UNIPROT:P17174 - FACTA Search

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Query: UNIPROT:P17174 (aspartate aminotransferase)
14,872 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The hepatoprotective effects of bergenin, a major constituent of Mallotus japonicus, were evaluated against carbon tetrachloride (CCl(4))-induced liver damage in rats. Bergenin at a dose of 50, 100 or 200 mg/kg was administered orally once daily for successive 7 days and then a mixture of 0.5 ml/kg (ip) of CCl(4) in olive oil (1:1) was injected two times each at 12 and 36 h after the final administration of bergenin. The substantially elevated serum enzymatic activities of alanine/aspartate aminotransferase, sorbitol dehydrogenase and gamma-glutamyltransferase due to CCl(4) treatment were dose dependently restored towards normalization. Meanwhile, the decreased activities of glutathione S-transferase and glutathione reductase were restored towards normalization. In addition, bergenin also significantly prevented the elevation of hepatic malondialdehyde formation and depletion of reduced glutathione content in the liver of CCl(4)-intoxicated rats in a dose dependent fashion. The results of this study clearly indicate that bergenin has a potent hepatoprotective action against CCl(4)-induced hepatic damage in rats.
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PMID:Hepatoprotective effects of bergenin, a major constituent of Mallotus japonicus, on carbon tetrachloride-intoxicated rats. 1099 88

The hepatoprotective effects of acetylbergenin were examined against D -galactosamine (GalN)-induced liver damage in rats, compared with that of bergenin reported previously. Acetylbergenin was synthesized from acetylation of bergenin, isolated from Mallotus japonicus, to increase lipophilic and physiological activities. Acetylbergenin was administered orally once daily for 7 days and then GalN (400 mg kg(-1), i.p.) was injected at 24 h and 96 h after the final administration of acetylbergenin. Acetylbergenin reduced the elevated serum enzyme activities of alanine/aspartate aminotransferase, sorbitol dehydrogenase and gamma -glutamyltransferase and the formation of hepatic malondialdehyde induced by GalN. Acetylbergenin also significantly restored towards normalization the decreased levels of glutathione and the decreased activities of glutathione S-transferase and glutathione reductase induced by GalN. Therefore, these results suggest that acetylbergenin has hepatoprotective effects against GalN-induced hepatotoxicity by inhibiting lipid peroxidation and maintaining an adequate level of GSH for the detoxification of xenobiotics as underlying hepatoprotective mechanisms. In addition, lipophilic acetylbergenin showed more activity in the hepatoprotection than that of the much less lipophilic bergenin reported previously.
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PMID:Effects of acetylbergenin against D -galactosamine-induced hepatotoxicity in rats. 1102 10

The present study was undertaken to investigate whether or not the hepatoprotective activity of acetylbergenin was superior to bergenin in carbon tetrachloride (CCl4)-intoxicated rat. Acetylbergenin was synthesized by acetylating bergenin, which was isolated from Mallotus japonicus. The hepatoprotective effects of acetylbergenin were examined against CCl4-induced liver damage in rats by means of serum and liver biochemical indices. Acetylbergenin was administered orally once daily for 7 successive days, then a 0.5 ml/kg mixture of CCl4 in olive oil (1:1) was intraperitoneally injected at 12 h and 36 h after the final administration of acetylbergenin. Pretreatment with acetylbergenin reduced the elevated serum enzymatic activities of alanine/aspartate aminotransferase, sorbitol dehydrogenase and gamma-glutamyltransferase in a dose dependent fashion. Acetylbergenin also prevented the elevation of hepatic malondialdehyde formation and depletion of glutathione content dose dependently in CCl4-intoxicated rats. In addition, the decreased activities of glutathione S-transferase and glutathione reductase were restored to almost normal levels. The results of this study strongly suggest that acetylbergenin has potent hepatoprotective activity against CCl4-induced hepatic damage in rats by glutathione-mediated detoxification as well as having free radical scavenging activity. In addition, acetylbergenin doses of 50 mg/kg showed almost the same levels of hepatoprotective activity as 100 mg/kg of bergenin, indicating that lipophilic acetylbergenin is more active against the antihepatotoxic effects of CCl4 than those of the much less lipophilic bergenin.
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PMID:Protective effects of acetylbergenin against carbon tetrachloride-induced hepatotoxicity in rats. 1133 30

The hepatoprotective effects of bergenin, a major constituent of Mallotus japonicus, were evaluated against D-galactosamine (GalN)-induced liver damage in rats. Bergenin (50, 100 and 200 mg/kg) was given orally once daily for 7 successive days and then GalN 400 mg/kg was injected intraperitoneally to rats at 24 and 96 h after the final administration of bergenin. Pretreatment with bergenin reduced the increased enzyme activities of alanine/aspartate aminotransferase, sorbitol dehydrogenase, gamma-glutamyltransferase and the elevated level of malondialdehyde induced by GalN. Bergenin restored the decreased hepatic contents of glutathione as well as the decreased activities of glutathione S-transferase and glutathione reductase by GalN towards normalization, suggesting that the hepatoprotective effects of bergenin may consist in maintaining adequate levels of hepatic glutathione for the removal of xenobiotics. The present results indicate that bergenin has hepatoprotective effects against GalN-induced hepatotoxicity in rats.
