Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.6.1.2 (alanine aminotransferase)
26,722 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Perfluorooctanesulfonate (PFOS) is a widely disseminated persistent compound found at low (part-per-billion) concentrations in serum and liver samples from humans and fish-eating wildlife. This study investigated the hypotheses that early hepatocellular peroxisomal proliferation and hepatic cellular proliferation are factors in chronic liver response to dietary dosing, that lowering of serum total cholesterol is an early clinical measure of response to treatment, and that liver and serum PFOS concentrations are proportional to dose and cumulative dose after sub-chronic treatment. PFOS was administered in diet as the potassium salt at 0, 0.5, 2.0, 5.0, and 20 parts per million (ppm) to Sprague Dawley rats for 4 or 14 weeks. At 4 weeks, effects included decreased serum glucose and an equivocal (<twofold) increase in hepatic palmitoyl CoA oxidase (PCoAO) activity in 20 ppm dose-group males in one of two assay systems [corrected]. At 14 weeks, the 20 ppm males had increased liver weight, decreased serum cholesterol, increased non-segmented neutrophils, and increased ALT. Relative liver weights and urea nitrogen were increased in both sexes at 14 weeks. Hepatocytic hypertrophy and cytoplasmic vacuolation were observed in the 5 or 20 ppm male and the 20 ppm female dose groups. An increase in hepatic PCoAO activity was not observed at 14 weeks, and the average hepatocyte proliferation index was not increased, although, individual animals had mild increases. Serum and liver PFOS concentrations were proportional to dose and cumulative dose. Serum concentrations were generally higher in females than in males. The liver-to-serum PFOS ratios ranged from approximately 3:1 to 12:1. After 14 weeks, the no-observed-adverse effect level (NOAEL) in males and females was 5 ppm. The NOAEL corresponded to mean serum PFOS concentrations of 44 ppm (microg/ml) in males and 64 ppm in females and mean liver PFOS concentrations of 358 ppm in males and 370 ppm in females. Results for this study: (1) did not provide strong evidence for hepatocellular peroxisomal or cellular proliferation at the doses tested; (2) suggested that lowering of serum total cholesterol may not be the earliest clinically-measurable response to treatment in the rat; and (3) confirmed that serum and liver PFOS concentrations on repeated dosing are proportional to dose and cumulative dose.
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PMID:Sub-chronic dietary toxicity of potassium perfluorooctanesulfonate in rats. 1250 46

[molecular structure: see text] p-tert-Butylcatechol is used as an antioxidant, stabilizer, and polymerization inhibitor for styrene, butadiene, neoprene, and other olefins and reactive monomers. p-tert-Butylcatechol was nominated by the National Cancer Institute and the U.S. Food and Drug Administration for testing based on reports of its increasing levels of production and use and to compare the toxicity of p-tert-butylcatechol with that of similar antioxidants, butylated hydroxyanisole and butylated hydroxytoluene, which are added to food. Male and female F344/N rats and B6C3F1 mice were exposed to p-tert-butylcatechol (greater than 99% pure) in feed for 15 days or 14 weeks. Genetic toxicology studies were conducted in Salmonella typhimurium, rat bone marrow cells, and mouse peripheral blood erythrocytes. In the 15-day studies, groups of five male and five female rats and mice were fed diets containing 0, 3,125, 6,250, 12,500, 25,000, or 50,000 ppm p-tert-butylcatechol (equivalent to average daily doses of approximately 290 to 2,470 mg p-tert-butylcatechol/kg body weight to rats and 590 to 8,200 mg/kg to mice). All animals in the 50,000 ppm groups were killed moribund on day 8 (rats) or by day 7 (mice). Mean body weights of all groups of rats exposed to 6,250 ppm or greater were significantly less than those of the controls. Mean body weights of male mice exposed to 12,500 or 25,000 ppm and of 25,000 ppm female mice were significantly less than those of the controls. Female rats, male and female mice in the 25,000 ppm groups, and 12,500 ppm male mice lost weight during the studies. Feed consumption by exposed rats generally decreased with increasing exposure concentration; feed consumption by exposed mice was similar to that by the controls. Thymus weights of 25,000 ppm rats and mice were significantly less than those of the controls. Gross findings noted at necropsy included thin carcasses for three male and all female rats in the 12,500 ppm groups and all male and female rats and mice in the 25,000 and 50,000 ppm groups. No exposure-related lesions were observed microscopically. In the 14-week studies, groups of 10 male and 10 female rats and mice were fed diets containing 0, 781, 1,562, 3,125, 6,250, or 12,500 ppm p-tert-butylcatechol (equivalent to average daily doses of approximately 70 to 1,030 mg/kg to rats and 135 to 2,815 mg/kg to mice). All animals survived to the end of the studies. Mean body weights of male rats exposed to 1,562 ppm or greater, female rats exposed to 3,125 ppm or greater, male mice exposed to 12,500 ppm, and female mice exposed to 6,250 or 12,500 ppm were significantly less than those of the controls. Feed consumption by male and female rats in the 6,250 and 12,500 ppm groups at week 1 and the 12,500 ppm groups at week 14 was less than that by the controls; feed consumption by exposed and control mice was similar. An erythrocytosis, indicated by increased hematocrit values, hemoglobin concentrations, and erythrocyte counts, was observed in 6,250 and 12,500 ppm rats on day 4 and in 12,500 ppm rats on day 22. At these time points, a transient hepatic effect was demonstrated by increases in alanine aminotransferase activities and bile salt concentrations in exposed rats. In 12,500 ppm male rats, absolute left cauda epididymis, epididymis, and testis weights