopathological studies. These results suggest that the Sargassum polycystum alcoholic extract may probably acted as a natural antioxidant against acetaminophen induced hepatic oxidative stress.
The signal transduction mechanism for aluminum (Al3+)-induced stimulation of bone formation and its crosstalk with the prostaglandin E2 (PGE2) signaling pathway were studied in calvarial osteoblasts from 25-week-old rats (MOB) and those from 90-week-old rats (AOB). Alkaline phosphatase activity, the rate of [3H]proline incorporation into collagenase-digestible proteins, the total area and number of mineralized bone nodules (BN) and the content of calcium in BN, which are the markers for differentiation of osteoblasts, were dose–dependently stimulated by the treatment with Al3+ at a concentration range of 10-7-10-5 M in the cultures of both MOB and AOB. The stimulatory effects of Al3+ on the differentiation markers were abolished by the pretreatment of the cells with pertussis toxin (PTX), an inhibitor of Gi protein, indicating that the effects of Al3+ are mediated through a receptor coupled with Gi protein. Al3+ increased inositol-1,4,5-triphosphate (IP3) production and intracellular concentration of Ca2+ ([Ca2+]i) in the cultures of MOB and AOB: these effects were not observed in the presence of PTX, indicating that the effects of Al3+ are mediated through the activation of phosphatidylinositol-specific phospholipase C (PI-PLC). We have previously shown that 17-phenyl-ω-trinor-PGE2, a selective agonist for an EP1 subtype of PGE2 receptor (EP1), stimulates the differentiation markers in the cultures of MOB through the activation of PI-PLC, but not in those of AOB because of the lack of EP1. The levels of the differentiation markers obtained in the presence of the EP1 agonist were increased by the addition of Al3+ in the cultures of MOB and AOB, while Al3+ increased the levels of IP3 production and [Ca2+]i in the presence of the EP1 agonist only in the cultures of AOB. These results indicate a possibility that PI-PLC molecules stimulated by the signal through Gi protein and those stimulated by the signal through EP1 belong to the same pool and that the Al3+ signal through Gi protein induces cell differentiation via a pathway(s) independent of PI-PLC in addition to that (those) dependent on the PI-PLC. We have also shown that 11-deoxy-PGE1, a selective agonist for an EP2/EP4 subtype of PGE2 receptor (EP2/EP4), inhibits cell differentiation in the cultures of both MOB and AOB. Al3+ had no effect on the basal levels of cAMP production, but the levels induced by the EP2/EP4 agonist were dose–dependently reduced by the treatment with Al3+ at a concentration range of 10-7-10-5 M. The inhibitory effect of Al3+ on adenylyl cyclase was abolished by the pretreatment with PTX. These results indicate that Al3+ suppresses adenylyl cyclase activity induced by the EP2/EP4-mediated signal through the Gi protein-coupled receptor.
Dioxins are present as impurities in agrochemicals applied to the soil. To examine the possibility that dioxins end up in the atmosphere, we compare the homologue composition and some characteristic isomer distributions of polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs) in air and soil samples collected at sites in Ishikawa Prefecture, Japan. Tetrachloro dibenzo-p-dioxin (TeCDD) was the most abundant PCDD homologue in the air samples, while octachloro dibenzo-p-dioxin (OCDD) was the most abundant PCDD homologue in the soil samples. However, at several site, the most predominant homologue in the soil sample was not OCDD but TeCDD. The mean ratio of TeCDDs to PCDDs in the air samples was significantly smaller in winter than in other seasons, but no such seasonal variation was observed in the distribution of PCDF homologues. The abundance of PCDF homologues was inversely related to the number of chlorine substitutions in the air samples. The contribution of each toxic isomer (2,3,7,8-chlorine-substituted) to the total toxicity equivalency quantity (TEQ) in the air samples tended to be intermediate between their contributions to the TEQs in the soil and cinder samples. This result suggested that the air samples were influenced by both soil/dust suspension and combustion. In order to clarify the contributions of agrochemicals to dioxins in the air, we focused on the ratios of several characteristic isomers that are indicators of agrochemicals (chloronitrophen: CNP and pentachlorophenol: PCP) to their homologues. Significant decreases in the ratios of the isomers to their homologues in the air samples were observed only in winter, probably as a result of suppression of dust suspension by the snow cover. Therefore, the contribution of combustion to the dioxin concentration in the air was thought to be relatively large in winter.