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PMID:Effects of bergenin, the major constituent of Mallotus japonicus against D-galactosamine-induced hepatotoxicity in rats. 1149 Jan 98

The diagnostic utility of alpha-glutathione S-transferase (alphaGST) in the assessment of acute hepatotoxicity was compared with a range of markers including alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Rats were given a single oral dose of either alpha-naphthylisothiocynate (AN IT), bromobenzene (BrB). or thioacetamide (TAM) at concentrations previously shown to induce marked hepatotoxicity. The progression of each hepatic lesion was monitored by the measurement of a battery of markers, including alphaGST, in plasma collected at time points ranging from 3 h to 7 days after dosing. alphaGST was seen to increase significantly at 24 h (ANIT/BrB) and 3 h (TAM) postdosing, corresponding with histopathological findings. For each compound, when the degree of insult was most severe, fold increases in alphaGST were greater than those seen with ALT and AST, yet lower than those seen with glutamate dehydrogenase (BrB and ANIT). sorbitol dehydrogenase (TAM), or total bilirubin and bile acids (ANIT). Elevations in alphaGST were also detected no earlier than any other marker. AlphaGST in the rat was shown to be a valid marker of hepatotoxicity; however, its measurement offered no additional information in detecting either the time of onset/recovery or the severity of each type of hepatic injury induced.
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PMID:Alpha-glutathione S-transferase in the assessment of hepatotoxicity--its diagnostic utility in comparison with other recognized markers in the Wistar Han rat. 1205 54

In a recent study in rats, alanine aminotransferase (ALT), the preferred plasma biomarker of hepatocellular injury in rats, was ineffective at detecting marked hepatic necrosis produced by acetaminophen (Human and Experimental Toxicology 19, 277-83, 2000). In contrast, glutamate dehydrogenase (GLDH) was markedly elevated. Accordingly, these enzymes were comprehensively evaluated as plasma biomarkers of hepatocellular injury in rats using several other models of hepatic injury, including partial hepatectomy and exposure to methapyrilene, dexamethasone, cyproterone, isoniazid, lead nitrate, and Wyeth-14643. Other enzymes also evaluated were aspartate aminotransferase (AST), sorbitol dehydrogenase (SDH), and the hepatobiliary marker alkaline phosphatase (ALP). Compared to plasma ALT increases, plasma GLDH increases were up to 10-fold greater, up to 3-fold more persistent, and occurred at times following hepatocellular injury when plasma ALT was not increased. Plasma GLDH activity was not inhibited by the test compounds, whereas ALT was substantially inhibited by both isoniazid and lead nitrate. While plasma GLDH activity was unaffected by induction, ALT was induced by cyproterone and dexamethasone, and ALP was induced by Wyeth-14643 and partial hepatectomy. GLDH was concluded to be a more effective biomarker of acute hepatic injury than ALT, AST, SDH or ALP in the rat, based primarily on the large increase following hepatocellular injury, prolonged persistence in the blood following injury, high sensitivity for detection of injury (including pre-necrotic injury), high tissue specificity, and lower susceptibility to inhibition or induction.
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PMID:Advantages of glutamate dehydrogenase as a blood biomarker of acute hepatic injury in rats. 1214 42

Cupric sulfate is an inorganic salt which is widely used in industry, agriculture, and veterinary medicine. Its applications include use as an algicide in potable waters and as a feed additive and therapeutic agent in swine, sheep, and cattle. Because copper salts are found in human water supplies, toxicity studies of cupric sulfate pentahydrate were conducted in male and female F344/N rats and B6C3F1 mice by the drinking water (2-week studies only) and dosed feed routes (2-week and 13-week studies). Animals were evaluated for hematology, clinical chemistry, urinalysis, reproductive toxicity, tissue metal accumulation, and histopathology. In the 2-week drinking water studies, groups of five rats and five mice per sex received cupric sulfate at concentrations of 300 to 30,000 ppm for 15 days. One female rat, one male mouse, and three female mice in the 3000 ppm groups and all rats and mice in the 10,000 and 30,000 ppm groups died before the end of the studies. The remaining mice and rats in the 3000 ppm groups gained little or lost weight. Water consumption in the three highest dose groups of both species was reduced by more than 65%. Clinical signs observed in these groups were typical of those seen in moribund animals and were attributed to dehydration. The only gross or microscopic change specifically related to cupric sulfate toxicity was an increase in the size and number of cytoplasmic protein droplets in the epithelium of the renal proximal convoluted tubule in male rats from the 300 and 1000-ppm groups. In the 2-week feed studies, groups of five rats and five mice per sex were fed diets containing 1000 to 16,000 ppm cupric sulfate. No chemical-related deaths occurred in any dose group. Compared to the controls, rats and mice in the two highest dose groups had reduced body weight gains which were attributed to decreased feed consumption. Hyperplasia with hyperkeratosis of the squamous epithelium on the limiting ridge of the forestomach was seen in rats and mice of each sex; this lesion was more severe in rats than in mice. Inflammation of the liver, periportal to midzonal in distribution, occurred in rats in