were decreased by 15%, 10%, and 9%, respectively, compared to the controls. The number of spermatid heads per testis and epididymal sperm motility of male rats in the 12,500 ppm group were significantly less than those of the controls. The numbers of cycling female rats and females with regular estrous cycles were decreased in the 6,250 and 12,500 ppm groups. Exposed groups of females had significantly fewer estrous cycles than did the controls. Estrous cycle length increased with increasing exposure concentration; female rats in the 6,250 and 12,500 ppm groups had significantly longer cycles and spent more time in diestrus and less time in proestrus, estrus, and metestrus than did the controls. Female mice in the 12,500 ppm group had a significantly longer estrous cycle than did the controls. The incidences of hyperkeratosis of the forestomach epithelium were significantly increased in male and female rats in all exposed groups and in 12,500 ppm female mice. The incidences of hyperplasia of the forestomach epithelium were significantly increased in male and female rats exposed to 3,125 ppm or greater, male mice exposed to 12,500 ppm, and female mice exposed to 6,250 or 12,500 ppm. The severities of the forestomach lesions were minimal to moderate in male rats and minimal to mild in female rats and in mice. All male rats exposed to 6,250 or 12,500 ppm had minimal cytoplasmic alteration in the liver. The absorption, distribution, metabolism, and excretion of p-tert-butylcatechol following intravenous injection, gavage dosing, or dermal application were determined in male F344/N rats and B6C3F1 mice. The absorption of [(14)C]-p-tert-butylcatechol following gavage dosing or dermal application was high. The percent absorption following dermal application increased with increasing dose. Peak concentrations of [(14)C]-p-tert-butylcatechol equivalents in plasma were reached 1 hour after gavage dosing (200 mg/kg) and 2 hours after dermal application (60 mg/kg); no parent compound was detected in the plasma extracts. Regardless of route of administration, p-tert-butylcatechol derived radioactivity was readily excreted in the urine and was markedly nonpersistent in the tissues. p-tert- Butylcatechol was excreted as p-tert-butylcatechol sulfate and other polar metabolites that included predominately sulfate conjugates; it was not excreted as the parent compound. One metabolite was determined to be an O-methyl- ON-sulfate of p-tert-butylcatechol. p-tert-Butylcatechol (10 to 1,000 microg/plate) was not mutagenic in any of several strains of S. typhimurium with or without rat or hamster liver S9. Bone marrow micronucleus tests in which 125 to 500 mg/kg p-tert-butylcatechol was administered three times by intraperitoneal injection to male rats gave negative results. No increases in the frequencies of micronucleated normochromatic erythrocytes were observed in the peripheral blood of male or female mice administered p-tert-butylcatechol in feed for 14 weeks. No significant alteration in the percentage of polychromatic erythrocytes in mouse bone marrow was observed. In summary, the primary toxicity of p-tert-butylcatechol was to the forestomach of rats and mice. In the 14-week study in rats, forestomach toxicity was observed at all exposure concentrations, and the no-observed-adverse-effect level (NOAEL) was not reached for this effect. In the 14-week study in mice, the NOAEL for forestomach toxicity was 1,562 ppm.
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PMID:NTP technical report on the toxicity studies of p-tert-butylcatechol (CAS No. 98-29-3) administered in feed to F344/N rats and B6C3F1 mice. 1259 14

C.I. Direct Blue 218 is a copper chelated dye used for cellulose, acetate, nylon, silk, wool, tissue, papers, and textile goods with a urea-formaldehyde finish. C.I. Direct Blue 218 is one of five chemicals/dyes that are part of the National Toxicology Program's Benzidine Dye Initiative, established to determine the toxicity and carcinogenicity of representative benzidine congeners, congener-derived dyes, and benzidine-derived dyes. Industrial grade C.I. Direct Blue 218 was selected for study because of its widespread use. Because of the high salt content, the dye was desalted prior to use. Toxicology and carcinogenesis studies were conducted by administering C.I. Direct Blue 218 in feed to groups of male and female F344/N rats and B6C3F1 mice for 14 days, 13 weeks, and 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, and Drosophila melanogaster. 14-DAY STUDY IN RATS: Groups of five male and five female F344/N rats were fed diets containing 0, 1,000, 3,000, 7,000, 15,000, or 30,000 ppm C.I. Direct Blue 218. All rats survived until the end of the study. Rats receiving 30,000 ppm lost weight, and the mean body weight gain of males receiving 15,000 ppm was significantly lower than that of the controls. Feed consumption by rats receiving 30,000 ppm was lower than that by the controls. Decreased organ weights at the 30,000 ppm level were related to the decreased body weights at this exposure level. 14-DAY STUDY IN MICE: Groups of five male and five female mice were fed diets containing 0, 1,000, 3,000, 7,000, 15,000, or 30,000 ppm C.I. Direct Blue 218. All mice survived until the end of the study. The final mean body weight of males receiving 30,000 ppm was 25% lower than that of controls and that of 30,000 ppm females was 20% lower than that of controls. Feed consumption by exposed and control groups was similar except for the 15,000 and 30,000 ppm groups. Feed spillage, due to reduced palatability, precluded the accurate determination of feed consumption by these two groups. Male and female mice receiving 30,000 ppm appeared hyperactive and emaciated during the last week of the study. Decreased organ weights were noted at 30,000 ppm and were attributed to the decreased mean body weights at this exposure level. 