The aim of the present investigation deals with the hematology and hepatorenal function of Caesalpinia bonducella Flem. and Bauhinia racemosa Lam. belonging to the Family: Caesalpiniaceae, and used in the traditional system of medicine. The tribal people of Kolli Hills, Tamil Nadu, India, use the leaves of Caesalpinia bonducella and the stem bark of Bauhinia racemosa in combination with some other herbs for the treatment of various tumors, liver disorders, inflammation and some other diseases. In ancient Ayurveda medicine these plants were mentioned to possess antitumor agents. Since there are no scientific reports regarding the toxicological aspects of these plants, the present investigation deals with the sub-chronic toxicity studies of a methanol extract of Caesalpinia bonducella (MECB) leaves and Bauhinia racemosa (MEBR) stem bark in Swiss albino mice. The MECB and MEBR were administered intraperitoneally (i.p) to Swiss albino mice twice a week for thirteen weeks. No significant alterations in hematological, biochemical and histopathological parameters were observed in the MECB- and MEBR-treated groups at the doses of 100 and 200 mg/kg body weight. Administration of MECB and MEBR at the dose of 400 mg/kg body weight elevated the levels of serum enzymes and altered the hematological parameters. Our results suggested that MECB and MEBR at doses 100 and 200 mg/kg body weight did not induce any toxic effects in the mice. Adverse effect was noted at the dose of 400 mg/kg body weight.
General toxicity studies on 2,2'-isobutylidenebis(4,6-dimethylphenol)(IBBMP) were conducted using male and female Wistar rats. In the acute test, the oral LD50 values were 119 mg/kg BW in males and 103 mg/kg BW in females. Hypersensitivity, loss of righting reflex and abdominal position were observed. In the subchronic test, rats were fed a diet containing IBBMP at levels of 0, 20, 100 or 500 ppm for 13 weeks with interim sacrifice at 4 weeks (equal to 0, 1.1, 5.5 or 27.9 mg/kg BW/day in males and 0, 1.1, 5.9 or 29.6 mg/kg BW/day in females). In both sexes, there were no changes in general condition, body weight gains and food intakes in all groups. No deaths were observed in all groups. Significant increase in AST was observed in 500 ppm males at Week 4. However, the change was not observed at Week 13. Slight but significant decreases in creatinine were also observed in 100 ppm females at Week 13 and 500 ppm males and females at Weeks 4 and 13. Total cholesterol (T-CHO) was significantly elevated in females of the 500 ppm group at Weeks 4 and 13. Absolute and relative liver weights were increased in 500 ppm of both sexes at Week 4. In females, the increases were also observed at Week 13. However, no remarkable histopathological findings were observed in all treated groups. In the chronic test, rats were fed a diet containing IBBMP at levels of 0, 100, 500 and 1500 ppm for 18 months with interim sacrifices at 6 and 12 months (equal to 0, 3.8, 19.4 or 59.4 mg/kg BW/day in males and 0, 4.3, 20.9 or 67.5 mg/kg BW/day in females). No remarkable changes in general appearance were observed in any rats. Body weight gains, food intakes and survival rates in all treated animals were comparable to those of the control. No remarkable changes in the hematological parameters were observed. T-CHO was significantly elevated in females of the 1500 ppm groups throughout the experiment. Significant increases or tendencies for increase in relative liver weights were observed in the 500 and 1500 ppm animals of both sexes. Increased incidences of swelling in liver cells were observed in 1500 ppm males at 6 months and 1500 ppm females at 12 and 18 months. At 18 months, dose-dependent increases in thickness of basement membrane of renal tubules and Bowman's capsule and cell infiltration to the interstitium of the kidney were observed in males. Significant increases of hyaline cast and basophilic change were also observed in 1500 ppm males. In females, increased incidences of hyaline cast were observed at 500 ppm and higher at 18 months. No other toxicity was apparent. No neoplastic lesions that could be attributed to IBBMP were observed in any organs of either sex. From the result of the chronic toxicity test, the no-observed-adverse-effect level (NOAEL) for IBBMP was concluded to be 100 ppm in the diet (4.26 mg/kg BW/day) in female rats on the basis of induction of hyaline cast in renal tubules at 500 ppm, whereas, in males, only a lowest-observed-adverse-effect level (LOAEL) was given as 100 ppm (3.84 mg/kg BW/day) on the basis of induction of thickening of basement membrane in renal tubules at 100 ppm.