the 8000 and 16,000 ppm groups. Depletion of hematopoietic cells was evident in rats of each sex in the bone marrow (8000 and 16,000 ppm) and spleen (16,000 ppm). Kidneys of male and female rats in the 4000, 8000, and 16,000 ppm groups had an increased number and size of protein droplets in the epithelia of the renal cortical tubules. In the 13-week feed studies, groups of 10 rats per sex received diets containing 500 to 8000 ppm cupric sulfate, and groups of 10 mice per sex received diets containing 1000 to 16,000 ppm cupric sulfate for 92 days; estimates of cupric sulfate consumption ranged from 32 to 551 mg/kg per day for rats and 173 to 4157 mg/kg per day for mice. There were no chemical-related deaths in rats or mice, and no clinical signs of cupric sulfate toxicity were recorded. Final mean body weights were lower than those of the controls for animals of both species receiving doses of 4000 ppm cupric sulfate and greater. In mice in the 13-week studies, there was a dose-related decrease in liver weights. Hematologic, clinical chemistry, and urinalysis evaluations of rats in the 13-week study revealed variable chemical-related changes that were, for the most part, restricted to the 4000 and 8000 ppm groups. Increases in serum alanine aminotransferase and sorbitol dehydrogenase activities in both sexes were indicative of hepatocellular damage, as were increases in 5'-nucleotidase and bile salts in males. Decreases in mean cell volume, hematocrit, and hemoglobin indicated the development of a microcytic anemia, while increases in reticulocyte numbers at the same time points suggested a compensatory response to the anemia by the bone marrow. Increases in urinary glucose and N-acetyl-beta-D-glucosaminidase (a lysosomal enzyme) and aspartate aminotransferase (alpha-cytosolic enzyme) were suggestive of renal tubule epithelial damage. Dose-related increases in copper occurred in all male rat tissues examined (lissues examined (liver, kidney, plasma, and testis). These increases were accompanied by increases in zinc in the liver and kidney. Plasma calcium was significantly reduced in the 4000 and 8000 ppm groups, and there was a trend toward reductions in calcium in the kidney and testis as well. In the 8000 ppm group, plasma magnesium was significantly increased relative to the controls. Rats in the three highest dose groups had hyperplasia and hyperkeratosis of the forestomach, inflammation of the liver, and increases in the number and size of protein droplets in the epithelial cytoplasm and the lumina of the proximal convoluted tubules. These effects were similar to those seen in the 2-week feed study, and the incidence and severity of these lesions were dose related. Many of the droplets in male rat kidneys were large and had irregular crystalline shapes. These droplets stained strongly positive for protein but were negative by iron, PAS, and acid-fast (lipofuscin) staining methods. α-2-Microglobulin was present in the droplets of male rats, but there was no dose- related, qualitative difference in the content of this protein. In the 4000 and 8000 ppm groups, copper was distributed in a periportal to midzonal pattern in the liver and was restricted to the cytoplasm of the proximal convoluted tubule epithelium in the kidney. Copper was present in some, but not all, of the protein droplets. Transmission electron microscopy of the livers of rats of each sex revealed increases in the number of secondary lysosomes in hepatocytes in the periportal area. In mice of each sex receiving 4000 ppm cupric sulfate and higher in the 13-week study, there was a dose-related increase in hyperplasia with hyperkeratosis of the squamous mucosa on the limiting ridge of the forestomach. Minimal positive staining for copper was present in the liver and was limited to high-dose (16,000 ppm) male and female mice. Cupric sulfate produced no adverse effects on any of the reproductive parameters measured in rats or mice of either sex. In summary, administration of cupric sulfate to rats in feed or drinking water resulted in significant gastric changes and hepatic and renal damage. The primary lesion in rats was an increase in the size and number of proteinaceous droplets in the epithelial cytoplasm and lumen of the proximal convoluted tubule. For rats in the 13-week study, the no-observed-adverse-effect level (NOAEL) for evidence of histologic injury to the kidney was 1000 ppm for males and 500 ppm for females, while the NOAEL for liver inflammation was 1000 ppm for males and 2000 ppm for females. Hyperplasia with hyperkeratosis of the epithelium on the limiting ridge separating the forestomach from the glandular stomach was also seen in rats of each sex, and the NOAEL for this change was 1000-ppm cupric sulfate in the feed. Additionally, clinical pathology alterations noted in the 13-week study, along with histologic changes in bone marrow noted in the 2-week feed study, were indicative of a microcytic anemia with a compensatory bone marrow response. Mice appeared to be much more resistant to the toxic effects of cupric sulfate than rats. The primary target tissue in mice was the epithelium of the limiting ridge of the forestomach. The NOAEL for the hyperplasia and hyperkeratosis seen at this site in mice was 2000-ppm cupric sulfate in the feed. Synonyms: Chalcanthite; Copper sulfate; cupric sulfate pentahydrate; bluestone; blue vitriol; Roman vitriol; Salzburg vitriol. (NOTE: These studies were supported in part by funds from the Comprehensive Environmental Response, Compensation, and Liability Act trust fund (Superfund) by an interagency agreement with the Agency for Toxic Substances and Disease Registry, U.S. Public Health Service.)