13-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats were fed diets containing 0, 3,000, 10,000, or 20,000 ppm C.I. Direct Blue 218. All male and female rats survived until the end of the study. Rats exposed to 3,000,10,000, or 20,000 ppm C.I. Direct Blue 218 received approximate daily doses of 200, 600 or 1,300 mg dye/kg body weight (males) and 200, 800, or 1,400 mg/kg (females). The final mean body weight of male rats receiving 20,000 ppm was 24% lower than that of the controls and the final mean body weight of female rats receiving 20,000 ppm was 15% lower than that of the controls. Feed consumption by exposed and control groups was similar except in the 20,000 ppm groups where feed spillage was noted. Absolute and relative kidney weights of rats receiving 10,000 or 20,000 ppm were significantly greater than those of controls. Significantly decreased organ weights were noted, particularly in the 20,000 ppm groups, and were attributed to the lower mean body weights at this exposure level. The hematocrit, hemoglobin, mean erythrocyte volume, and mean erythrocyte hemoglobin values in male and female rats receiving 10,000 and 20,000 ppm were significantly lower than those of controls. Serum levels of alanine aminotransferase and sorbitol dehydrogenase in male and female rats receiving 20,000 ppm were significantly higher than those of controls, which is consistent with hepatocellular injury. Male rats receiving 10,000 ppm and male and female rats receiving 20,000 ppm had hepatic lesions consisting of intracytoplasmic pigment in periportal Kupffer cells, minimal to mild individual hepatocyte necrosis, increased numbers of binucleated and multinucleated hepatocytes, and minimal bile duct hyperplasia. Male and female rats receiving 20,000 ppm had ys receiving 20,000 ppm had yellow-green pigment within the cytoplasm of proximal convoluted tubules of the kidney. Microconcretions of mineral were observed along the corticomedullary junction of the kidney in most female rats, but the numbers of microconcretions in kidney sections were increased in females that received 20,000 ppm. 13-WEEK STUDY IN MICE: Groups of 10 male and 10 female B6C3F1 mice were fed diets containing 0, 3,000, 10,000, or 20,000 ppm C.I. Direct Blue 218. There were no deaths attributed to C.I. Direct Blue 218. Mice exposed to 3,000, 10,000, or 20,000 ppm C.I. Direct Blue 218 received approximate daily doses of 400, 1,500, or 3,600 mg dye/kg body weight (males) and 400, 1,800, or 4,000 mg/kg (females). The final mean body weight of males that received 20,000 ppm was 24&percnt; lower than that of the controls, and the final mean body weight of females that received 20,000 ppm was 14&percnt; lower than that of controls. Feed consumption by exposed mice was similar to that by controls except in the 20,000 ppm groups where feed spillage was noted. Significant differences in organ weights were noted at 20,000 ppm which were attributed primarily to the lower mean body weights in these exposure groups. The hematocrit, hemoglobin, mean erythrocyte volume, and mean erythrocyte volume, and mean erythrocyte hemoglobin values were significantly lower in males and females receiving 10,000 and 20,000 ppm. Serum levels of alanine aminotransferase and sorbitol dehydrogenase in male and female mice receiving 10,000 and 20,000 ppm were significantly higher than those of controls, indicating hepatic injury. Male and female mice receiving 20,000 ppm had hepatic lesions consisting of centrilobular hepatocyte hypertrophy and karyomegaly, multifocal individual hepatocyte necrosis, oval cell proliferation, and periportal Kupffer cells with intracytoplasmic pigment. Males and females receiving 20,000 ppm also had increased numbers of pigmented macrophages within the red pulp of the spleen. 2-YEAR STUDY IN RATS: The doses selected for the 2-year study of C.I. Direct Blue 218 were based on the lower final mean body weights and the occurrence of hepatic lesions in the 20,000 ppm groups in the 13-week study. Groups of 60 male and 60 female rats were fed diets containing 0, 1,000, 3,000, or 10,000 ppm C.I. Direct Blue 218 for 103 weeks. Nine or 10 rats from each group were evaluated after 15 months. Survival, Body Weights, Feed and Compound Consumption, and Clinical Findings: Survival of female rats receiving 10,000 ppm was slightly, but not significantly, lower than that of the controls. Mean body weights of male and female rats in the 10,000 ppm groups were approximately 5&percnt; to 14&percnt; lower than those of the controls after week 15, and the final mean body weights of male and female rats at this level were 11&percnt; and 9&percnt; lower than those of the controls, respectively. Feed consumption by exposed male and female rats was similar to that by the controls and was estimated to deliver daily doses of 40, 120, and 440 mg dye/kg body weight to males and 50, 140, and 470 mg/kg to females. No chemical-related clinical signs of toxicity were noted. Hematology and Clinical Chemistry: The hematocrit, hemoglobin, mean erythrocyte volume, and mean erythrocyte hemoglobin values in 10,000 ppm female rats were significantly lower than those of controls, while in males only the mean erythrocyte hemoglobin value was significantly lower. Serum levels of alanine aminotransferase and sorbitol dehydrogenase in male and female rats receiving 10,000 ppm were significantly higher than those of the controls at the 15-month interim evaluation. Pathology Findings: Squamous cell papillomas of the oral mucosa (pharynx) occurred in five males receiving 10,000 ppm but not in the lower exposure groups or in controls. A squamous cell carcinoma occurred in one 10,000 ppm male and a benign basosquamous tumor was observed in another. The incidence of oral mucosal neoplasms in the 10,000 ppm males was significantly greater than that in controls and exceeded the range observed in untreated historical controls (lO/l,253, 0.8&percnt;; range 0&percnt;-4&percnt;). These neoplasms were considered chemical related. Administration of C.I. Direct Blue 218 to rats produced