The reaction products obtained from the mixture of 1-nitropyrene (1-NP) and sodium chloride were investigated on three metallic oxides as soil components under xenon lamp irradiation in the presence of indoor air. These chemicals including 1-NP were extracted with benzene/ethanol (4/1, v/v) and analyzed by gas chromatography/mass spectrometry (GC/MS). The amounts of 1-NP gradually decreased as irradiation time elapsed on all three metallic oxides (TiO2: titanium dioxide, anatase form; SiO2: silicon dioxide, silicic anhydride form; and Al2O3: aluminum oxide). In TiO2 in particular, 1-NP showed a greater decrease than the other two metallic oxides for all irradiation times. Six types of dinitropyrenes (DNPs) were detected from the reaction products (1,3-, 2,4-, 1,2-, 1,6-, 1,8- and 1,7-DNP). In both TiO2 and Al2O3, all 6 DNPs were detected, while in SiO2, 5 DNPs were confirmed except for 2,4-DNP. In TiO2, 1,7-DNP was formed in especially rich amounts for all irradiation times in comparison with the other metallic oxides. We presumed that 4- and 2-NPs were generated from 1-NP by the photochemical reaction of OH radical, and that 2,4-, 1,2- and 1,7-DNPs were formed continuously by the nitration of these isomers. The formation of 2,4-, 1,2- and 1,7-DNPs was confirmed for the first time on the metallic oxides by the photochemical reaction system of the 1-NP-NOx-Cl ion. NOx in the indoor air was shown to be a source of nitrogen used in forming DNPs in these metallic oxides. The yields and formation patterns of DNPs differed in the 3 metallic oxides as the irradiation time was extended. Hence, the nature of the photochemical reaction in the formation of DNPs differed depending on the type of metallic oxide in question. In SiO2, mutagenicity increased gradually up to 6 hr of irradiation when mutagenic potency showed 2.6 million revertants/sample, and then decreased to 1.5 million revertants/sample at 12 hr. In Al2O3, mutagenicity increased gradually as irradiation time elapsed to a maximum of 1.64 million revertants/sample. In TiO2, mutagenicity decreased rapidly to 60% at 10 min and thereafter decreased gradually to 22% at 12 hr.
The bioavailability of zinc yeast as a functional food ingredient in rats was investigated. Zinc yeast, zinc sulfate, or zinc oxide was used. Serum zinc concentrations were significantly increased by a single oral administration of zinc yeast, zinc sulfate or zinc oxide at a dose of 10 mg Zn/100 g body weight. A significant increase was observed 1 hr after administration and it was also seen with the lowest dose of Zn 0.5 mg/100 g of zinc yeast or zinc oxide. A single oral administration of zinc yeast, zinc sulfate, or zinc oxide (10 mg Zn/100 g) caused a significant increase in liver zinc content. A significant increase in femoral-diaphyseal and -metaphyseal zinc contents was observed with the administration of zinc yeast or zinc sulfate. When zinc yeast or zinc oxide (10 mg Zn/100 g) was orally administered once daily for 7 days to rats, a significant increase in zinc levels in the serum, liver, and femoral-metaphyseal tissues was seen. Femoral-diaphyseal zinc content was significantly increased with the administration of zinc yeast. A significant increase in calcium content and alkaline phosphatase activity in the femoral-diaphyseal and -metaphyseal tissues occurred with the administration of zinc yeast or zinc oxide. The effect of zinc yeast was greater than that of zinc oxide. This study demonstrated that zinc yeast has high bioavailability in rats, and that its administration induces an anabolic effect on bone calcification in vivo. Zinc yeast may be useful as a functional food ingredient.
An antiarrhythmic drug mexiletine, which is metabolized by CYP2D6 and, to a lesser extent, by CYP1A2, is known to sometimes induce allergic reactions. Since mexiletine itself is chemically inert, metabolic activation of the drug, required for the formation of protein adduct, is thought to be a first step in the induction of the allergic reactions. In the present study, we screened several cytochrome P450 (CYP) enzymes for their ability to form protein adducts with mexiletine. Of the 10 CYPs examined (CYP1A1, 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, 3A4 and 3A5), CYP2D6 was most efficient in adduct formation with microsomal proteins. On autoradiographs of SDS-PAGE-separated proteins, a 52 kDa band was detected in the CYP2D6-expressing microsomes. These results suggest that the mexiletine-protein adduct is formed mainly by CYP2D6-dependent metabolic activation.
This research investigated lead in airborne particles smaller than or equal to ten micrometer (PM10) in diameter and mass of PM10 in the Bangkok Metropolitan Area. One hundred and thirty two samples were collected by standard high volume technique from the Bangkok Metropolitan Area during 1999-2000, filtered and measured for lead by flameless atomic absorption spectrophotometry. Concentration of lead in air particles (24 hr average) was 73.22 ng/m3 considerably less than the Thai ambient air quality standard value of 1500 ng/m3. Highest and lowest concentrations, 299.38 and 2.96 ng/m3 were found in Yoawarach road and Phahonyotin road, respectively. This and previous studies indicate a reduction in the concentration of lead in airborne particles since the 1991 campaign to use unleaded gasoline. The results of the study also showed a significant correlation between lead contents and mass of PM10. However, no correlation was observed between the concentration of lead in airborne particles and traffic density. This is probably due to the banning of leaded gasoline throughout the country since 1996 so that lead emissions and subsequent elimination of lead emissions via the exhaust system of vehicle is no longer an issue.
