EC:2.6.1.2 - FACTA Search

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)

To compare incidence, risk factors and morphologic pattern of hepatocellular carcinoma (HCC) development in hepatitis B virus (HBV) and hepatitis C virus (HCV) related cirrhosis, 401 patients were followed prospectively by periodic ultrasound examination for 14-189 months (mean: 84.8+/-36.7). During follow-up, 77 (19.2%) patients developed HCC, with 5 and 10 year cumulative incidence of 10 and 27.5%, respectively. The risk of HCC was significantly higher in HBV and HCV co-infected patients (P=0.014) compared to those with single HBsAg or anti-HCV (antibodies to hepatitis C virus) positivity. In anti-HCV positive cases the annual risk of HCC increased from 2% in the first 5 year period to 4% in the third 5 year period, while it decreased from 2 to 0% in the same time periods in the HBsAg positive group. By Cox's regression, age above 59 years (P=0.001), male sex (P=0.09), longer duration (P=0.04) and more advanced stage (P=0.01) of cirrhosis, lower platelets count (P=0.001) and higher ALT levels were significant risk factors for HCC in anti-HCV positive patients, while only high alpha-fetoprotein (AFP) levels during follow-up (P=0.04) was a significant risk factor for HCC in HBsAg positive cases. The pattern of HCC was nodular in 63 (81.8%) patients and infiltrating in 14 (18.2%), and the former type was associated with older age (P=0.0001), longer duration (P=0.002) and more advanced stage (P=0.0001) of cirrhosis but not with the viral etiology of disease. In contrast, development of infiltrating HCC was unrelated to age and disease duration and stage, and was associated with male sex (P=0.01), HBV infection (P=0.06) and HBV and HCV co-infection (P=0.0001). Our results indicate different incidence profile, risk factors and patterns of morphogenesis of HCC development in HBV and HCV associated cirrhosis, suggesting different mechanisms of carcinogenesis.
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PMID:Patterns of hepatocellular carcinoma development in hepatitis B virus and hepatitis C virus related cirrhosis. 1167 30

Oltipraz, developed as an antischistosomal agent, protects against the hepatotoxicity of many xenobiotics and is known to be an effective inhibitor of experimental carcinogenesis in rodents. In the present study, we investigated its effects on the development of lesions in LEC rats, established as a mutant strain characterized by a hereditary predisposition for hepatic damage with severe jaundice. A total of 35 male 6-week-old LEC rats were divided into 2 groups, one administered diet supplemented with oltipraz at a dose of 400 ppm, and the other fed basal diet alone. Animals in each group were sequentially sacrificed at 10, 15, and 25 weeks after commencement of the oltipraz administration. Eight animals died or became moribund in the oltipraz group during weeks 10 and 11 of the treatment, whereas only one rat in the nontreatment group died after 16 weeks. All dead or moribund animals showed severe or moderate jaundice. The treatment caused a decrease in body weight gain from 9 to 13 weeks, and an increase in relative liver weight at each sacrifice point. Serum biochemical assays performed at week 25 revealed elevated levels of serum AST, ALT, LDH, ALP, gamma-GTP, and Cu in the treated-animals. The glutathione level in the livers of oltipraz-treated animals was significantly higher than that in the control rats. Histopathologically, enlarged hepatocytes with large nuclei, focal necrosis, pigment granule-laden Kupffer cells and hypertrophy of renal tubule cells were observed in both groups, but the severity of these changes was greater in the oltipraz group. Our results thus indicate that spontaneous hepatic damage in LEC rats is enhanced by oltipraz, by a mechanism that remains to be elucidated.