significantly increased incidences of forestomach basal cell hyperplasia in males receiving 3,000 or 10,000 ppm (0 ppm, 0/50; 1,000 ppm, 2/50; 3,000 ppm, 10/50;10,000 ppm, 19/50) and in females receiving 10,000 ppm (1/50, 1/49, 5/50, 11/49). Further, there were marginal increased incidences of focal squamous hyperplasia in the 3,000 and 10,000 ppm males (1/50,1/50, 6/50, 4/50). Squamous cell papillomas of the forestomach were seen in two 3,000 ppm males and in one 10,000 ppm male; no papillomas were observed in the controls. A squamous cell carcinoma was also seen in one 3,000 ppm male. Because of the uncommon occurrence of forestomach neoplasms in untreated control male rats (4/1,253, 0.3&percnt;; range 0&percnt;-2&percnt;) and the slight increase in the incidence of focal hyperplasia, these neoplasms may have been chemical related. The incidence of uterine endometrial stromal polyps in each exposed group of female rats was significantly greater than that of the controls (1/50,12/50,10/50, 10/50). Because the incidences in the exposed groups did not increase in a dose-related manner and the incidence in the controls was unusually low (historical incidence: 205/1,251,16.4&percnt;; range 2&percnt;-30&percnt;), the higher incidence of stromal polyps in the exposed groups was not considered chemical related. 2-YEAR STUDY IN MICE: The dose selection for the 2-year study was based on the lower final mean body weights and the liver lesions observed at the 20,000 ppm level in the 13-week study. Groups of 60 male and 60 female mice were fed diets containing 0, 1,000, 3,000, or 10,000 ppm C.I. Direct Blue 218 for 103 weeks. Nine or 10 mice from each exposure group were evaluated after 15 months. Survival, Body Weights, Feed and Compound Consumption, and Clinical Findings: Survival of exposed male and female mice was similar to that of the controls. Mean body weights of male and female mice receiving 10,000 ppm were 10&percnt; to 29&percnt; lower than those of the controls during most of the study, and the final mean body weights in these groups were 19&percnt; lower than that of the controls for males and 27&percnt; lower than that of the controls for females. Feed consumption by exposed mice was similar to that by controls and the diets were estimated to deliver daily doses of approximately 120, 360, and 1,520 mg of dye/kg body weight to males and 140, 470, and 2,050 mg/kg to females. No chemical-related clinical signs of toxicity were noted. Hematology and Clinical Chemistry: Hematocrit, hemoglobin, and mean erythrocyte volume values in males and females receiving 10,000 ppm were significantly lower than those of the controls. Serum levels of alanine aminotransferase and/or sorbitol dehydrogenase values in male and female mice that received 10,000 ppm were significantly higher than those of controls, which is consistent with hepatocellular damage. Pathology Findings: The administration of C.I. Direct Blue 218 to mice produced significantly increased incidences of hepatocellular adenoma (0 ppm, 16/50; 1,000 ppm, 19/50; 3,000 ppm, 17/50; 10,000 ppm, 40/50) and hepatocellular carcinoma (7/50, 3/50, 8/50,17/50) in males receiving 10,000 ppm, and a significantly increased incidence of hepatocellular adenoma in females receiving 3,000 or 10,000 ppm (7/49, 12/50, 17/49, 41/49). In females that received 10,000 ppm, the incidence of hepatocellular carcinoma was marginally increased. Consistent with these findings, the incidence of hepatocellular foci of cytologic alteration, a preneoplastic lesion, was also increased in males and females in the 10,000 ppm groups. The increased incidences of hepatocellular foci, adenomas, and carcinomas were considered chemical related. Uncommon renal tubule neoplasms also occurred at low incidences in male mice receiving C.I. Direct Blue 218, but not in controls. Renal tubule adenomas were seen in two males receiving 1,000 ppm, one male receiving 3,000 ppm, and one male receiving 10,000 ppm. A renal tubule carcinoma was also seen in one male that received 1,000 ppm. Because renal tubule neoplasms are uncommon in male mice (4/1,366, 0.3&percnt;; range 0&percnt;-2&percnt;), these neoplasms may have been chemical related. Carcinomas of the small intestine occurred in four male mice receiving 10,000 ppm. One was observed at the 15-month interim evaluation, while the other three were observed in mice at the end of the study. One control male mouse also had a carcinoma of the small intestine. Because of the uncommon occurrence of small intestine neoplasms in untreated male mice (12/1,374, 0.9&percnt;; range 0&percnt;-4&percnt;), the slightly higher incidence of these neoplasms in males receiving 10,000 ppm may have been chemical related. Carcinomas of the small intestine also occurred in one 3,000 ppm and one 10,000 ppm female, but the low incidences precluded drawing an association with chemical administration. GENETIC TOXICOLOGY: C.I Direct Blue 218 was not mutagenic in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537 tested with and without exogenous metabolic activation (S9). It was also tested in a modified Salmonella test protocol which employed reductive metabolism supplied by flavin mononucleotide or rat cecal bacteria, followed by oxidative metabolism; results of this test using strain TA1538 were also negative. C.I. Direct Blue 218 induced a small but significant increase in sister chromatid exchanges in Chinese hamster ovary cells at the highest dose tested without S9. No increase in chromosomal aberrations were observed in Chinese hamster ovary cells with or without S9. C.I. Direct Blue 218 did not induce sex-linked recessive lethal mutations in germ cells of male Drosophila melanogaster. CONCLUSIONS: Under the conditions of these 2-year feed studies, there was some evidence of carcinogenic activity of C.I. Direct Blue 218 in male F344/N rats based on the occurrence of pharyngeal neoplasms. Squamous cell neoplasms of the forestomach may have been chemical related. There was