Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P17174 (aspartate aminotransferase)
 14,872 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tepoxalin [5- (4-chlorophenyl)-N-hydroxy-1-(4-methoxyphenyl)-N-methyl-1H-pyrazole -3-propanamide] is an orally active anti-inflammatory agent, which inhibits both cyclooxygenase and 5-lipoxygenase activities. The oral toxicity of tepoxalin was evaluated in 1- and 6-month rat (up to 50 mg/kg/day) and dog (up to 150 mg/kg bid) studies. In rats, increased liver weight, centrilobular hypertrophy, and hepatic necrosis were observed at dosages >/=20 mg/kg/day. Renal changes indicative of analgesic nephropathy syndrome (i.e., papillary edema or necrosis, cortical tubular dilatation) were seen at >/=15 mg/kg. In rats treated for 1 month, these hepatic and renal effects were largely reversible after a 1-month recovery period. Gastrointestinal erosions and ulcers were seen in female rats given 40 mg/kg/day for 6 months. Changes in clinical pathology parameters included decreases in red blood cell count, hemoglobin, and hematocrit mean values; elevation in platelet counts; and an increase in prothrombin and activated partial thromboplastin times. Mild increases in alanine aminotransferase, aspartate aminotransferase, and cholesterol were also noted in rats. Decreased erythrocyte parameters, increased leukocyte counts, and decreased total protein, albumin, and/or calcium were noted in some dogs in the 300 mg/kg/day group following 6 months of dosing. Small pyloric ulcerations were seen at 100 and 300 mg/kg/day dosages for up to 6 months. In both rats and dogs, no accumulation of tepoxalin or its carboxylic acid metabolite was detected in plasma following multiple dosing over a range of 5 to 50 mg/kg/day for rats and 20 to 300 mg/kg/day for dogs. Plasma concentrations of the carboxylic acid metabolite were severalfold higher than those of the parent compound. The no-effect dosages in rats (5 mg/kg/day) and dogs (20 mg/kg/day) were approximately one and six times the ED50 (3.5 mg/kg), respectively, for inhibition of inflammatory effects in the adjuvant arthritic rat without gastric mucosal damage. In terms of severity, the relative lack of gastrointestinal side effects, within the estimated therapeutic dose range, distinguishes tepoxalin from most marketed anti-inflammatory drugs.
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PMID:Preclinical toxicity evaluation of tepoxalin, a dual inhibitor of cyclooxygenase and 5-lipoxygenase, in Sprague-Dawley rats and beagle dogs. 881 16

In the end-stage renal disease patient, certain uremic compounds could influence the cellular accumulation of aluminum (Al). In this study, we examined the effect of 15 uremic ultrafiltrate fractions obtained by HPLC on the uptake and toxicity of Al in mouse hepatocytes (MH) in culture, a model system in which Al is taken up bound to transferrin (Tf). Uremic fractions 4 to 8, 12, 14, and 15 increased cellular Al uptake and aspartate aminotransferase release and decreased cell growth when Tf-Al, not Al citrate, was added to culture media. Compounds that have been extracted previously from these ultrafiltrate fractions (p-cresol, xanthine, tryptophan, hippuric acid, and o-hydroxyhippuric acid) were then tested for their effect on Al uptake and toxicity in MH at concentrations found in uremic serum. Significant Al uptake by MH was observed only when p-cresol was added together with Tf-Al. Time-response curves showed increased Al uptake and toxicity at p-cresol concentrations of 3 mg/dl in culture media. Dose-response curves confirmed that Al uptake and cell toxicity were proportional to p-cresol from 1.5 mg/dl to 3 mg/dl in culture media. p-Cresol was not toxic to MH in the absence of Tf-Al in media. p-Cresol increased Tf-associated Al uptake only because there was no effect on Al uptake when Al citrate was substituted, and studies with Tf-I125-Al in the presence of this compound showed increased Tf-I125 taken up by MH. p-Cresol did not increase Tf saturation with Al. p-Cresol also increased Tf-Al uptake in Friend erythroleukemia and neuroblastoma cells in culture. Our studies suggest that p-cresol and uremic fractions 4 to 8, 12, 14, and 15 increase the uptake and toxicity of Al in cultured MH. These compounds may play a role in the accumulation and toxicity of Al in the liver of end-stage renal disease patients and possibly in all cells that express Tf receptors.
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PMID:P-Cresol, a uremic compound, enhances the uptake of aluminum in hepatocytes. 918 61