This paper describes for the first time a massive intoxication episode due to consumption of shellfish contaminated with 7-O-acyl-derivative dinophysistoxin-1, named Dinophysistoxin-3 (DTX-3). 7-O-acyl-derivative dinophysistoxin-1, a compound recently described in the literature, was found in shellfish samples collected in the Chilean Patagonia fjords. This compound does not inhibit Protein Phosphatases and also does not elicit the symptoms described for Diarrheic Shellfish Poisoning (DSP). The data showed here, give evidence of metabolic transformation of 7-O-acyl-derivative dinophysistoxin-1 (DTX-3) into Dinophysistoxin-1 (DTX-1, Methyl-Okadaic acid) in intoxicated patients. This metabolic transformation is responsible for the diarrheic symptoms and the intoxication syndrome showed by patients that consumed contaminated shellfish, which showed only the presence of 7-O-acyl-derivative dinophysistoxin-1. Patients fecal bacterial analysis for the presence of enteropathogens was negative and the mouse bioassay for DSP, performed as described for regulatory testing, was also negative. The HPLC-FLD and HPLC-MS analysis showed only the presence of DTX-3 as the only compound associated to DSP toxins in the contaminated shellfish samples. No other DSP toxins were found in the shellfish sample extracts. However, the patient fecal samples showed DTX-1 as the only DSP toxins detected in fecal. Moreover, the patient fecal samples did not show DTX-3. Since 7-O-acyl-derivative dinophysistoxin-1 (DTX-3) was the only compound associated to DSP toxins detected in the shellfish samples, an explanation for the diarrheic symptoms in the intoxicated patients would be the metabolic transformation of DTX-3 into DTX-1. This transformation should occur in the stomach of the poisoned patients after consuming 7-O-acyl-derivatives dinophysistoxin-1 (DTX-3) contaminated bivalves.
An acidic microenvironment formed by vacuolar ATPase (V-ATPase) expressed in plasma membranes of osteoclasts is thought to be indispensable for bone resorption. This study examined the efficacy of a novel V-ATPase inhibitor, FR202126, in reducing alveolar bone loss caused by experimental periodontitis in rats. FR202126 inhibited H+ transport in plasma membrane vesicles of murine osteoclasts, whereas FR202126 exerted no effect on H + transport of mitochondrial ATPase or gastric H+,K+-ATPase, indicating that FR202126 is a specific inhibitor of V-ATPase. As expected from the mechanism, FR202126 remarkably inhibited in vitro bone resorption whatever bone resorptive factors were added. Moreover, FR202126 was also able to exert an inhibitory effect on in vivo bone resorption. Experimental periodontitis was induced by ligature wire tied around the contact between the first and second maxillary molars. Insertion of ligature wire for 7 days induced alveolar bone destruction by activating osteoclasts. Oral administration of FR202126 (u.i.d.) significantly prevented alveolar bone loss in experimental periodontitis which may offer a new approach to treatment of periodontal disease.
The effects of selective β2-adrenoceptor agonists on proinflammatory cytokines and the expression of stress-inducible proteins have not yet been clarified. We investigated the effect of a higher dose (60 mg/kg intravenously) of salbutamol, a selective β2-adrenoceptor agonist, on the induction of interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α in plasma and the expression of protein and mRNA of metallothioein-1 (MT-1), heme oxygenase-1 (HO-1) and inducible nitric oxide synthase (iNOS) in heart, lung, liver and spleen in rats. The plasma IL-6 concentration was significantly increased after administration with a maximum increase at 3 hr in a dose-dependent manner, but IL-1β and TNF-α concentrations were not changed. MT-1 mRNA increased in heart, lung and liver, but not in spleen, and MT-1 protein increased in endocardium, fibroblasts of lung and periportal regions in liver. HO-1 mRNA was not changed in lung, decreased at 3 hr in liver and spleen, and increased at 6 hr in liver. Contrary to liver, HO-1 mRNA in the heart increased at 3 hr and decreased at 6 hr. HO-1 protein increased in cardiomyocytes and centrilobular regions in the liver. iNOS mRNA increased in lung, liver and spleen, but decreased in the heart, and iNOS protein increased in alveolar type II cells and hepatocytes, and decreased in necrotic cardiomyocytes. In contrast, a lower dose (6 mg/kg intravenously) of salbutamol suppressed lipopolysaccharide-induced HO-1 and iNOS mRNA. We conclude that salbutamol tissue- and dose-dependently alters the expression of stress-inducible proteins.