no evidence of carcinogenic activity of C.I Direct Blue 218 in female F344/N rats given 1,000, 3,000, or 10,000 ppm. There was clear evidence of carcinogenic activity of C.I. Direct Blue 218 in male and female B6C3F1 mice based on increased incidences of hepatocellular adenomas and carcinomas. The occurrence of a few neoplasms of the kidney and small intestine in male mice may have been related to C.I. Direct Blue 218 treatment. The administration of C.I. Direct Blue 218 produced an increased incidence of forestomach basal cell hyperplasia in rats and hepatocellular foci of cytologic alteration in mice. Synonyms: cuprate(4-), [mu-[(3,3'-dihydroxy[1,1'-biphenyl]-4,4'-diyl)bis[5-amino-4-hydroxy- 2,7-naphthalnedisulfonato]](8-)]]di-, tetrasodium; copper, [tetrahydrogen-3,3'-[(3,3'-dihydroxy-4,4'-biphenylylene)bis(azo)]bis [5-amino-4-hdroxy-2,7-naphthalenedisulfonato](4-)]di-, tetrasodium salt; 1-naphthol-3,6-disulfonic acid, 2,2'-(3,3'-dihydroxy-4,4'-biphenylylenebisazo)bis [8-amino-, dicopper deriv., tetrasodium salt
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PMID:NTP Toxicology and Carcinogenesis Studies of C.I. Direct Blue 218 (CAS No. 28407-37-6) in F344/N Rats and B6C3F1 Mice (Feed Studies). 1261 1

5,5-Diphenylhydantoin and its sodium salt are primarily used in the treatment of grand mal and psychomotor seizures, often in combination with other anticonvulsants, including phenobarbital. 5,5-Diphenylhydantoin is a suspected human carcinogen and was one of three compounds selected by the NTP to investigate the potential value of perinatal exposures in assessing chemical carcinogenicity. Chronic toxicity and carcinogenicity studies of 5,5-diphenylhydantoin were conducted in male and female F344/N rats and B6C3F1 mice. The studies were designed to determine the following: a) the effects of 5,5-diphenylhydantoin in the diet given to rats and mice during the adult (F1) period only (a typical carcinogenicity study), b) the toxic and carcinogenic effects of 5,5-diphenylhydantoin in rats and mice receiving perinatal (F0) exposure only (dietary exposure of dams prior to breeding and throughout gestation and lactation), and c) the effects of combined perinatal and adult exposure to 5,5-diphenylhydantoin. Genetic toxicology studies were conducted in Salmonella typhimurium, mouse Iymphoma cells, cultured Chinese hamster ovary cells, Drosophila melanogaster, and mouse bone marrow cells. STUDIES IN F344/N RATS: A 13-week toxicity study was conducted to select the exposure levels for adults in the 2-year study. The exposure levels for the 13-week study ranged from 300 to 4,800 ppm 5,5-diphenylhydantoin in the diet. The final mean body weights of males and females exposed to 2,400 or 4,800 ppm were significantly decreased. All groups showed a net weight gain over the study period, although the mean body weight gain of females in the 4,800 ppm group was only one-half that of the controls. Feed consumption also decreased with increasing exposure level. No chemical-related gross lesions were present in the tissues of exposed rats. Microscopically, centrilobular hypertrophy of hepatocytes was observed in the liver of rats in the 4,800 ppm groups. Based on these results, 2,400 ppm was selected as the highest exposure for the adult-only portion of the 2-year carcinogenicity study. A gestational study was performed to select the exposure levels for the perinatal portion of the 2-year study. The exposure levels ranged from 80 to 2,400 ppm 5,5-diphenylhydantoin in the diet of the dams. The 2,400 ppm exposure level was found to have reproductive and embryotoxic effects, as none of the sperm-positive females delivered litters. In the 800 ppm group, a greater number of pups died between postnatal day 1 and day 28 than in the control group. No gross external malformations were observed among fetuses or pups surviving to term in any exposure group, and no gross or histopathologic lesions were observed in the animals exposed to 800 ppm for 4 weeks following weaning. Based on these results, 630 ppm was selected as the highest exposure level for the perinatal portion of the 2-year carcinogenicity study. The eight F0:F1 exposure combinations selected for the 2-year study are listed in the table (contained in full report - page 6). In the 2-year study, male and female rats in the 630:2,400 ppm groups evaluated at 9 months had increased relative liver weights. Hematologic evaluations indicated mild but consistent chemical-related increases in erythrocyte and platelet counts in male and female rats. Mild decreases in triglyceride concentrations and alanine aminotransferase enzyme activity were seen generally in the high-exposure groups. In the 2-year study, the survival of exposed rats was similar to that of the controls. However, body weights of exposed rats were lower than those of the controls, and body weights were 11% to 35~ lower in rats receiving adult exposure of 2,400 ppm 5,5-diphenylhydantoin. Feed consumption was similar for exposed and control groups. Hepatocellular neoplasms, primarily adenomas, occurred with a positive trend in male rats fed 5,5-diphenylhydantoin only as adults (0:0 ppm, 0/50; 0:800 ppm, 2/50; 0:2,400 ppm, 4/50). There were no increased neoplasm incidences at other sites in exposed males or at any site in exposed females.emales. Perinatal-only or combined perinatal and adult exposure to 5,5-diphenylhydantoin did not enhance the overall incidences of liver neoplasms in male or female rats. However, the finding of 5/49 hepatocellular adenomas in the 630:2,400 male rat group was consistent with the marginally elevated liver neoplasm rate observed in the 0:2,400 group. Decreased incidences of a number of different neoplasms in exposed groups were most likely related to the lower body weights. STUDIES IN B6C3F1 MICE: A 13-week toxicity study was conducted to select the exposure levels for adults in the 2-year study. The exposure levels for the 13-week study ranged from 75 to 1,200 ppm 5,5-diphenylhydantoin