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PMID:NTP technical report on the toxicity studies of Cupric Sulfate (CAS No. 7758-99-8) Administered in Drinking Water and Feed to F344/N Rats and B6C3F1 Mice. 1220 95

Coumarin is the basic structure of numerous naturally occurring compounds with important and diverse physiological activities. More than a thousand coumarin derivatives have been described, varying from simple coumarins containing alkyl and hydroxyl side chains to complex coumarins with benzoyl, furanoyl, pyranoyl, or alkylphosphorothionyl substituents. Coumarin and 3,4-dihydrocoumarin were nominated by the Food and Drug Administration and the National Cancer Institute for study because of the widespread use of coumarin in perfumes, cosmetics, and other products as a fragrance, continued interest in coumarin compounds as flavor-enhancing agents for foods, and the interest in structure-activity relationships of this important group of compounds. Coumarin is believed to be metabolized to a 3,4-epoxide intermediate, which may be responsible for its toxic effects, while 3,4-dihydrocoumarin, which lacks the 3,4-double bond, is not considered likely to form an epoxide intermediate. Toxicity and carcinogenicity studies were conducted by administering coumarin (97% pure) in corn oil by gavage to groups of male and female F344/N rats and B6C3F1 mice for 16 days, 13 weeks, and 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, Drosophila melanogaster, and B6C3F1 mice. 16-DAY STUDY IN RATS: Groups of five male and five female rats received coumarin in corn oil by gavage at doses of 0, 25, 50, 100, 200, or 400 mg per kg body weight, 5 days a week for a total of 12 doses in a 16-day period. All female rats and four male rats receiving 400 mg/kg died. The mean body weight gains and final mean body weights of surviving dosed male and female rats were similar to those of the controls. There were no clinical signs of organ-specific toxicity, and there was no evidence of impaired blood coagulation from measurements of capillary clotting time or prothrombin and activated partial thromboplastin time. 16-DAY STUDY IN MICE: Groups of five male and five female mice received coumarin in corn oil by gavage at doses of 0, 40, 75, 150, 300, or 600 mg per kg body weight, 5 days a week for a total of 12 doses in a 16-day period. All mice receiving 600 mg/kg, two male mice receiving 300 mg/kg, and one male mouse receiving 75 mg/kg died. The mean body weight gains and final mean body weights of surviving dosed male and female mice were similar to those of the controls. Clinical findings of inactivity, excessive lacrimation, piloerection, bradypnea, ptosis, or ataxia were observed in some mice from the 300 and 600 mg/kg groups within the first several hours after dosing. Capillary clotting time and platelet counts of dosed mice were similar to those of controls. 13-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats received coumarin in corn oil by gavage at doses of 0,19, 38, 75,150, or 300 mg per kg body weight. Three male and three female rats receiving 300 mg/kg died. The mean body weight gains and final mean body weights of male rats that received 150 and 300 mg/kg were significantly lower than those of the controls. There were no clinical signs related to specific organ toxicity. Male and female rats receiving coumarin exhibited dose-related decreases in mean erythrocyte volume and mean erythrocyte hemoglobin, and dose-related increases in erythrocyte counts. Serum levels of total bilirubin and one or more cytoplasmic enzymes including alanine aminotransferase, aspartate aminotransferase, ornithine carbamoyltransferase, and/or sorbitol dehydrogenase in males and females receiving 300 mg/kg were higher than those of controls. The absolute and relative liver weights of male and female rats that received 150 and 300 mg/kg were significantly greater than those of the controls. Centrilobular hepatocellular degeneration and necrosis, chronic active inflammation, and bile duct hyperplasia were observed in the liver of rats receiving 150 or 300 mg/kg. The high dose selected for the 2-year study was 100 mg/kg, which was just below the level at which mortality, lower final mean body weiody weights, and treatment-related liver lesions were observed in the 13-week study. 13-WEEK STUDY IN MICE: Groups of 10 male and 10 female mice received coumarin in corn oil by gavage at doses of 0, 19, 38, 75, 150, or 300 mg per kg body weight. Two male mice receiving 300 mg/kg died. The mean body weight gain and final mean body weight of surviving male mice that received 300 mg/kg were significantly lower than those of the controls. No clinical signs of toxicity were observed. Male and female mice receiving coumarin exhibited dose-related decreases in mean erythrocyte volume and mean erythrocyte hemoglobin. The absolute and relative liver weights of males and females that received 150 and 300 mg/kg were significantly greater than those of the controls. Centrilobular hepatocellular hypertrophy was observed in male and female mice receiving 300 mg/kg. The high dose selected for the 2-year study was 200 mg/kg, which was just below the level at which mortality and liver lesions were observed in the 13-week study. 