Aldehyde dehydrogenase 2 (ALDH2) is an important enzyme that oxidizes acetaldehyde. Approximately 45% of Chinese and Japanese individuals are inactive ALDH2 phenotype; acute acetaldehyde toxicity has not been evaluated in these populations. We compared the acute acetaldehyde toxicity between wild-type (Aldh2+/+) and Aldh2-inactive transgenic (Aldh2-/-) mice who were administered an intraperitoneal (ip) injection of a single dose of acetaldehyde. This comparison was made based on the LD50 values of acetaldehyde and the symptoms following the ip injection. Blood acetaldehyde level was measured in the 400 mg/kg dose group. Immediately after administration of acetaldehyde, the mice exhibited hypoactivity and staggering gait. Subsequently, symptoms such as pale skin, prone position, coma, and abnormal deep respiration were observed. In cases of death, dyspnea, wheezing, and hypothermia were observed from 15 to 30 min after the administration. In cases of survival, crouching, bradypnea, flushing and piloerection were observed. Significant latency of symptom recovery was found in the Aldh2+/- mice as compared with the Aldh2+/+ mice; however, no statistical difference was observed in the acetaldehyde LD50 values. This might be attributable to the absence of a significant difference in the blood acetaldehyde concentrations in both mice during the first 0−15 min following administration; however, acetaldehyde elimination delay was observed in the Aldh2-/- mice as compared with the Aldh2+/+ mice. Acetaldehyde toxicity difference was observed between the Aldh2+/+ and Aldh2-/- mice; however, no difference in acetaldehyde lethality was observed by administration of a single dose of an ip acetaldehyde injection.
Aldehyde dehydrogenase 2 (ALDH2) is an important enzyme that oxidizes acetaldehyde. Approximately 45% of Chinese and Japanese individuals have the inactive ALDH2 genotypes (ALDH2*2/*2 and ALDH2*1/*2); acute inhalation toxicity of acetaldehyde has not been evaluated in these populations. We compared the toxicity between wild-type (Aldh2+/+) and Aldh2-inactive transgenic (Aldh2-/-) mice by using the paired acute inhalation test modified from the acute toxic class method (OECD TG433). Blood acetaldehyde level was measured 4 hr after the inhalation. A pair of Aldh2+/+ and Aldh2-/- mice was put into a chamber and was exposed to 5000 ppm of acetaldehyde. At the start of the inhalation, the mice exhibited hypoactivity and closing of the eyes. Subsequently, symptoms such as crouching, bradypnea, and piloerection were observed. Flushing was observed only in the Aldh2+/+ mice. Symptoms such as tears, straggling gait, prone position, pale skin, abnormal deep respiration, dyspnea, and one case of death were observed only in the Aldh2-/- mice. The symptoms did not change 1 hr after inhalation in the Aldh2+/+ mice. In contrast, in the Aldh2-/- mice, the symptoms became more severe until the end of the inhalation. The blood acetaldehyde level in the Aldh2-/- mice was approximately twice that in the Aldh2+/+ mice 4 hr after inhalation. The Aldh2-/- mice evidently showed more severe toxicity as compared with the Aldh2+/+ mice due to acute inhalation of acetaldehyde at a concentration of 5000 ppm. Acetaldehyde toxicity in Aldh2+/+ and Aldh2-/- mice was estimated and classified one class different. Based on this study, acetaldehyde inhalations were inferred to pose a higher risk to ALDH2-inactive human individuals.
We evaluated the toxicity of tetradecanoic acid methyl ester sodium salt (C14-MES), a major component of fabric detergents, following the test guidelines of the Organization for Economic Cooperation and Development. The rat acute oral LD50 was 1,000 mg/kg in males and 500 mg/kg in females. Applying the combined repeated dose and reproductive/developmental toxicity screening test (ReproTox), we exposed groups of Crj:CD (SD) IGS rats to C14-MES in the diet at concentrations of 0, 0.3, 0.6, or 1.2%. We observed decreases in fibrinogen levels and longer prothrombin time at the 1.2% treated level in females and decreases in serum triglyceride levels in both sexes at the 0.6% and 1.2% treatment levels, but the effects were not clinically significant. The no-observed-effect-level (NOEL) for repeated dose toxicity was 0.3% (175 mg/kg body weight/day for males, 249 for females). The NOEL for reproduction/developmental toxicity was 1.2% (740 mg/kg for males, 1039 for females). C14-MES was negative in the reverse gene mutation assay and the chromosomal aberration test and did not induce skin sensitization in the guinea pig maximization test. These data confirm that C14-MES is of low hazard potential.