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PMID:Enhancing effects of oltipraz on the development of spontaneous hepatic lesions in LEC rats. 1195 Jan 60

To examine the association of cell cycle regulatory gene inactivation with human cell immortalization, we determined the expression status of INK4a, Rb, and WAF1/ CIP1, in eleven in vitro immortalized human cell lines, including fibroblasts and keratinocytes. Two human papillomavirus type 16 E6 expressing cell lines with telomerase activity, including a fibroblast cell line and a keratinocyte cell line, expressed no detectable p16(INK4a). These cell lines had a hyperphosphorylated pRb and reduced expression of p21(WAF1/CIP1). All of seven fibroblast cell lines immortalized either spontaneously or by (60)Co, X-rays, 4-nitroquinoline 1-oxide or aflatoxin B(1), maintaining their telomeres by the ALT (alternative lengthening of telomeres) pathway, displayed loss of expression of p16(INK4a) and hyperphosphorylation of pRb. Levels of p21(WAF1/CIP1) expression varied among the cell lines. Two fibroblast cell lines that became immortalized following infection with a retrovirus vector encoding human telomerase catalytic subunit (hTERT) cDNA were also accompanied by inactivation of p16(INK4a) and pRb pathways. Acquisition of telomerase activity alone was not sufficient for immortalization of these cell lines. Taken together, all the cell lines including fibroblasts and keratinocytes, with either telomerase activity or the ALT pathway for telomere maintenance showed loss of expression of p16(INK4a) and hyperphosphorylation of pRb. These demonstrate the association of inactivation of both p16(INK4a) and pRb with immortalization of human cells including fibroblasts and epithelial cells and telomerase-positive cells and ALT-positive cells.
Carcinogenesis 2002 Dec
PMID:Association of p16(INK4a) and pRb inactivation with immortalization of human cells. 1250 35

4,4'-Thiobis(6- t -butyl- m -cresol) (TBBC) is used in the rubber and plastics industries as an antioxidant. TBBC is also used as a stabilizer in polyethylene and polyolefin packaging materials for foodstuffs. Toxicology and carcinogenesis studies were conducted by administering TBBC (99% pure) in feed to groups of male and female F344/N rats and B6C3F1 mice for 15 days, 13 weeks, and 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and cultured Chinese hamster ovary cells. 15-DAY STUDY IN RATS: Groups of 10 male and 10 female F344/N rats were fed diets containing 0, 1,000, 2,500, 5,000, 10,000 or 25,000 ppm TBBC for 15 days. Rats given to 1,000, 2,500, 5,000, or 10,000 ppm received approximate doses of 95, 235, 335, or 365 mg TBBC per kilogram body weight per day (males) or 85, 220, 325, or 270 mg/kg per day (females). Approximate doses for rats receiving 25,000 ppm could not be calculated due to early deaths. All 25,000 ppm rats and three male and four female 10,000 ppm rats died. Surviving rats in the 10,000 ppm groups had a significant weight loss and the final mean body weights of 5,000 and 10,000 ppm male and female rats were significantly lower than those of the controls. Male and female rats exposed to 5,000, 10,000, or 25,000 ppm TBBC consumed markedly less feed than the controls. Diarrhea occurred in 5,000, 10,000, and 25,000 ppm males and females. The principal lesions attributed to the administration of TBBC were renal papillary and tubule necroses which occurred in 10,000 ppm rats. Focal necrosis or erosions of the glandular stomach also occurred in some 10,000 ppm rats. Changes observed in the thymus and spleen were attributed to debilitation or stress; bone marrow depletion was attributed to nutrient deficiency accompanying weight loss. 15-DAY STUDY IN MICE: Groups of 10 male and 10 female B6C3F1, mice were fed diets containing 0, 1,000, 2,500, 5,000, 10,000, or 25,000 ppm TBBC for 15 days. Mice given 1,000, 2,500, or 5,000 ppm received approximate doses of 285, 585, or 475 mg TBBC per kilogram body weight per day (males) or 360, 950, or 1,030 mg/kg per day (females). Approximate doses for mice given 10,000 or 25,000 ppm could not be calculated due to early deaths. All 10,000 and 25,000 ppm mice died, as did eight males and eight females given 5,000 ppm. A significant weight loss occurred in surviving 5,000 ppm males and females and the final mean body weights of 2,500 ppm females and 5,000 ppm males and females were significantly lower than those of the controls. Feed consumption by mice given 5,000, 10,000, or 25,000 ppm was markedly reduced. Diarrhea occurred in all 25,000 ppm mice and in most male and female mice given 5,000 or 10,000 ppm. Renal tubule necrosis occurred in eight males and three females in the 5,000 ppm groups. Lymphocytic depletion of Iymphoid tissues in many 5,000 ppm males and females was attributed to debilitation and stress or to nutrient deficiency accompanying weight loss. 13-WEEK