in the diet. With the exception of one male, all mice exposed to 1,200 ppm died before the end of the study. No other chemical-related deaths occurred. All groups of mice except the 1,200 ppm groups gained weight over the 13-week period; however, an exposure related decrease in body weight gain was seen in males and females. Feed consumption by exposed and control groups was generally similar. Chemical related histomorphologic lesions were present in the liver of exposed mice, particularly 600 ppm males, and consisted of centrilobular hypertrophy of hepatocytes. Females appeared to be less sensitive than males to the effects of 5,5-diphenylhydantoin on growth and on histomorphologic liver lesions. Based on these results, 300 ppm (males) and 600 ppm (females) were selected as the highest exposure levels for the adult-only portion of the 2-year carcinogenicity study. A gestational study was performed to select the exposure levels for the perinatal portion of the 2-year study. The exposure levels for males and females ranged from 20 to 600 ppm 5,5-diphenylhydantoin in the diet. In general, reproductive performance and maternal care were poor in all groups, including the controls, thus restricting the sample size and sensitivity of this evaluation. There were no litters in the 600 ppm group, and maternal weight gain was depressed. There were no gross external malformations among pups surviving to term, and no gross or histopathologic lesions were observed in any mice exposed for 4 weeks following weaning. Based on these results, 210 ppm was selected as the highest exposure level for the perinatal portion of the 2-year carcinogenicity study. The F0:F1 exposure combinations selected for the 2-year study are listed in the following table (contained in full report - page 7). For mice evaluated at 9 months, males and females receiving the highest F0:F1 exposure levels had increased relative liver weights. In the 2-year study, the survival of exposed animals was similar to that of the controls; however, body weights were lower for exposed groups, and decreased body weights were most severe in adult females receiving 600 ppm 5,5-diphenylhydantoin. Feed consumption was similar for exposed and control groups. The incidences of hepatocellular neoplasms were increased in female mice receiving adult-only exposure (0:0 ppm, 5/48; 0:200 ppm, 14/49; 0:600 ppm, 30/50) or combined perinatal and adult exposure (210:200 ppm, 16/50; 210:600 ppm, 34/50). A marginally increased incidence of liver neoplasms (12/49) occurred in females in the perinatal-only (210:0) exposure group. There were no chemical-related increased incidences of liver neoplasms in males receiving adult-only or perinatal-only exposure. However, males receiving the high-exposure combined perinatal and adult exposure regimen (210:300 ppm) had an increased incidence of liver neoplasms (41/50) compared to the 0:0 (29/50), 0:300 (26/49), and 210:0 (33/50) groups. As a result, there was a significant enhancement (interaction) associated with combined perinatal and adult exposure. Such enhancement of neoplasia did not occur in female mice. Decreased incidences of malignant neoplasms in exposed groups were most likely related to the lower body weights. GENETIC TOXICOLOGY: In general, tests for genotoxic activity of 5,5-diphenylhydantoin were negative. All in vitro testing was performed in the presence and the absence of exogenous metabolic activation (S9). 5,5-Diphenylhydantoin did not induce mutations in Salmonella typhimurium, in L5178Y mouse Iymphoma cells, or in germ cells of male Drosophila melanogaster, nor did it induce chromosomal aberrations in cultured Chinese hamster ovary cells. A small but statistically significant increase was obtained in the cultured Chinese hamster ovary cell test for induction of sister chromatid exchanges in the presence of S9; without S9, no increase in sister chromatid exchanges was observed. In vivo, 5,5-diphenylhydantoin did not induce micronuclei polychromatic erythrocytes or chromosomal aberrations in bone marrow cells of male mice; equivocal results were obtained in an in vivo test for induction of sister chromatid exchanges in mouse bone marrow cells. CONCLUSIONS: Adult-Only Exposure: Under the conditions of these 2-year, adult-only, dietary exposure studies, there was equivocal evidence of carcinogenic activity of 5,5-diphenylhydantoin in male F344/N rats based on marginally increased incidences of hepatocellular neoplasms. There was no evidence of carcinogenic activity of 5,5-diphenylhydantoin in female F344/N rats given 240, 800, or 2,400 ppm. There was no evidence of carcinogenic activity of 5,5-diphenylhydantoin in male B6C3F1 mice given 30,100, or 300 ppm. There was clear evidence of carcinogenic activity of 5,5-diphenylhydantoin in female B6C3F1 mice based on increased incidences of hepatocellular neoplasms. Perinatal-Only Exposure: Perinatal exposure alone (through dietary administration of 210 ppm 5,5-diphenylhydantoin during the perinatal period) caused a marginal increase in the incidences of hepatocellular neoplasms in female B6C3F1 mice evaluated 2 years after cessation of exposure. In male and female F344/N rats, exposure to 630 ppm during the perinatal period did not influence the incidences of hepatocellular or other neoplasms. Similarly, exposure of male B6C3F1 mice to dietary levels of 210 ppm 5,5-diphenylhydantoin during the perinatal period did not affect neoplasm incidences. No teratologic effects were observed. Combined Perinatal and Adult Exposure: Combined perinatal and adult dietary exposure to 5,5-diphenylhydantoin confirmed the findings of the increased incidences of hepatocellular neoplasms for adult-only exposures in male F344/N rats and female B6C3F1 mice, although combined exposure did not enhance these neoplastic effects. However, in male B6C3F1 mice, combined perinatal and adult exposure resulted in increased incidences of hepatocellular neoplasms (hepatocellular carcinomas and multiple adenomas) that were not seen when dietary exposure was limited to the adult exposure period only. Synonyms: Diphenylhydantoin; 5,5-diphenyl-2,4-imidazolidinedione Trade names: Difhydan; Dihycon; Di-Hydan; Di-Lan; Dilabid; Dilantin; Ekko; Hydantol; Lehydan; Zentropil