Fibrosing cholestatic hepatitis (FCH) has recently been described after solid organ transplantation in patients with hepatitis C virus (HCV) infection. Typically, FCH is characterized by an ominous clinical course leading to progressive hepatic failure and death if liver transplantation is not performed. Two HCV-infected patients underwent cadaveric renal transplantation for end-stage renal disease resulting from membranous nephropathy and diabetic nephropathy. The time intervals between transplantation and the biopsy diagnosis of FCH for the two patients were 7 months and 10 years. Both patients presented with jaundice, hyperbilirubinemia, and mild-to-moderate elevations in serum aspartate aminotransferase. One patient was also found to have type II mixed cryoglobulinemia. Interferon-alpha therapy was begun after a diagnosis of FCH was established by liver biopsy. Liver test abnormalities normalized rapidly. When cholestatic hepatic deterioration develops in an HCV-infected organ allograft recipient, the diagnosis of FCH should be considered and a liver biopsy performed. Our observations indicate that FCH can respond to antiviral therapy.
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PMID:Hepatitis C virus-associated fibrosing cholestatic hepatitis after renal transplantation: response to interferon-alpha therapy. 982 26

Some hemodialysis patients, without taking any acnegenic agents, developed severe nodulocystic acne with unknown causes. Because nodulocystic acne poorly responds to conventional acne therapy and increases the black pigmentation in the face, it severely interferes with the quality of life of these patients. To investigate whether isotretinoin is effective in treating hemodialysis patients with severe nodulocystic acne, we undertook a prospective, randomized, single-blind study. A total of 20 patients with nodulocystic acne participated in the study, of whom 18 completed it. Ten patients received isotretinoin 10 mg/day (5 mg/capsule) for 3 months as a study group and the other 10 took placebo for 3 months as a control group. The severity of acne and treatment-related side effects were evaluated monthly by a questionnaire and laboratory evaluation which included liver function tests, blood lipids and blood platelet counts. The results showed isotretinoin treatment significantly reduced the severity of acne of the study group patients after 1 month (scales of acne severity: 4.0 +/- 0.0 vs. 3.13 +/- 0.35, p < 0. 01) and 3 months (4.0 +/- 0.0 vs. 1.5 +/- 0.76, p < 0.01) of follow-up. In addition, the severity of acne of the study group patients was significantly less than that of the control group patients after 1 month (3.13 +/- 0.35 vs. 3.80 +/- 0.42, p < 0.01) and 3 months (1.5 +/- 0.76 vs. 3.70 +/- 0.48, p < 0.001) of treatment. Only mild side effects were noted. No significant changes of biochemical evaluation were found except that a mild elevation of aspartate aminotransferase was noted in the study group patients. However, two study group patients withdrew from the trial because of isotretinoin-related side effects and toxic hepatitis. In summary, our study first demonstrated that the small dose of isotretinoin effectively treated nodulocystic acne of hemodialysis patients and the side effects were mild. This result suggests that isotretinoin may be the treatment of choice for nodulocystic acne in end-stage renal disease patients with renal replacement therapy. The liver function and other isotretinoin-related side effects in these patients should be carefully monitored.
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PMID:Hemodialysis-related nodulocystic acne treated with isotretinoin. 993 49

Artemisia abyssinica leaves, a traditional medicine for the treatment of various disorders, were fed to male Wistar rats at 2% and 10% of the standard diet for 6 weeks. A 2% A. abyssinica leaf diet was not toxic to rats. Depression in growth, hepatopathy and nephropathy were observed in rats fed a diet containing 10% of A. abyssinica leaves. These findings were accompanied by leukopenia, anaemia and alterations of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) and gamma glutamyl transferase (GGT) activities with changes in concentrations of total protein, albumin, cholesterol and urea.
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PMID:Effects of various levels of dietary Artemisia abyssinica leaves on rats. 1103 26