2-YEAR STUDY IN RATS: Groups of 60 male and 60 female rats were administered coumarin in corn oil by gavage at doses of 0, 25, 50, or 100 mg per kg body weight. After 15 months, 10 animals from each group were evaluated. Survival, Body Weights, and Clinical Findings: None of the male rats receiving 100 mg/kg and only two males receiving 50 mg/kg survived until the end of the study (vehicle control, 28/50; 25 mg/kg, 9/50; 50 mg/kg, 2/51; 100 mg/kg, 0/50). Survival of dosed female rats was similar to that of the controls (29/50, 38/50, 36/50, 30/50). The reduced survival in dosed male rats was primarily attributed to chemical-related exacerbation of spontaneously occurring renal disease. Final mean body weights of female rats that received 100 mg/kg and all dosed groups of male rats were lower than those of the controls. There were no clinical signs of toxicity in rats, other than nonspecific signs relating to debilitation as a result of renal or other spontaneous disease. Hematology and Clinical Chemistry: At the 15-month interim evaluation, the values for one or more hematologic parameters including mean erythrocyte volume, mean erythrocyte hemoglobin in 50 and 100 mg/kg rats, and hematocrit or hemoglobin in 100 mg/kg rats were significantly lower than those of controls. Activated partial thromboplastin times were also significantly lower in 50 and 100 mg/kg males, while platelet counts were significantly higher. Activities of alanine aminotransferase, sorbitol dehydrogenase, or g-glutamyltransferase in 50 and 100 mg/kg male and 100 mg/kg female rats were significantly higher than those of the controls at the 15-month interim evaluation. Pathology Findings: The principal lesions associated with the administration of coumarin to rats for up to 2 years occurred in the liver, kidney, and forestomach. While the hepatic lesions were seen in all groups of males, they occurred only in the 50 and 100 mg/kg females. The lesions consisted of a spectrum of changes including hepatocellular necrosis, fibrosis, cytologic alteration, and increased severity of bile duct hyperplasia. The incidences of hepatocellular neoplasms were not increased in dosed rats. There was a chemical-related increase in the average severity of nephropathy in all groups of dosed male and female rats. There were corresponding increased incidences of parathyroid gland hyperplasia in all groups of dosed males, probably as a result of compromised renal function. In the standard evaluation of single kidney sections, a low incidence of renal adenomas was seen in all groups of males and in 100 mg/kg females (males: vehicle control, 1/49; 25 mg/kg, 2/50; 50 mg/kg, 2/51; 100 mg/kg, 1/50; females: 0/49, 0/50, 0/50, 2/49). An evaluation of step sections identified additional individuals with renal tubule focal hyperplasia (males: 2/49, 12/50, 10/51, 6/50; females: 1/49, 0/50, 4/50, 2/49) and adenoma (males: 0/49, 4/50, 5/51, 4/50; females: 0/49, 0/50, 1/50,1/49) in the dosed groups. The incidences of forestomach ulcers in all groups of dosed male rats and in 100 mg/kg female rats were significantly greater than those of the controls (males: 7/48, 24/50, 35/51, 34/50; females: 1/48, 1/49, 6/50, 9/48). STOP-EXPOSURE EVALUATION: A group of 40 male rats received 100 mg/kg coumarin in corn oil by gavage for 9 months, when 20 of the animals were necropsied and evaluated. The remainder of the male rats received only the corn oil vehicle during the 15-month recovery period. Similarly, a group of 30 male rats received 100 mg/kg coumarin in corn oil by gavage for 15 months, when 10 of the rats were necropsied and evaluated. The remaining 20 rats received only corn oil during the 9-month recovery period. A group of 20 vehicle control male rats were necropsied at 9 months, and another 10 vehicle control male rats were necropsied at 15 months. While chemical-related hepatic lesions were seen at both the 9- and 15-month interim evaluations, the incidences and severities of these lesions following the recovery period were generally similar to controls. Thus, the hepatic lesions produced by 9 or 15 months of exposure were reversible. In contrast to the liver lesions, the severity of nephropathy in male rats following the recovery period was significantly greater than that of males examined at the 9- and 15-month interim evaluations. This is not unexpected, since nephropathy is a progressive degenerative disease that naturally increases in severity with age. The incidence of renal tubule hyperplasia in the 15-month stop-exposure group (dosed for 15 months followed by the recovery period) and the incidence of renal tubule adenoma in the 9-month stop-exposure group were significantly greater than those of the control group. 2-YEAR STUDY IN MICE: Groups of 70 male and 70 female mice were administered coumarin in corn oil by gavage at doses of 0, 50, 100, or 200 mg per kg body weight for up to 2 years. After 15 months, 19 or 20 mice from each group were evaluated. Survival, Body Weights, and Clinical Findings: Survival of dosed male and female mice was similar to that of the controls (males: vehicle control, 43/50; 50 mg/kg, 47/50; 100 mg/kg, 42/50; 200 mg/kg, 37/51; females: 33/50, 40/50, 42/51, 28/51). The mean body weights of 200 mg/kg male and female mice were lower than those of controls throughout much of the study. There were no clinical findings related to chemical administration. Hematology and Clinical Chemistry: Mean erythrocyte volume, mean erythrocyte hemoglobin, and hematocrit of 200 mg/kg males and mean erythrocyte volume of 200 mg/kg females were significantly lower than those of the controls. Blood platelet counts of 200 mg/kg males and females were significantly higher than those of controls. There were no biologically significant differences in enzyme activities between dosed and control mice. Pathology Findings: The principal toxic lesions associated with the administration of coumarin to mice occurred in the liver. The incidences of centrilobular hypertrophy in 100 and 200 mg/kg males and 200 mg/kg females were significantly greater than those of controls. The incidences of syncytial alteration in all male dose groups and in 200 mg/kg females were also significantly greater than controls. The