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PMID:Toxicology and Carcinogenesis Studies of 5,5-Diphenylhydantoin (CAS No. 57-41-0) (Phenytoin) in F344/N Rats and B6C3F1 Mice (Feed Studies). 1262 14

Intravenous administration of glycyrrhizin has potential efficacy on decreasing serum aminotransferase levels in patients with chronic hepatitis. However, patients receiving this treatment are recommended to attend hospital regularly for several years. To improve the quality of life for these patients, we developed a glycyrrhizin suppository. In this pilot study, we examined the most effective and safe material contents of the suppository and revealed clinical efficacy for patients with biopsy-proven chronic hepatitis C comparing intravenous administration of glycyrrhizin. As content combinations of the suppository, a mixture of 300 mg of glycyrrhizinic ammonium salt and 60 &mgr;g of sodium capric acid, with pH neutralization, was confirmed to be most effective and safe condition, based on analysis of serum glycyrrhizin levels and the grade of rectal irritations in tested patients. The efficacy on decreasing serum alanine aminotransferase levels for 12-week administration of the suppository in 13 patients with chronic hepatitis C was similar to that in another 13 patients intravenously administered glycyrrhizin. Moreover, no serious side effects were observed. In conclusion, the usage of the newly developed suppository of glycyrrhizin can improve the quality of life for chronic hepatitis C patients, especially those who do not respond with viral clearance to interferon therapy. Using this suppository, larger and longer-term studies are needed.
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PMID:Efficacy of a glycyrrhizin suppository for the treatment of chronic hepatitis C: a pilot study. 1278 98

Management of HCV infection and related liver disease with treatment currently available lead to a sustained virological response in 20% of patients using interferon (IFN)-alpha mono-therapy and approximately 40-45% in those on combination therapy with ribavirin.The aim of the present investigation was to compare the effect of consensus interferon alphacon-1 (C-IFN), and IFN-alpha 2b plus ribavirin, in patients relapsing after treatment with interferon alone. A total of 112 randomised patients with relapsing HCV infection (M/F=53/59), were treated for 24 weeks with: (A) IFN-alpha 2b starting with 5/6MU/day till negativity of HCV-RNA followed by 3MU every other day, plus ribavirin 15mg/kg/day (n=34); (B) C-IFN 9microg/day (n=40); (C) ursodeoxycholic acid (UDCA; sodium salt) 450mg/day (n=37). At the end of treatment, patients were observed at follow-up for 24 weeks.Clearance of HCV-RNA was achieved by the end of treatment in 23 patients (68%) in Group A and 21 also showed a biochemical response with normal ALT; in Group B, 33 patients (82%) had both a virological and a biochemical response; in Group C, one patient cleared HCV-RNA. At the end of follow-up (sustained-response), 29% of patients in Group A (n=10/34) had negative PCR (seven patients relapsed at the 4th week, six at the 12th); in Group B, a sustained response was achieved in 58% (p<0.03; two patients relapsed at the 4th week, three at the 12th and five at the 24th).MAJOR SIDE EFFECTS COMPRISED: neutropenia (n=17) and decrease in Hb>1.5g/dl (n=33) in Group A, recurrence of psoriasis in two patients in Group B and abdominal discomfort and diarrhoea in 11 patients in Group C.Rapid clearance of circulating HCV-RNA was induced by C-IFN (66% at three weeks, 71% at six weeks): this was a good prognostic index both for end of treatment and sustained response. Treatment with C-IFN lead to a higher response rate compared to that of recombinant IFN-alpha 2b in association with ribavirin. The action of C-IFN is superior in the time taken to reach the maximal response rate during treatment and in the lower prevalence of relapse of the infection.
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PMID:Consensus interferon versus interferon-alpha 2b plus ribavirin in patients with relapsing HCV infection. 1466 12

Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from the Clinical Studies Knowledge Area of Prous Science Integrity(R), the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: 3,4-DAP; Adefovir dipivoxil, ADL-10-0101, alefacept, alemtuzumab, alosetron hydrochloride, ALT-711, aprepitant, atazanavir sulfate, atlizumab, atvogen; Bortezomib; CETP vaccine, clevudine, crofelemer; DAC:GLP-1, darbepoetin alfa, decitabine, drotrecogin alfa (activated), DX-9065a; E-7010, edodekin alfa, emivirine, emtricitabine, entecavir, erlosamide, erlotinib hydrochloride, everolimus, exenatide; Fondaparinux sodium, frovatriptan, fulvestrant; Gemtuzumab ozogamicin, gestodene; Homoharringtonine, human insulin; Imatinib mesylate, indiplon, indium 111 (111In) ibritumomab tiuxetan, inhaled insulin, insulin detemir, insulin glargine, ivabradine hydrochloride; Lanthanum carbonate, lapatinib, LAS-34475, levetiracetam, liraglutide, lumiracoxib; Maxacalcitol, melagatran, micafungin sodium; Natalizumab, NSC-640488; Oblimersen sodium; Parecoxib sodium, PEG-filgrastim, peginterferon alfa-2(a), peginterferon alfa-2b, pexelizumab, pimecrolimus, pleconaril, pramlintide acetate, pregabalin, prucalopride; rAHF-PFM, Ranelic acid distrontium salt, ranolazine, rDNA insulin, recombinant human soluble thrombomodulin, rhGM-CSF, roxifiban acetate, RSD-1235, rubitecan, ruboxistaurin mesilate hydrate; SC-51, squalamine; Tegaserod maleate, telbivudine, tesaglitazar, testosterone gel, tezosentan disodium, tipranavir; Vatalanib succinate; Ximelagatran; Yttrium 90 (90Y) ibritumomab tiuxetan; Zoledronic acid monohydrate.
