Forgot your password?
New user?
New Window Opens on the Secret Life of Microbes: Scientists Develop First Microbial Profiles of Ecosystems
CAS announces the release of SciFinder Scholar for Mac OS X
Press Releases
Press Releases
| Check out our New Publishers' Select for Free Articles |
Archives of Toxicology (v.74, #1)
Effect of cadmium or magnesium on calcium-dependent central function that reduces blood pressure by Den'etsu Sutoo; Kayo Akiyama (pp. 1-4).
The effect of intracerebroventricular (i.c.v.) administration of cadmium or magnesium on central calcium-dependent blood pressure regulation was investigated. The systolic blood pressure of spontaneously hypertensive rats (SHR; male, 13 weeks of age) decreased following i.c.v. administration of cadmium chloride (20 nmol/rat), and increased following i.c.v. administration of magnesium chloride (20, 600, and 1200 nmol/rat). The hypotensive effect of cadmium was suppressed by i.c.v. administration of W-7 (a calmodulin antagonist, 30 μg/rat). Taking into consideration these results with our previous reports, it is suggested that cadmium binds to the calcium-binding sites of calmodulin and activates calcium/calmodulin-dependent enzymes in a disorderly manner, whereas magnesium does not. Therefore, cadmium increases dopamine synthesis in the brain via a calmodulin-dependent system, and the resultant increase in dopamine levels inhibits sympathetic nerve activity and reduces blood pressure in SHR.
Keywords: Key words Blood pressure; Calcium/calmodulin; Cadmium; Dopamine synthesis in brain; Magnesium; Spontaneously hypertensive rats (SHR)
Evidence that the reactions of nickel in the presence of vitamin C do not produce toxic oxygen intermediates such as hydroxyl but ascorbate and carbon radicals by Henryk J. Salacinski; Paul O'Brien (pp. 5-12).
A variety of reactions containing different amounts of nickel ions together with vitamin C were prepared and used in spin trapping experiments designed to show nickel is not a Fenton active metal. Carbon based radicals were observed at low ratios of ascorbate to nickel, and ascorbate radical was observed at high ratios of ascorbate to nickel. No buffer effects were observed. There was no evidence for oxygen intermediates as products of the reaction with 5,5-dimethyl-1-pyrroline N-oxide (DMPO) or α-(4-pyridyl-1-oxide)-N-tert-butylnitrone (POBN), seeming to indicate nickel is not a Fenton metal. To test this hypothesis further trapping studies were run with the singlet oxygen trap 2,2,6,6-tetramethyl-4-piperidone hydrochloride, in which dioxygen was found not to affect the formation of carbon radicals. These results help to explain the damage to DNA observed in the presence of vitamin C and nickel in vitro.
Keywords: Key words Nickel; Vitamin C; Non-Fenton; Carbon radical
Role of high-energy phosphates and their metabolites in protection of carbofuran-induced biochemical changes in diaphragm muscle by memantine by Ramesh C. Gupta; John T. Goad (pp. 13-20).
A combined antidotal treatment with memantine HCl (MEM, 18 mg/kg, s.c.) and atropine sulfate (ATS, 16 mg/kg, s.c.) provided complete protection against acute carbofuran toxicity (1.5 mg/kg, s.c.) in rats by multiple mechanisms. Carbofuran, in addition to inhibiting serine-containing esterases, also perturbed the activities of mitochondrial/cytoplasmic biomarker enzymes (creatine kinase, CK; and lactic dehydrogenase, LDH) in diaphragm muscle. The observed changes in the activity of biomarker enzymes were reflected in serum as a result of their leakage from the diaphragm due to a depletion of high-energy phosphates, such as adenosine triphosphate (ATP, 27%) and phosphocreatine (PCr, 33%) and their metabolites (ADP, 36%; AMP, 35%; and Cr, 38%). Combined treatment with MEM and ATS provided protection and reversal of the induced changes in biomarkers by preventing depletion of high-energy phosphates and thus maintaining normal cell membrane characteristics, including permeability and integrity. These results, along with those reported previously, indicate that MEM antagonizes carbofuran toxicity by multiple mechanisms.