The concentrations of endogenous copper (Cu) and zinc (Zn) in the liver and kidney of female rats were measured after ingestion of cadmium (Cd)-polluted (1.06 ppm) rice or cadmium-supplemented (1.1, 5, 20, and 40 ppm) rice for 12, 18, and 22 months. In the liver, the Cd concentration increases in a dose-dependent manner for the first 18 months. After 18 months, the concentration remained stationary in the low-dose groups, increased in the 5-ppm group, and decreased in the 20- and 40-ppm groups. The Cu concentration was almost unchanged through the experiment, and the Zn concentration increased in a dose-dependent manner. In the kidneys, changes in the Cd concentration resembled that in the liver. The concentrations of Cu increased in a dose-dependent manner at 12 and 18 months. The Zn concentration increased more in the 5-ppm group but not dose dependently.
The acute toxicity of endocrine disrupters in two crustaceans, Americamysis bahia (A. bahia) and Daphnia magna (D. magna), was investigated and the toxicological responses compared. Bisphenol A had the lowest toxicity to D. magna, the 48 hr median lethal concentrations (LC50) values was 12.8 mg/l. However, the toxic sensitivity of A. bahia to bisphenol A was approximately 10-fold higher than for D. magna (48 hr LC50; 1.34 mg/l). The 48 hr LC50 of estradiol-17β was 2.97 and 1.69 mg/l in D. magna and A. bahia, respectively. Nonylphenol had the highest lethal toxicity against both A. bahia (48 hr LC50; 0.051 mg/l) and D. magna (48 hr LC50; 0.18 mg/l). However, ecdysteroids, and ecdysteroidal activity insecticides, such as tebufenozide, and juvenile hormone analog, had no toxic effects against either A. bahia or D. magna at the concentrations tested in this study. These results suggest that A. bahia is a more suitable toxicity test organism for endocrine disrupters than D. magna because of the higher sensitivity of A. bahia to the toxicological effect.
1,4-Dioxane has been classified by the US Environmental Protection Agency and the International Agency for Research on Cancer as a compound that may be carcinogenic in humans. Although there are several reports of 1,4-dioxane being detected in the environment, such as in tap water, there have been few reports on the content of 1,4-dioxane in food. We therefore studied the intake of 1,4-dioxane in food based on the average intake of food in the Kanto area of Japan as reported by the Ministry of Health, Labor and Welfare. The food was cooked in the normal manner and then homogenized in a mixer. A 20 g of sample of the homogenate was added to a solution of the purified water with 0.2 μg of 1,4-dioxane-d8 as a surrogate and the 200 ml azeotropic solution was recovered using the steam distillation method. This solution was applied to a pair of active carbon solid-phase cartridges and the analyte was eluted from each cartridge with dichloromethane. The eluted solution was prepared for gas chromatographic/mass spectrometric analysis by reduction to a volume of 1 ml under a gentle stream of nitrogen. The detection limit of the analysis was 2 μg/kg. We found that the 1,4-dioxane content of 12 food groups ranged between 2 μg/kg and 15 μg/kg. From these results, the total daily intake of 1,4-dioxane was calculated to be 0.440 μg. An intake of this magnitude corresponds to 0.055% of the calculated total daily intake (TDI) (16 μg/kg body weight/day). This study indicates that the amount of 1,4-dioxane intake contributed by food is very low and that this value does not represent a potential problem as it does not raise the risk of carcinogenesis.
Some kinds of vegetable oil and a partially-hydrogenated oil shorten the survival of the stroke-prone spontaneously hypertensive (SHRSP) rats compared with perilla seed oil, soybean oil and lard. The n-3/n-6 ratio of constituent fatty acids, phytosterol content and other factors in these oils have been proposed to affect the survival of this strain. Here, we examined the safety of a fat produced by the inter-esterification of perilla oil and lard (Perilla-Lard) on the bases of the survival of SHRSP rats. The mean survival time decreased in the order of the butter, the Perilla-Lard, the lard, the margarine and the partially-hydrogenated soybean oil (Hyd.Soy) group. The correlations between survival time and cholesterol content or phytosterol content in the diet were analyzed, and the probable health benefits of the new margarine-type fats made of animal fats and oils with high n-3/n-6 ratios were discussed.
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