Metabolic profiling studies on the toxicological effects of realgar in rats by H NMR spectroscopy

The toxicological effects of realgar after intragastrical administration (1 g/kg body weight) were investigated over a 21 day period in male Wistar rats using metabonomic analysis of ¹H NMR spectra of urine, serum and liver tissue aqueous extracts. Liver and kidney histopathology examination and serum clinical chemistry analyses were also performed. ¹H NMR spectra and pattern recognition analyses from realgar treated animals showed increased excretion of urinary Kreb's cycle intermediates, increased levels of ketone bodies in urine and serum, and decreased levels of hepatic glucose and glycogen, as well as hypoglycemia and hyperlipoidemia, suggesting the perturbation of energy metabolism. Elevated levels of choline containing metabolites and betaine in serum and liver tissue aqueous extracts and increased serum creatine indicated altered transmethylation. Decreased urinary levels of trimethylamine-N-oxide, phenylacetylglycine and hippurate suggested the effects on the gut microflora environment by realgar. Signs of impairment of amino acid metabolism were supported by increased hepatic glutamate levels, increased methionine and decreased alanine levels in serum, and hypertaurinuria. The observed increase in glutathione in liver tissue aqueous extracts could be a biomarker of realgar induced oxidative injury. Serum clinical chemistry analyses showed increased levels of lactate dehydrogenase, aspartate aminotransferase, and alkaline phosphatase as well as increased levels of blood urea nitrogen and creatinine, indicating slight liver and kidney injury. The time-dependent biochemical variations induced by realgar were achieved using pattern recognition methods. This work illustrated the high reliability of NMR-based metabonomic approach on the study of the biochemical effects induced by traditional Chinese medicine.     

Subchronic toxicity study of ulvan from Ulva pertusa (Chlorophyta) in Wistar rats

Ulvan extracted from Ulva pertusa (Chlorophyta) is a group of sulfated heteropolysaccharide, for simplicity, the sulfated polysaccharide is referred to as ulvan in this paper. To our knowledge, there is no detailed report investigating the toxicity of ulvan. In this study, the subchronic (6 months) toxicity of varying levels of ulvan extracted from U. pertusa was investigated in Wistar rats after oral administration. ALT, ALB, ALP, WBC, PLT, and liver relative organ weigh of female rats showed significantly difference at 3000 mg/kg body weight per day, compared with control group. On the other hand, TG, T-CHO concentrations of female rats (6 months) were significantly decreased at 600, 1200 and 3000 mg/kg body weight per day. This result proved that ulvan had antihyperlipidemic activity. Beside, ulvan showed anticoagulant activity in this study. Overall, our findings indicated that ulvan had affected specific hematology, serum biochemistry parameters and liver, and had great differences between males and females rats.     

Subchronic toxicity study of Coptidis Rhizoma in rats

Ethnopharmacological relevance

Coptidis Rhizoma (CR) is a medical herb from the family Ranunculacease that has been used to treat gastroenteritis, dysentery, diabetes mellitus, and severe skin diseases.

Aim of the study

To evaluate the no-observed-adverse-effect level (NOAEL) and the toxicity of CR, following repeat oral administration to rats for 13 weeks.

Materials and methods

CR was administered by oral gavage to groups of rats (n=10/group, each sex) at dose levels of 0 (control), 25, 74, 222, 667 or 2000 mg/kg/day 5 times per week for 13 weeks. Mortality, clinical signs, body weights, food consumption, hematology, serum chemistry, urinalysis, vaginal cytology and sperm morphology, organ weights, gross and histopathological findings were compared between control and CR groups.

Results

Urinalysis showed a significant increase in N-acety1-β-glucosaminidase in males in the 2000 mg/kg/day group (P<0.01). However, no mortality or remarkable clinical signs were observed during this 13-week study. No adverse effects on body weight, food consumption, hematology, serum chemistry, organ weights, gross lesion, histopathology, vaginal cytology, sperm motility, or deformity were observed in the males or female rats treated with CR.

Conclusions

On the basis of these results, the NOAEL of CR is determined to be 667 mg/kg/day for males and 2000 mg/kg/day for females.     

Safety of high doses of Propionibacterium freudenreichii ET-3 culture in healthy adult subjects

Propionibacterium freudenreichii ET-3 (7025) culture, a cell-free product of whey fermentation by P. freudenreichii ET-3, has been shown to promote the growth of Bifidobacteria through the action of 1,4-dihydroxy-2-naphthoic acid (DHNA). Here we report the results of two clinical studies designed to evaluate the safety of high doses of P. freudenreichii ET-3 culture medium. Study 1 had a randomized, double-blind, crossover design. Ten healthy male and four healthy female subjects received 45 tablets of either P. freudenreichii ET-3 culture medium (total daily intake of 3g solid content and 283.5μg of DHNA; active group) or placebo (unfermented product) during two 1-week supplementation periods separated by a 4-week washout period. In Study 2, 11 healthy men took four tablets of P. freudenreichii ET-3 culture medium per day (total daily intake of 0.267g solid content and 22.5μg of DHNA) for a period of 13weeks. In both studies, hematological, clinical chemistry, and urinary parameters were measured before and after each supplementation period and gastrointestinal symptoms were assessed by questionnaire. In Study 1, there were no statistically significant differences between placebo and active supplementation periods in any measured parameter and the incidence of gastrointestinal symptoms were similar between groups. In Study 2, total protein, white blood cell count, hemoglobin, and mean corpuscular hemoglobin concentration decreased significantly from baseline and mean corpuscular volume and urine pH increased from baseline. The changes in hematological parameters were deemed not to be due to P. freudenreichii ET-3 culture medium supplementation given that all parameters remained within normal ranges and were not consistent with any clinically meaningful effect.