Keywords: Key words Memantine; Atropine; Carbofuran muscle toxicity; Acetylcholinesterase; Creatine kinase
Effect of human plasma on the reactivation of sarin-inhibited human erythrocyte acetylcholinesterase by F. Worek; P. Eyer; D. Kiderlen; H. Thiermann; L. Szinicz (pp. 21-26).
The reactivation of organophosphate-inhibited acetylcholinesterase (AChE) by oximes inevitably results in the formation of highly reactive phosphoryloximes (POX), which are able to re-inhibit the enzyme. In this study, the dependence of POX formation on AChE concentration was investigated with sarin-inhibited human erythrocyte AChE (EryAChE). A marked dependence was found with obidoxime but not with the experimental oxime HI 6, suggesting great differences in the decomposition rates of the respective POXs. At a physiological erythrocyte content the reactivation of EryAChE was markedly affected by POX with obidoxime and pralidoxime (2-PAM) but not with the newer oximes HI 6 and HLö 7. Addition of extensively dialysed, sarin-treated human plasma reduced the reactivation by obidoxime and 2-PAM even more. Obidoxime and 2-PAM were superior to HI 6 and HLö 7 in reactivating butyrylcholinesterase (BChE). This effect was pronounced in diluted plasma, but was obscured in concentrated plasma, probably because of re-inhibition by the generated POX. Addition of native erythrocytes to sarin-treated plasma resulted in marked inhibition of EryAChE in the presence of obidoxime, suggesting a higher affinity of the POX for EryAChE. The results indicate that obidoxime and 2-PAM may reactivate sarin-inhibited AChE insufficiently due to re-inhibition by the POX formed. In addition, the re-inhibition of EryAChE may be aggravated by the POX that is produced during BChE reactivation. These reactions must be regarded as therapeutically detrimental and disqualify those oximes which are capable of forming stable POX by reactivation of BChE.
Keywords: Key words Organophosphate; Acetylcholinesterase; Oximes; Human; Reactivation
The phosphoryl oxime-destroying activity of human plasma by D. Kiderlen; F. Worek; R. Klimmek; P. Eyer (pp. 27-32).
The potential of obidoxime and other pyridinium-4-aldoximes to reactivate dimethyl- and diethylphosphorylated cholinesterases is markedly restricted by the inevitable formation of rather stable phosphoryl oximes (POXs) with high anticholinesterase activity. This effect is hardly seen with very dilute enzyme preparations, but becomes significant at physiological enzyme concentrations. Human plasma with the butyrylcholinesterase irreversibly blocked by soman was able to stimulate obidoxime-induced reactivation of concentrated erythrocyte acetylcholinesterase (EryAChE) to the same extent as was observed with a dilute preparation, suggesting phosphoryl oxime-destroying capacity. The inactivating factor, which was tentatively termed POX-hydrolase, had (1) a molecular weight of >100 kDa; (2) required Ca2+, which could not be substituted by Zn2+ or Mg2+; and (3) lost its catalytic activity reversibly in the presence of ethylenediaminetetraacetic acid (EDTA). The enzyme activity varied widely (20-fold) among different subjects and did not follow the activity pattern of human serum paraoxonase (PON1). Rabbit plasma with its particularly high paraoxonase content showed only weak POX-hydrolase activity. These data suggest POX-hydrolase to be a different entity. POX-hydrolase was most active with the putative phosphoryl-obidoxime from paraoxon-ethyl, less with the product from paraoxon-methyl and least with that from diisopropylfluorophosphate. The analogue TMB-4 reacted similarly to obidoxime. The putative phosphonyl oximes arising by the reaction of obidoxime with nerve agents were apparently not cleaved. The variation in POX-hydrolase activity may additionally contribute to the variable response to oxime therapy in patients with organophosphate insecticide poisoning.