STUDY IN RATS: Groups of 10 male and 10 female F344/N rats were fed diets containing 0, 250, 500, 1,000, 2,500, or 5,000 ppm TBBC for 13 weeks. These exposure levels delivered approximate doses of 15, 30, 60, 165, or 315 mg TBBC per kilogram body weight per day (males) or 15, 35, 70, 170, or 325 mg/kg per day (females). All rats survived to the end of the study. The final mean body weight of 5,000 ppm males was 40% lower than that of the controls; the final mean body weight of 5,000 ppm females was 27% lower than that of the controls. Feed consumption by male and female rats exposed to 5,000 ppm TBBC was markedly lower than that by the controls throughout the study. The absolute and relative liver weights of 5,000 ppm females were significantly greater than those of the controls. Serum alkaline phosphatase (ALP) levels were significantly higher in 2,500 and 5,000 ppm males and slightly higher in 5,000 ppm females. Serum alanine aminotransferase levels were significantly higher in 2,500 and 5,000 ppm males and females. Hematocrit and hemoglobin concentrations and mean erythroions and mean erythrocyte volume (MCV) values were significantly lower in 1,000, 2,500, and 5,000 ppm males than in controls; MCV values were also significantly lower in 5,000 ppm females. A dose-related significant increase in forelimb and hindlimb grip strength was observed in exposed male and female rats. Histopathologic findings in the liver of 2,500 and 5,000 ppm males and females included hypertrophy of Kupffer cells, bile duct hyperplasia, and individual cell necrosis of hepatocytes; centrilobular hepatocyte hypertrophy also occurred in males and females exposed to 5,000 ppm TBBC. Macrophages were increased in size and number in the mesenteric Iymph nodes of males and females exposed to 5,000 ppm, and to a lesser extent in 2,500 ppm male and female rats. Pigmentation and degeneration of the renal cortical tubule epithelial cells was also present in males and females in the 2,500 and 5,000 ppm groups; cortical tubule necrosis occurred in 5,000 ppm males and females. 13-WEEK STUDY IN MICE: Groups of up to 10 male and 10 female B6C3F1 mice were fed diets containing 0, 100, 250, 500, 1,000, or 2,500 ppm TBBC for 13 weeks. These exposure levels delivered approximate doses of 15, 30, 65, 145, or 345 mg TBBC per kilogram body weight per day (males) or 10, 35, 60, 165, or 340 mg/kg per day (females). All mice survived to the end of the study. The final mean body weights of 2,500 ppm males and of 500,1,000, or 2,500 ppm females were significantly lower than those of the controls. Feed consumption by 2,500 ppm males averaged 24&percnt; lower than that by controls through week 3 and was similar to that by controls for the remainder of the study. Feed consumption by females receiving 2,500 ppm averaged 27&percnt; less than that by the controls during most of the study. The absolute and relative liver weights of males and females exposed to 2,500 ppm TBBC were slightly but significantly greater than those of the controls. Males exposed to 500, 1,000, or 2,500 ppm and females exposed to 2,500 ppm had significantly increased absolute and relative spleen weights. No clinical findings in mice were considered chemical related. Hematocrit concentrations and erythrocyte counts of males receiving 1,000 or 2,500 ppm were significantly less than those of the controls; hemoglobin concentration in males receiving 2,500 ppm was significantly less and mean erythrocyte volume was significantly less in males receiving 2,500 ppm. Females in the 1,000 and 2,500 ppm groups had significantly decreased hematocrit concentrations and erythrocyte counts; 2,500 ppm females also had significantly decreased hemoglobin concentrations and mean erythrocyte volumes. Kupffer cell hypertrophy, bile duct hyperplasia, and an increase in size and number of macrophages in mesenteric Iymph nodes were present in 2,500 ppm male and female mice. 2-YEAR STUDY IN RATS: Doses selected for the 2-year study of TBBC were based on the lower body weights and liver and kidney toxicity observed at 5,000 ppm in the 13-week study. Groups of 115 male and 75 female F344/N rats were fed diets containing 0, 500, 1,000, or 2,500 ppm TBBC for 2 years. Based on average daily feed consumption, these exposure levels resulted in a daily ingestion of TBBC of approximately 20, 40, or 100 mg/kg body weight for males and 20, 45, or 120 mg/kg body weight for females. Hematology, clinical chemistry, and urinalysis evaluations were performed on 15 male and 15 female rats from each group at 3, 9, and 15 months. Also at 15 months, an additional 10 male and 10 female rats from each group were evaluated for histopathology, hematology, and clinical chemistry. Forty male rats per group were evaluated for neurotoxic effects. Survival, Body Weights, Feed Consumption, and Clinical Findings: Two-year survival rates and mean body weights