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PMID:Gateways to clinical trials. 1467 84

By breeding and feeding salt to spontaneously hypertensive rats (SHR) continuously over a long period (until 60 wk old), rats with systolic blood pressures (SBP) of over 270 mmHg were prepared. It was studied whether or not supplying large amounts of vitamin C (200 mg/rat/d) over this period might bring any beneficial effect to blood pressure. Moreover, physico-chemical studies were performed to measure the components and enzymes in the blood and urine at 53 and 60 wk-old, and biochemical studies on vitamin C were also carried out in this experiment. Male (14 rats: 7 wk-old, 100-105 g) and female (15 rats: 7 wk-old, 95-100 g) SHR were divided into three groups and bred continuously for 53 wk. The A group rats were given salt (2.5 g/100 g of diet), the B group rats were given salt and vitamin C (500 mg/100 mL of drinking water), and the C group rats were controls. The results showed almost the same tendencies between male and female rats. The body weights of the SHR in groups A and B were slightly lower than group C. The amount of food intake in groups A and B was almost the same as group C. The amount of water intake was, in the order from highest to lowest, group A, B and C. The SBP of group A rats exhibited the highest value among the three groups. The SBP of group B rats given vitamin C simultaneously with the salt resulted in a low blood pressure level close to that of the controls (group C). Furthermore, the DBP (diastolic blood pressure) also reflected the antihypertensive effect of vitamin C as well. The heartbeat of the rats was highest in group A, and was comparable to the value in the rats receiving vitamin C simultaneously with salt. For the tests on occult blood and protein in the urine, group A rats showed strong positive reactions, whereas the group B and C rats had decreased results for both tests. The organ weights of the liver, stomach, spleen, adrenal gland and kidneys per 100 g rat body weight were not different among the three groups. The values for the bilirubin content, and the enzyme activities of ALT and AST in the blood showed to be the highest in the male rats of group A. The values from the group B rats decreased near to the normal value like the control group. Vitamin C was found to decrease the blood pressure in SHR, and also to work effectively to protect liver and kidney functions even under the condition of very high blood pressure, as high as 250 mmHg.
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PMID:Effects of vitamin C on high blood pressure induced by salt in spontaneously hypertensive rats. 1470 3

Hydrophobic bile salts induce either necrosis or apoptosis depending on the severity of the injury caused by them. Since bile salt-induced apoptosis is influenced by Ca2+- and protein kinase-signaling pathways, and both necrosis and apoptosis share common initiating mechanisms, we analyzed whether these signaling cascades also influence bile salt-induced necrosis in isolated rat hepatocytes. Taurochenodeoxycholate (TCDC, 0.25-1.50 mM, 2 h) reduced, in a dose-dependent manner, the percentage of viable hepatocytes, and increased the release of the cytosolic enzyme, lactate dehydrogenase (LDH) and alanine aminotransferase (ALAT), and that of the plasma membrane enzyme, alkaline phosphatase (AP). The PKC inhibitors, H7 (100 microM) and chelerythrine (2.5 microM), both prevented significantly TCDC-induced necrosis. On the contrary, the PKA activator, dibutyryl-cAMP, exacerbated TCDC-induced cell damage in a dose-dependent manner; this effect was more likely due to cAMP-mediated PKA activation, as the PKA inhibitor, KT5720 (1 microM), counteracted this effect. Instead, the intracellular Ca2+ chelator, BAPTA/AM (20 microM), was without effect. TCDC (1 mM) increased lipid peroxidation from 0.7 +/- 0.2 to 7.5 +/- 0.9 nmol of malondialdehyde per mg of protein, p < 0.001; the addition of the free radical scavenger, diphenyl-p-phenylendiamine, completely blocked this increase and prevented significantly TCDC-induced necrosis. PKC inhibition induced only a slight attenuation of TCDC-induced lipid peroxidation. Possible mechanisms accounting for the modulatory effect of signal transduction pathways on TCDC-induced necrosis, including signaling influence on TCDC transport events and TCDC-induced oxidative stress, are discussed.
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PMID:Signaling modulation of bile salt-induced necrosis in isolated rat hepatocytes. 1549 97

Liver donor pre-treatment with ursodeoxycholic acid (UDCA) may protect against injury during transplantation. In the present study we evaluated whether enteral administration of UDCA has an effect on bile flow and protects the liver from injury related to transplantation. Wistar rats were used in liver perfusion (LP) and transplantation (LTx) models. Rats were enterally administered UDCA (800 mg/kg) 3 h before cold perfusion. In LP, bile flow and bile acid composition were analysed. In LTx, serum ALT and liver histology were analysed. LP showed biliary UDCA enrichment up to 36+/-13% in pre-treated rats, causing higher bile flow (P = 0.026) compared with control rats. LTx showed lower ALT and TUNEL positive hepatocytes in the UDCA group (P < 0.02 and P < 0.05). In conclusion, augmented bile salt-dependent bile flow is preserved in the liver after cold storage. Enteral donor pre-treatment with UDCA protects the liver against ischaemia-reperfusion injury.
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PMID:Enteral donor pre-treatment with ursodeoxycholic acid protects the liver against ischaemia-reperfusion injury in rats. 1581 96


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