Keywords: Key words Phosphoryl oximes; Acetylcholinesterase; Plasma; Hydrolase; Organophosphate
Induction and inhibition of testicular germ cell apoptosis by fluoroacetate in rats by Kazutoshi Shinoda; Kunitoshi Mitsumori; Chikako Uneyama; Masato Uehara (pp. 33-39).
Fluoroacetate (FA), an inhibitor of aconitase, is known to lower the intracellular level of adenosine triphosphate (ATP), which recently has been suggested to be a possible determinant of the form of cell death, apoptosis or necrosis. To investigate which form of germ cell death occurs in FA-induced testicular toxicity, adult Sprague Dawley rats were given a single oral dose of FA (0.5 or 1.0 mg/kg) and euthanized at 3, 6, 12, 24, 48, and 72 h thereafter. Germ cell degeneration was histologically first found in early round spermatids at stage I and in spermatogonia at stages II-IV of seminiferous tubules 6 and 12 h, respectively, after dosing. Degenerating spermatogonia exhibited characteristic features of apoptosis as demonstrated by both electron microscopy and in situ terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL), whereas spermatids did not. At the 24 and 48 h time points, degenerating spermatids were continually present and subsequently formed multinucleated giant cells, while the number of degenerating spermatogonia and TUNEL-labeled spermatogonia was drastically and/or significantly decreased compared to those from the control group, indicating that spontaneous male germ cell apoptosis is inhibited. Coincident with these morphological changes, DNA laddering on gel electrophoresis was apparent only 12 h after dosing. The results demonstrate that FA induces either apoptosis or necrosis of male germ cells in the early stage after dosing and subsequently inhibits spontaneous apoptosis.
Keywords: Key words Fluoroacetate; Apoptosis; Testis; Toxicity
Cytotoxicity of capsaicin in monkey kidney cells: lack of antagonistic effects of capsazepine and Ruthenium red by E. E. Creppy; F. Richeux; M. -R. Carratú; V. Cuomo; C. Cochereau; R. Ennamany; D. Saboureau (pp. 40-47).
Capsaicin is a natural product of Capsicum peppers, excitatory effects of which have been shown to be mediated by the recently cloned vanilloid receptor 1 (VR1). Since previous studies have shown that capsaicin inhibits protein synthesis, experiments were performed to investigate whether this effect is mediated by VR1 receptor on cultured monkey kidney cells (Vero cells). The capsaicin uptake was assessed in cellular homogenate and in medium by high-performance liquid chromatography (HPLC) separation and quantification on C18 reverse-phase column and fluorescence detection. Toxic effects were assessed by incorporation of [3H]L-leucine into cellular proteins in the presence of capsazepine, the VR1 vanilloid receptor antagonist and Ruthenium red or tyrosine or calcium. Capsazepine (1 to 256 μM) did not modify the uptake rate of capsaicin for incubation times up to 24 h and did not antagonize capsaicin-induced protein synthesis inhibition. It rather inhibited protein synthesis per se from 100 to 256 μM. Ruthenium red which blocks mitochondrial calcium uptake, inhibited protein synthesis and did not antagonise or increase synergistically the effects of capsaicin. Interestingly in a medium deprived of calcium and supplemented by calcium chloride (10–50 μM) the protein synthesis inhibition induced by capsaicin is antagonised somehow. There was no prevention of capsaicin diffusion into the cells. Tyrosine, which seems to be the best preventive agent of capsaicin inhibitory effects, prevents its metabolism but not its diffusion. Capsaicin might enter cells by diffusion and interfere with protein synthesis machinery by competition with tyrosine which in turn prevents the metabolism of capsaicin. The results of the present study suggest that cell responses to capsaicin may be transduced through at least two molecular pathways, one involving VR1, since the receptor antagonist capsazepine fails to prevent the inhibitory effect of capsaicin in Vero cells of renal origin.
Keywords: Key words Capsaicin; Capsazepine; Ruthenium red; Cytotoxicity; Vero cells
Changes in serum α2u-globulin levels in male rats given diethylstilbestrol and applicability to a screening test for endocrine-disrupting chemicals by Masahiro Takeyoshi; Shunji Anai; Kazutoshi Shinoda (pp. 48-53).