of exposed male and female rats were generally similar to those of the controls. The mean body weights of 2,500 ppm male rats were slightly lower than those of the controls throughout the study. At week 65, the mean body weight of 2,500 ppm females was 14&percnt; lower than that of the controls, but the final mean body weight of this group was 6&percnt; lower than that of the control group. Feed consumption, behavior, and general health and appearance of exposed male and female rats were similar to those of the controls. Hematology and Clinical Chemistry: Results of the hematology evaluation were not uniformly consistent at 3, 9, and 15 months in one set of rats, nor were they consistent between the two sets of rats evaluated at 15 months. Slight but significant decreases in hematocrit levels, hemoglobin concentrations, and erythrocyte counts were observed in the 1,000 and 2,500 ppm groups in one set of males at 15 months. Similar significant decreases in hematocrit level and hemoglobin concentration occurred in 2,500 ppm females at 9 months. Mean erythrocyte hemoglobin and mean erythrocyte hemoglobin concentration of 2,500 ppm females were also significantly lower than those of controls at 9 months and in both sets of female rats evaluated at 15 months. Platelet counts of 2,500 ppm male and female rats were slightly but significantly higher than those of controls at 3 and 9 months. Platelet counts were also slightly but significantly increased in 2,500 ppm males of one set evaluated at 15 months, and in 2,500 ppm females of the second set evaluated at 15 months. Serum activities of alkaline phosphatase, alanine aminotransferase, and sorbitol dehydrogenase in 2,500 ppm males were significantly greater than those in the controls at 3, 9, and 15 months. Alkaline phosphatase activities in both sets of 1,000 ppm males evaluated at 15 months were also significantly greater than those of controls. Serum activities of alanine aminotransferase and sorbitol dehydrogenase in 2,500 ppm females were also significantly greater than those in controls at 3, 9, and 15 months. Neurotoxicity Findings: There were no significant inhibitory effects of TBBC on motor nerve excitability or conduction, neuromuscular transmission, or muscle contractility. There were no microscopic lesions in the sciatic nerve, quadriceps muscle, or teased nerve preparations of sciatic nerve that could be attributed to TBBC administration. Pathology Findings: At the 15-month interim evaluation, the absolute and relative liver weights of 2,500 ppm female rats were significantly greater than those of controls; at 15 months and at the end of the study, the incidences of Kupffer cell hypertrophy, hepatocyte cytoplasmic vacuolization, and mixed cell foci were also significantly increased. At the end of the study, the incidence of hepatocellular fatty change was significantly increased in 2,500 ppm females. The incidence of Kupffer cell hypertrophy was significantly increased in 2,500 ppm males at 15 months and at 2 years; the incidence of cytoplasmic vacuolization was significantly increased in all exposed males at 15 months but only moderately increased in 1,000 and 2,500 ppm males at 2 years; the incidence of basophilic foci was significantly increased in 2,500 ppm males at 15 months and the incidence of mixed cell foci was significantly increased in 1,000 and 2,500 ppm male rats at 2 years. The incidences of hepatocellular adenoma or carcinoma (combined) in exposed male rats were not significantly greater than that in the controls (0 ppm, 1/50; 500 ppm, 3/50; 1,000 ppm, 3/50; 2,500 ppm, 5/49), were within the historical control range, and were not considered chemical related. The severity of nephropathy was significantly increased in 2,500 ppm female rats. There was a significant negative trend in the incidence of mammary gland fibroadenoma, adenoma, or carcinoma (combined) in female rats (32/50, 24/50, 11/50, 16/50), and the incidences of fibroadenoma in 1,000 and 2,500 ppm females were significantly less than that of the controls. 2-YEAR STUDY IN MICE: Because of the reduction in body weights, the increase in liver and spleen weights, and the accompanying histopathologic changes in the liver of 2,500 ppm male and female mice in the 13-week study, the doses selected for the 2-year study were 250, 500, and 1,000 ppm. Groups of 80 male and 80 female mice were fed diets containing 0, 250, 500, or 1,000 ppm TBBC for 2 years. Based on average daily feed consumption, these exposure levels resulted in the daily ingestion of approximately 30, 60, or 145 mg TBBC/kg body weight for males and 45, 110, or 255 mg TBBC/kg body weight for females. Nine or 10 animals from each exposure group were evaluated at 3, 9, and 15 months. Survival, Body Weights, Feed Consumption, and Clinical Findings: Two-year survival rates of exposed male and female mice were similar to those of the