incidences of eosinophilic foci, a putative preneoplastic lesion, and of hepatocellular adenoma were significantly greater in the 50 and 100 mg/kg females. Hepatocellular carcinomas occurred with low incidences in the dosed females, but none occurred in the controls. The overall incidence of hepatocellular neoplasms (benign and malignant combined) in the 50 and 100 mg/kg females (control, 8/50; 50 mg/kg, 27/49; 100 mg/kg, 31/51; 200 mg/kg, 13/50) exceeds the range in historical controls (range 2&percnt;-34&percnt;; 129/898, 14.4&percnt;) from recent NTP studies. The reason for a lack of liver response in 200 mg/kg female mice is not known, but may be due in part to the decrease in body weight. While the incidences of eosinophilic foci were marginally greater in dosed male mice, the incidences of hepatocellular neoplasms were similar among the dosed and control groups. The incidences of alveolar/bronchiolar adenomas were significantly greater in 200 mg/kg male and female mice than in the controls. Further, the incidence of alveolar/bronchiolar carcinoma in 200 mg/kg females was also significantly greater than in controls. The overall incidence of pulmonary neoplasms (benign and malignant combined) in the 200 mg/kg groups (males: 14/50, 9/50,15/50, 25/51; females: 2/51, 5/49, 7/49, 27/51) exceeds the range in historical controls (males: range 6&percnt;-28&percnt;; 166/900, 18.4&percnt;; females: range 0&percnt;-14&percnt;; 58/899, 6.5&percnt;) from recent NTP studies. The incidence of squamous cell papilloma of the forestomach in 50 mg/kg males was greater than that of the controls (2/50, 8/50, 2/50, 0/51) and also exceeds the range of this neoplasm in control male mice from recent NTP studies (range 0&percnt;-14&percnt;; 27/902, 3.0&percnt;). The incidence of squamous cell papilloma of the forestomach in 50 mg/kg female mice was also slightly increased (1/52, 5/50, 2/51, 2/51); however, the incidence did not exceed the NTP historical range (27/901, 3&percnt;; range, 0&percnt;-10&percnt;). GENETIC TOXICOLOGY: Coumarin induced gene mutations in Salmonella typhimurium strain TA100 in the presence, but not in the absence, of exogenous metabolic activation (S9); no mutations were induced in strains TA98, TA1535, or TA1537, with or without S9. In Chinese hamster ovary cells, coumarin induced sister chromatid exchanges in the absence of S9, and chromosomal aberrations in the presence of S9. Coumarin did not induce sex-linked recessive lethal mutations in germ cells of male Drosophila melanogaster treated either as adults by feeding or injection, or as larvae by feeding. No increase in the frequency of micronucleated erythrocytes was observed in peripheral blood of male and female B6C3F1 mice administered coumarin by gavage for 13 weeks. CONCLUSIONS: Under the conditions of these 2-year gavage studies there was some evidence of carcinogenic activity of coumarin in male F344/N rats based on increased incidences of renal tubule adenomas. There was equivocal evidence of carcinogenic activity of coumarin in female F344/N rats based on a marginally increased incidence of renal tubule adenomas. There was some evidence of carcinogenic activity of coumarin in male B6C3F1 mice based on the increased incidence of alveolar/bronchiolar adenomas. There was clear evidence of carcinogenic activity of coumarin in female B6C3F1 mice based on increased incidences of alveolar/bronchiolar adenomas, alveolar/bronchiolar carcinomas, and hepatocellular adenomas. The marginally increased incidences of squamous cell papillomas of the forestomach in male and female mice receiving 50 mg/kg may have been related to coumarin administration. The administration of coumarin to rats was also associated with an increased severity of nephropathy in the kidney and of bile duct hyperplasia in the liver, increased incidences of ulcers of the forestomach, and necrosis, fibrosis, and cytologic alteration of the liver. Administration of coumarin to mice was also associated with centrilobular hypertrophy, syncytial alteration, and eosinophilic focus in the liver. Synonyms: 5,6-benzo-alpha-pyrone, 2H-1-benzopyran-2-one, 2H-benzolblpyran-2-one, 1,2-oxo-1,2-benzopyran, 1,2-benzopyrone, cis-o-coumarinic acid lactone, coumarinic anhydride, cumarin, o-hydroxycinnamic acid lactone, kumarin, [2-propenoic acid, 3-(-2-hydroxyphenyl)-delta-lactone], Rattex, tonka bean camphor
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PMID:NTP Toxicology and Carcinogenesis Studies of Coumarin (CAS No. 91-64-5) in F344/N Rats and B6C3F1 Mice (Gavage Studies). 1261 89

Plasma bile acids, plasma amino acids, and the total hepatic pools of aspartate aminotransferase, gamma glutamyltransferase, glutamate dehydrogenase, and sorbitol dehydrogenase were compared in control sheep (Group 1), sheep with subclinical pyrrolizidine alkaloid toxicosis (Group 2), and in sheep with acute hepatocellular necrosis associated with the hemolytic phase of chronic copper poisoning (Group 3). Subclinical pyrrolizidine alkaloid toxicosis was not associated with any changes in bile acid or amino acid status but was associated with a significant decline in the hepatic pools of sorbitol dehydrogenase and aspartate aminotransferase. This observation could not be explained in terms of enzyme leakage from damaged hepatocytes and suggested that pyrrolizidine alkaloids might specifically inhibit hepatocellular enzyme synthesis. Group 3 sheep also had reduced hepatic enzyme pools which were at least partly referable to enzyme leakage from damaged hepatocytes. In these sheep, increases in plasma bile acids were a more sensitive index of hepatic function than were either increased aromatic amino acid concentration or the ratio between branched chain and aromatic amino acids.