Streptozotocin (STZ) has drawn attention as a potential source of oxidative stress, which induces genotoxicity. We investigated the effects of STZ on DNA damage in the liver and kidney, as well as the protective effects of antioxidants, by using the alkaline single-cell gel electrophoresis assay, and by measuring the ratio of 8-hydroxy-2'-deoxyguanosine (8-OHdG) to dG. A single intraperitoneal injection of STZ (150 mg/kg) increased serum levels of glucose, aspartate aminotransferase (AST), alanine aminotransferase (ALT) and blood urea nitrogen (BUN), and also caused DNA damage in the liver and kidney, which recovered slowly with time. Antioxidants,(ascorbic acid, trolox and probucol) prevented the STZ-induced elevation of DNA damage in the liver and kidney and inhibited the increase in serum levels of AST, ALT and BUN. Thus ascorbic acid, trolox, and probucol protected the mice against STZ-induced DNA damage that might contribute to the development of hepatic or renal disease.
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PMID:DNA damage and the effect of antioxidants in streptozotocin-treated mice. 1206 20

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

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

Standard toxicologic endpoints, supplemented by additional examinations, were studied for groups of 10 Fischer 344 rats/sex given drinking water formulated to supply 0, 50, 250, or 1000 mg diethylene glycol monobutyl ether (DGBE)/kg/day for 13 weeks. These dose levels were based upon initial investigations using drinking water formulated to supply 0, 1000, 1500 or 2000 mg DGBE/kg/day for two weeks. All rats survived the respective treatment intervals with no adverse treatment-related in-life effects, including no alterations in a functional observational battery. In both studies, rats given > or = 1000 mg/kg/day consumed less water and feed and weighed slightly less than controls. For rats given > or = 1000 mg DGBE/kg/day, the liver and red blood cells (RBC) were the primary target organs although the effects were slight. In the 13-week study, rats given 1000 mg/kg/day had statistically significant increased relative liver weight (7-10%) and hepatic cytochrome P450s (24-39%) and UGT (approximately 16%) levels along with slight, statistically significant, decreases in serum total protein, cholesterol and aspartate aminotransferase. Histopathologically, very slight hepatocyte hypertrophy and increased individual hepatocyte degeneration were found in females only. At 1000 mg/kg/day, the RBC count, hemoglobin (Hgb) and hematocrit (Hct) were minimally, but statistically significantly, decreased (5.1-8.7%) but RBC morphology, RBC indices, reticuloctye count and bone marrow and spleen histopathology were unaffected. Absolute and relative kidney weights statistically significantly increased (6-13%) with an equivocal increase in minor histopathologic changes typical of early spontaneous nephropathy. There were no adverse effects on urinalysis, clinical chemistry, sperm parameters or testis histopathology. At 250 mg/kg/day, there were equivocal decreases (approximately 2-3%) in RBC count, Hgb and Hct that were statistically significant for the RBC count and Hgb, but these changes were within the historical control range. This dose level was considered the no adverse effect level (NOAEL).
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PMID:Diethylene glycol monobutyl ether (DGBE): two- and thirteen-week oral toxicity studies in Fischer 344 rats. 1568 Jun 84

Strychnos potatorum Linn. seeds are used in the Indian traditional system of medicine for the treatment of hepatopathy, nephropathy, gonorrhoea, leucorrhoea, gastropathy, bronchitis, chronic diarrhoea, strangury, renal and vesicle calculi, diabetes and eye diseases. The present study describes the hepatoprotective and antioxidant activities of the seed powder (SPP) and aqueous extract (SPE) of Strychnos potatorum seeds against CCl4-induced acute hepatic injury. Hepatic injury was achieved by injecting 3 ml/kg, s.c. of CCl4 in equal proportion with olive oil. Both SPP and SPE at the doses 100 and 200 mg/kg, p.o. offered significant (p < 0.001) hepatoprotective action by reducing the serum marker enzymes like serum glutamate oxaloacetate transaminase (SGOT) and serum glutamate pyruvate transaminase (SGPT). They also reduced the elevated levels of ALP and serum bilirubin. Reduced enzymic and nonenzymic antioxidant levels and elevated lipid peroxide levels were restored to normal by administration of SPP and SPE. Histopathological studies further confirmed the hepatoprotective activity of SPP and SPE when compared with the CCl4 treated control groups. The results obtained were compared with Silymarin (50 mg/kg, p.o.), the standard drug. In conclusion, SPE (200 mg/kg, p.o.) showed significant hepatoprotective activity similar to that of the standard drug, Silymarin (50 mg/kg, p.o.).
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PMID:Studies on hepatoprotective and antioxidant actions of Strychnos potatorum Linn. seeds on CCl4-induced acute hepatic injury in experimental rats. 1638 23


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