controls. The final mean body weights of male and female mice exposed to 1,000 ppm were 8&percnt; and 18&percnt; lower than those of the controls, respectively. The final mean body weights of females exposed to 250 or 500 ppm were 8&percnt; to 9&percnt; lower than that of the controls. Feed consumption by exposed males was similar to that by controls, and there were no clinical findings attributed to TBBC administration. Hematology and Clinical Chemistry: Hematocrit level, hemoglobin concentration, and erythrocyte count in 1,000 ppm male mice were significantly lower than those in controls at the 15-month interim evaluation. Serum alkaline phosphatase activities in 1,000 ppm males were slightly but significantly greater than those in controls at 3 and 9 months, as was the serum alkaline phosphatase activity in 1,000 ppm females at 9 months. Serum levels of total bilirubin in all exposed groups of males were significantly greater than those in controls at 9 and 15 months. Pathology Findings: In the liver of male mice, negative trends in the incidences of fatty change, clear cell foci, and adenoma or carcinoma combined occurred at the end of the 2-year study. There were no compound-related increased incidences of neoplasms or nonneoplastic lesions in mice receiving TBBC for 2 years. A negative trend in the incidence of fatty change in the liver of male mice also occurred at 15 months. GENETIC TOXICOLOGY: 4,4'-Thiobis(6- t -butyl- m -cresol) was not mutagenic in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537 with or without exogenous metabolic activation (S9). Sister chromatid exchanges were induced in cultured Chinese hamster ovary cells treated with TBBC, with and without S9, but no increases in chromosomal aberrations were noted in cultured Chinese hamster ovary cells after treatment with TBBC. CONCLUSIONS: Under the conditions of these 2-year feed studies, there was no evidence of carcinogenic activity of 4,4'-thiobis(6- t -butyl- m -cresol) in male or female F344/N rats administered 500, 1,000, or 2,500 ppm or in male or female B6C3F1, mice administered 250, 500, or 1,000 ppm. Nonneoplastic lesions associated with exposure to TBBC included: Kupffer cell hypertrophy, cytoplasmic vacuolization, and mixed cell foci in the liver of male and female rats, fatty change in the liver of female, rats, and an increase in the severity of nephropathy in the kidney of female rats. In addition, decreased incidences of fibroadenoma, adenoma, or carcinoma (combined) were observed in the mammary gland of female rats. Decreases also occurred in the incidences of fatty change, clear cell foci, and adenoma or carcinoma (combined) in the liver of male mice. Synonyms: 4,4'-Thiobis(6- t -butyl-3-cresol); bis(3- t -butyl-4-hydroxy-6-methylphenyl)sulfide
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PMID:NTP Toxicology and Carcinogenesis Studies of 4,4'-Thiobis(6- t -butyl- m -cresol) (CAS No. 96-69-5) in F344/N Rats and B6C3F1 Mice (Feed Studies). 1259 28

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

Feeding menhaden oil, high in n-3 fatty acids, or a mixture of lard and corn oil with a polyunsaturated-to-monounsaturated fatty acid ratio of 1:1 was hypothesized to inhibit promotion of hepatocarcinogenesis in rats by decreasing hepatic prostaglandin (PG) levels. Ten-day-old female Sprague-Dawley rats were injected with diethylnitrosamine (DEN, 15 mg/kg body wt ip). At 4 wk of age, rats were fed fumonisin B1(50 mg/kg diet) for 5 wk in diets containing 14% lard + 6% corn oil, 10% lard + 10% corn oil, 14% menhaden oil + 6% corn oil, and 7% menhaden oil + 13% corn oil. Plasma alanine aminotransferase activity was 20% lower in rats fed 10% lard than in rats fed the other diets (P < 0.05). In menhaden oil-fed rats, total plasma cholesterol concentrations decreased 26% (P < 0.05) and hepatic phospholipid C20:5n-3, C22:5n-3, and C22:6n-3 fatty acid concentrations increased compared with lard-fed rats. Hepatic n-3 fatty acids were threefold greater in rats fed 10% lard than in rats fed 14% lard. The liver-associated natural killer cell activity in rats fed menhaden oil was 58% lower than in rats fed lard (P < 0.03). Rats fed lard had threefold (P < 0.05) greater area of _-glutamyltransferase-positive altered hepatic foci (AHF) than did rats fed menhaden oil. There was no significant difference in placental glutathione S-transferase-positive AHF among the groups. Hepatic PGF2alpha production was 60-80% greater in rats fed 14% lard than in rats fed the other diets (P < 0.05). Hepatic PGE2 was 48% less in rats fed 14%; menhaden oil than in rats fed 14% lard (P < 0.05). Although gamma-glutamyltransferase-positive focal area was inhibited by menhaden oil, only 14% menhaden oil inhibited PGE2. Feeding 10% lard inhibited PGF2alpha, but not the development of AHF. Therefore, decreased hepatic PGs did not explain the inhibition of carcinogenesis.