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PMID:Changes in plasma bile acids, plasma amino acids, and hepatic enzyme pools as indices of functional impairment in liver-damaged sheep. 1267 2

1,2,3-Trichloropropane is a colorless liquid used as a paint and varnish remover, solvent, and degreasing agent, and as a crosslinking agent in the synthesis of polysulfides and hexafluoropropylene. 1,2,3-Trichloropropane may be found as an impurity in certain nematocides and soil fumigants and as a contaminant of drinking and ground water. Studies on the toxic and carcinogenic effects of 1,2,3-trichloropropane were initiated because of the close structural relationship of this chemical to other short-chain halogenated compounds that were demonstrated to be carcinogenic in experimental animals, and because of the potential for human exposure. Toxicology and carcinogenicity studies were conducted by administering 1,2,3-trichloropropane (greater than 99% pure) in corn oil by gavage to groups of F344/N rats and B6C3FI mice for 17 weeks and 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium strains, mouse lymphoma cells, and Chinese hamster ovary cells. 17-Week Studies: Groups of 20 male and 20 female rats received 1,2,3-trichloropropane in corn oil by gavage at doses of 8, 16, 32, 63, 125, or 250 mg/kg body weight 5 days per week for up to 17 weeks; 30 male and 30 female rats received corn oil alone and served as controls. Animals were evaluated at 8 or 17 weeks. All rats in the 250 mg/kg groups died by week 5. One male and four female rats in the 125 mg/kg groups died during the study. The mean body weight gains and final mean body weights of males receiving 63 mg/kg and of males and females receiving 125 mg/kg were lower than those of the controls. Hematocrit values, hemoglobin concentrations, and erythrocyte counts decreased with dose in males and females. Serum alanine aminotransferase, aspartate aminotransferase, and sorbitol dehydrogenase activities were significantly increased in some female rats receiving 125 mg/kg. Serum pseudocholinesterase activity decreased with dose in females. Increases in kidney and liver weights were related to chemical administration. The principal toxic lesions associated with the administration of 1,2,3-trichloropropane to rats were hepatocellular necrosis, karyomegaly, and biliary hyperplasia of the liver; renal tubule necrosis, regeneration, and karyomegaly of the kidney; and necrosis and inflammation of the nasal olfactory and respiratory epithelium. Groups of 20 male and 20 female mice received 1,2,3-trichloropropane in corn oil by gavage at doses of 8, 16, 32, 63, 125, or 250 mg/kg 5 days per week for up to 17 weeks; 30 male and 30 female mice received corn oil alone and served as controls. Sixteen male and seven female mice in the 250 mg/kg groups died by week 4. The final mean body weights and mean body weight gains of dosed mice were similar to those of the controls, except those of 250 mg/kg males, which were lower than those of controls. The principal toxic lesions associated with the administration of 1,2,3-trichloropropane were hepatocellular necrosis and karyomegaly of the liver; necrosis, regeneration, and hyperplasia of the bronchiolar epithelium in the lung; and acanthosis (hyperplasia) and hyperkeratosis of the forestomach epithelium. 2-Year Studies: Groups of 60 male and 60 female rats received 0, 3, 10, or 30 mg 1,2,3-trichloropropane/kg body weight in corn oil by gavage 5 days per week for up to 104 weeks. Selection of 30 mg/kg as the high dose in these studies was based on the following chemical-related effects in the 17-week studies: deaths and liver and kidney lesions at 125 and 250 mg/kg and reduced final mean body weights and mean body weight gains at 63 mg/kg or greater. Groups of 60 male and 60 female mice received 0, 6, 20, or 60 mg 1,2,3-trichloropropane/kg body weight in corn oil by gavage 5 days per week for up to 104 weeks. Selection of 60 mg/kg as the high dose was based on chemical-related deaths and lesions of the liver, lung, and forestomach at 125 and 250 mg/kg in the 17-week studies. 15-Month Interim Evaluations: Up to 10 rats and 10 mice from each dose group were evaluated at 15 months. Absolute and relative liver and kidned kidney weights of dosed rats were significantly greater than those of the controls. Chemical-related nonneoplastic lesions and neoplasms of the forestomach, oral mucosa, pancreas (males), kidney, mammary gland (females), preputial gland, and clitoral gland were observed in dosed rats. Chemical-related nonneoplastic lesions and neoplasms of the forestomach and liver (females) were observed in dosed mice. Survival and Body Weight in the 2-Year Studies: Survival of male and female rats receiving 10 or 30 mg/kg 1,2,3-trichloropropane was significantly lower than that of controls. Two-year survival rates of male rats were: control, 34/50; 3 mg/kg, 32/50; 10 mg/kg, 14/49; 30 mg/kg, 0/52; and of females were: 31/50, 30/49, 8/52, 0/52. At 30 mg/kg, survival was markedly reduced due to chemical-related neoplasms, and survivors were killed in weeks 67 (females) or 77 (males). Final mean body weights of 30 mg/kg rats were 13&percnt; lower for males and 12&percnt; lower for females than those of controls; mean body weights of 3 and 10 mg/kg rats were similar to controls. Survival rates of mice receiving 6, 20, or 60 mg/kg 1,2,3-trichloropropane were also significantly lower than those of controls. Two-year survival rates of male mice were: 42/52, 18/51, 0/54, 0/56; and of female mice were: 41/50, 13/50, 0/51, 0/55. Because of reduced survival at 20 and 