Single subcutaneous injections of 5 and 10 mg/kg of braxin C (BC), ptaquiloside, a toxin isolated from bracken fern, have been shown to induce hemorrhagic cystitis in guinea pigs. In order to determine whether the hemorrhagic cystitis induced by BC is due to the urotoxic effects or not, BC was administered to the guinea pigs in which the flow of urine to the urinary bladder had been intercepted by cannulation of the ureters under anesthesia. In the animals treated ureteral cannulation, edema and hemorrhage were observed in the urinary bladder following BC administration (10 mg/kg s.c.). These findings suggest that BC induced hemorrhagic cystitis is mediated by hematogenous and not urotoxic factors.
To clarify the mechanism of glucose intolerance induced by FK506, a novel immunosuppressant, 5 or 10 mg/kg/day of FK506 was dosed orally to rats for 2 weeks, and <125>I-insulin binding to the erythrocytes, plasma glucose and insulin levels, and pancreatic insulin content were examined. Insulin binding to the erythrocytes of rat dosed with FK506 was similar to that to erythrocytes of the placebo control; Scatchard analysis confirmed that FK506 did not cause damage to the insulin receptor of the erythrocytes. Contrarily, FK506 caused a clear decrease of pancreatic insulin content as well as a slight decrease of plasma insulin level. The results suggest that the glucose intolerance induced by FK506 is associated with a decrease of insulin secretion, but is not associated with impairment of the insulin receptor.
The effect of ethanol on pharmacokinetics of paraquat was studied in rabbits by intravenous (i.v.) bolus injection of ethanol 0.5 g/kg (or normal saline, in the control group) followed by an i.v. dose of paraquat 20 mg/kg. A greater apparent volume of distribution (Vd), faster distribution rate constants and lower peak plasma concentration (P<0.01) of paraquat were observed in the ethanol-treated than that in the control rabbits. The total clearance of paraquat was not significantly different between the two groups. The effect of ethanol on the intestinal absorption of paraquat was estimated by in situ intestinal perfusion technique in rats. The perfusate contained paraquat 50μg/ml alone or with 1% or 2% ethanol. Inulin 320μg/ml was added to the perfusate for the measurement of water net flux. The absorption clearance of paraquat as well as the absorption of water increased (P<0.01) about two-fold in the presence of ethanol. The results of this study suggest that ethanol may potentiate paraquat toxicity by increasing intestinal absorption and tissue distribution. The critical lethal plasma concentration of paraquat is supposed to be lower in the presence of ethanol owing to increased volume of distribution.
General toxicity studies on 2, 2'-methylenebis(4-methyl-6-tert-butylphenol) (MBMBP) were conducted using male and female Wistar rats. LD<50> values were greater than 5 g/kg BW by oral administration for both sexes. Diarrhea was observed until 5 days. In the subchronic test, rats were fed diet containing MBMBP at 0, 0.12, 0.6 or 3.0% for 12 weeks. Severe suppression of body weight gain was observed in both sexes of 0.6 and 3.0% groups. Death accompanied by hemorrhage from nasal cavity was observed in 0.6 and 3.0% males and 3.0% females. Dose-dependent toxicity to the liver in both sexes was observed in blood chemical analysis. Histopathologically, testicular atrophy and decrease of spermatogenesis were dose- and time-dependently observed in all treated males. Atrophy of ovaries was evident in 0.6 and 3.0% females. Thymus atrophy and bone marrow hypoplasia were observed in both sexes of 0.6 and 3.0% groups. In the chronic test, rats were fed diet containing MBMBP at 0, 0.01, 0.03 and 0.1% for 18 months. Body weight gain was only suppressed in both sexes receiving 0.1%. Histopathologically, testicular atrophy and decrease of spermatogenesis were apparent in 0.1% males. No neoplastic response by MBMBP administration was noted. NOAEL was concluded to be 0.03% in the diet (12.7 mg/kg BW/day for male rats and 15.1 mg/kg BW/day for female rats).
The genotoxicity of polyoxyethylene hydrogenated castor oil 60 (HCO-60) was examined in reverse mutation test in bacteria, chromosome aberration test in vitro and micronucleus test in mice. The in vitro tests were done with and without metabolic activation using rat liver microsomal fraction. HCO-60 did induce neither reverse mutation in Salmonella typhimurium TA100, TA98, TA1535, and TA1537 and in Escherichia coli WP2uvrA, nor chromosome aberrations in Chinese hamster V79 cells. In addition, no increase in micronucleated polychromatic erythrocytes was elicited in the bone marrow of BDF1 male and female mice. It is concluded that HCO-60 was not genotoxic in these in vitro and in vivo assays.
Since phosphatidylcholine is a primary membrane component and its peroxidation may result in disruption and dysfunction of the biomembrane, we used phosphatidylcholine hydroperoxide (PCOOH) as an index of oxidative-stress-related injury. We detected the occurrence of PCOOH in both liver and plasma from rats subjected to hepatic ischemia-reperfusion, and demonstrated that liver and plasma PCOOH levels reflect the extent of liver injury. However, the accuracy in measuring PCOOH levels, particularly in blood samples, is still in question since PCOOH may be rapidly eliminated by phospholipase A2 enzymes, which are widespread, easily activated, and have a preference for oxidized glycerophospholipids. When PCOOH levels were determined, using high-performance liquid chromatography to detect chemiluminescence (CL), the plasma samples showed a broad CL peak that began to elute at the same time as in the liver samples, but lasted longer. The peak appeared to contain hydroperoxides from multiple lipid classes. In addition to PCOOH, the hydroperoxides of sphingomyelin and lysophosphatidylcholine (SPHOOH and LPCOOH) were identified in the plasma of rats subjected to ischemia-reperfusion using thin layer chromatography separation and subsequent visualization, infrared spectroscopy, and hydrolysis under mild alkaline conditions. These results indicate that the occurrence of SPHOOH and LPCOOH, as well as PCOOH, may reflect liver damage related to ischemia-reperfusion.
When female SD rats were continuously treated with Etretinate throughout pre-mating, gestation, and lactation periods, the resulting F1 pups exhibited low viability and inhibition of somatic growth after birth (Hummler et al., 1981). Nevertheless, these pups showed no notable change in body weight and external appearance at birth. We used the cross-fostering (between control and treated groups) method and investigate the neonatal viability and the growth hormonal changes in order to assess which treatment period of gestation or lactation was mainly involved in these effects and what changes were actually induced in the F1 pups. The results showed that low viability and inhibition of somatic growth after birth were mainly related to treatment during the gestation period, and these effects were augmented by treatment during the lactation period. Serum GH and IGF-I levels were increased on day 21 in F1 pups groups in which inhibition of somatic growth was observed. These results indicated that treatment with Etretinate during the gestation period might induce a decrease in the number of receptors of GH and IGF-I or other changes, such as a poor-response in target tissues due to a down-regulation, with an increase of serum GH and IGF-I levels.