α2u-Globulin (AUG) is a major rat urinary protein, which has a molecular weight of 16 kDa (kidney type) or 19 kDa (native type). The biosynthesis of this protein is under multi-hormonal regulation. In this study, we investigated changes in serum AUG level and their association with changes in the reproductive organs of male rats after the administration of the estrogenic chemical, diethylstilbestrol (DES) at doses ranging from 0.01 mg/kg per day to 100 mg/kg per day by gavage for 14 days. Our aim was to establish basic data for the development of a new screening method for endocrine disrupting chemicals based on serum AUG levels. DES treatment decreased the weight of testes in a dose-dependent manner; and was accompanied by atrophic histopathological changes in testes. Testis weights were significantly decreased by the group given 1 mg/kg per day DES; however, histopathological abnormalities were found in the group given 0.1 mg/kg per day DES. In four of five animals in the group given 1 mg/kg per day there was no significant decrease in testis weight and only a slight or moderate degeneration of the pachytene spermatocytes. Despite these findings, serum AUG levels in this group decreased markedly, while the serum AUG level markedly decreased even in the animals with no histopathological change in the 1 mg/kg per day or 0.1 mg/kg per day groups with no histopathological change also showed decreased serum AUG level. These results suggest that the serum AUG level may be a sensitive parameter for detecting the activity of estrogenic chemicals in intact male rats. Although a uterotropic assay has been proposed for immature female or ovariectomized female rats and is currently undergoing validation studies internationally, there is no screening method for estrogenic chemicals in intact male animals. More data on AUG changes by treatment with other estrogenic chemicals are needed in order to determine the sensitivity and specificity of this response to estrogens. Nonetheless, an AUG-based screening test for estrogenic chemicals may be useful owing to its applicability to conventional toxicity studies and an apparently higher sensitivity of this parameter compared to organ weight change or histology of testis in intact male rats and applicability to conventional toxicity studies.
Keywords: Key wordsα2u-Globulin; Diethylstilbestrol; Endocrine disrupter; Rat; Screening
Lack of oxidative DNA damage or initiation of carcinogenesis in the kidneys of male F344 rats given subchronic exposure to p-dichlorobenzene (pDCB)at a carcinogenic dose by Takashi Umemura; Yukio Kodama; Yuji Kurokawa; Gary M. Williams (pp. 54-59).
p-Dichlorobenzene (pDCB) is a male rat kidney carcinogen believed to act through α2u-globulin nephropathy. Recent data on metabolism, however, suggest a potential for generating oxidative stress. To examine possible mechanisms of kidney carcinogenesis, pDCB was studied for ability to produce 8-oxodeoxyguanosine (8-oxodG) in kidney nuclear DNA and for initiating activity in a two-stage renal carcinogenesis model. F344 male rats were given pDCB by intragastric instillation, 5 days/week for 13 weeks at 300 mg/kg per day, which is a carcinogenic dose with chronic administration. To assess initiation after exposure, trisodium nitrilotriacetic acid (NTA), a kidney tumor promoter was given in the drinking water at 1000 ppm for 39 weeks. At the end of the exposure segment, pDCB did not produce an increase of 8-oxodG levels in the kidney nuclear DNA in contrast to potassium bromate (KBrO3). Following NTA promotion, no neoplastic lesions occurred in rats given pDCB, although diethylnitrosamine carcinogenesis was enhanced. Thus, pDCB did not produce oxidative DNA damage in the rat kidney or effect initiation of kidney carcinogenesis. These data suggest that oxidative stress is not involved in pDCB-induced renal carcinogenesis. The α2u-globulin-mediated chronic nephropathy probably acts as a promoter, not an initiation of renal carcinogenesis. Accordingly, pDCB is assessed to have no cancer hazard to humans who are not susceptible to the α2u-globulin nephropathy.
Keywords: Key wordsp-Dichlorobenzene; 8-Oxodeoxyguanosine; Cell proliferation; Renal carcinogenesis