60 mg/kg due to chemical-related neoplasms, survivors were killed in weeks 73 (60 mg/kg females), 79 (60 mg/kg males), or 89 (20 mg/kg males and females). Final mean body weights were 16&percnt; lower for 60 mg/kg males, 18~ lower for 60 mg/kg females, and 13&percnt; lower for 20 mg/kg males than those of controls. Final mean body weights of 6 mg/kg males and females and 20 mg/kg females were similar to controls. Neoplasms and Nonneoplastic Lesions in the 2-Year Studies: Administration of 1,2,3-trichloropropane to rats induced benign and malignant neoplasms of the oral mucosa (pharynx and tongue), forestomach, and preputial and clitoral glands in males and females; benign neoplasms of the exocrine pancreas and kidney in males, and malignant neoplasms of the mammary gland in females. The incidences of squamous cell papillomas and carcinomas of the oral mucosa were significantly increased in 10 and 30 mg/kg rats, while the incidences of squamous cell papillomas or carcinomas (combined) of the forestomach were significantly increased in all dosed groups. The incidence of pancreatic acinar adenoma was significantly increased in dosed males, but not in dosed females. Similarly, the incidence of adenoma of the kidney was significantly increased in 10 and 30 mg/kg male rats only. The incidences of adenoma or carcinoma (combined) of the preputial gland in 30 mg/kg males and of the clitoral gland in 10 and 30 mg/kg females (homologous organs) were significantly increased. The incidence of adenocarcinoma of the mammary gland was significantly increased in the 10 and 30 mg/kg females. The incidences of Zymbal's gland carcinomas were increased in 30 mg/kg males and females. Adenocarcinomas of the intestine occurred in small numbers of dosed rats and may have been chemical related. In mice, the incidence of squamous cell carcinoma of the oral mucosa was significantly increased only in 60 mg/kg females. In contrast, the incidences of squamous cell papilloma and carcinoma of the forestomach were significantly increased in all groups of dosed mice. The incidences of hepatocellular adenoma or carcinoma (combined) were significantly increased in all dosed groups of males and 60 mg/kg females. The incidences of harderian gland adenoma were significantly increased in 20 mg/kg males and in 60 mg/kg males and females. The incidences of uterine adenoma, adenocarcinoma, and stromal polyp were significantly increased in 60 mg/kg females. Genetic Toxicology: 1,2,3-Trichloropropane was mutagenic in vitro in the presence of S9 metabolic activation. At two laboratories, positive responses were obtained for mutagenicity in Salmonella typhimurium strains TA97, TA98, TA100, and TA1535 in the presence of S9; no mutagenic activity was observed in TA1537, with or without S9. 1,2,3-Trichloropropane induced trifluorothymidine resistance in L5178Y mouse lymphoma cells with, but not without, S9. In cultured Chinese hamster ovary cells, sister chromatid exchanges and chromosomal aberrations were induced by 1,2,3-trichloropropane; however, significant increases in the endpoints of both cytogenetic effects occurred only in the presence of S9. Conclusions: Under the conditions of these 2-year gavage studies, there was clear evidence of carcinogenic activity of 1,2,3-trichloropropane in male F344/N rats based on increased incidences of squamous cell papillomas and carcinomas of the oral mucosa and forestomach, adenomas of the pancreas and kidney, adenomas or carcinomas of the preputial gland, and carcinomas of the Zymbal's gland. Adenomatous polyps and adenocarcinomas of the intestine may have been related to chemical administration. There was clear evidence of carcinogenic activity of 1,2,3-trichloropropane in female F344/N rats based on increased incidences of squamous cell papillomas and carcinomas of the oral mucosa and forestomach, adenomas or carcinomas of the clitoral gland, adenocarcinomas of the mammary gland, and carcinomas of the Zymbal's gland. Adenocarcinomas of the intestine may have been related to chemical administration. There was clear evidence of carcinogenic activity of 1,2,3-trichloropropane in male B6C3F1 mice based on increased incidences of squamous cell papillomas and carcinomas of the forestomach, hepatocellular adenomas or carcinomas of the liver, and harderian gland adenomas. Squamous cell papillomas of the oral mucosa may have been related to chemical administration. There was clear evidence of carcinogenic activity of 1,2,3-trichloropropane in female B6C3F1, mice based on increased incidences of squamous cell carcinomas of the oral mucosa, squamous cell papillomas and carcinomas of the forestomach, hepatocellular adenomas or carcinomas of the liver, harderian gland adenomas, and uterine adenomas, adenocarcinomas, and stromal polyps. Nonneoplastic lesions associated with exposure to 1,2,3-trichloropropane included increased severity of nephropathy in male rats and increased incidences of basal cell and squamous hyperplasia of the forestomach, acinar hyperplasia of the pancreas, renal tubule hyperplasia, and preputial or clitoral gland hyperplasia in male and female rats. Increased incidences of squamous hyperplasia of the forestomach and eosinophilic foci in the liver in male and female mice were chemical related. Synonyms: Allyl trichloride, glycerol tnchlorohydrin, glyceryl tnchlorohydrin, trichlorohydrin
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PMID:NTP Toxicology and Carcinogenesis of 1,2,3-Trichloropropane (CAS No. 96-18-4) in F344/N Rats and B6C3F1 Mice (Gavage Studies). 1269 52

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