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PMID:Menhaden oil inhibited gamma-glutamyltransferase-positive altered hepatic foci in female Sprague-Dawley rats. 1267 44

The effect of sodium selenite (Se) was investigated against two-stage rat liver carcinogenesis initiated by a single intraperitoneal injection of N-nitrosodiethylamine (DEN, 200 mg kg(-1) i.p.) followed by promotion with phenobarbital (PB, 0.05%) in a basal diet. Se (4 p.p.m.) was administered per os daily throughout the entire experiment, before the initiation, or during the promotion stage. The plasma, liver (hepatoma and surrounding tissue) and kidney tissue were investigated biochemically for lactate dehydrogenase, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase and 5'-nucleotidase. These enzyme activities were increased (p < 0.001) in plasma of hepatoma-bearing rats compared with normal control rats. The elevation of these enzyme activities in plasma was indicative of the persistent deteriorating effect of DEN in cancer-bearing animals. Aminotransferase levels were decreased in hepatoma and surrounding liver tissue, whereas lactate dehydrogenase, alkaline phosphatase and 5'-nucleotidase were increased in the cancer condition. These enzyme activities were reversed to near normal control values in animals treated with Se. It is apparent that the beneficial effect of Se is primarily exerted on the initiation phase and secondarily during the promotion stage of DEN-initiated rat liver carcinogenesis. The analysis of marker enzyme activities taken together with our previous findings clearly indicates the antitumour efficacy of sodium selenite on DEN-induced hepatoma animals.
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PMID:Sodium selenite modulates tumour marker indices in N-nitrosodiethylamine-initiated and phenobarbital-promoted rat liver carcinogenesis. 1273 4

In order to explore a possibility that the custom of drinking green tea infusion is efficacious for reducing the carcinogenic risk of environmental exposure to pentachlorophenol (PCP), we examined the effects in a hepato- and cholangiocarcinogenesis model in mice exposed to diethylnitrosamine (DEN). In the first experiment, groups of 15 male mice were initially treated with DEN at a dose of 20 p.p.m. in the drinking water for the first 8 weeks followed by a 4 week recovery interval by PCP at concentrations of 0 (basal diet), 300 or 600 p.p.m. in the diet for 23 weeks. Further groups of animals were treated with DEN and PCP in the same manner and received 2% green tea infusion (GT) instead of the drinking water from week 10 until death. PCP exposure at the high dose promoted DEN-induced hepatocarcinogenesis, and also caused progression of cystic hyperplasias of the intrahepatic bile ducts to cholangiocellular tumors. Co-administration of GT was able to prevent the increases of incidences and multiplicities of DEN-induced hepatocellular tumors and also arrest the progression of cholangiocellular tumors. In the second experiment, co-treatment with GT in the drinking water from 1 week before 300 or 600 p.p.m. PCP treatment in the diet to the end of the experiment at week 3 in B6C3F1 male mice suppressed increases of serum ALT activities, 8-oxodeoxyguanosine levels in liver DNA and bromodeoxyuridine labeling indices of hepatocytes and intrahepatic biliary epithelial cells induced by PCP. These findings suggest that regular intake of green tea may reduce the carcinogenic risk posed by an environmental pollutant, PCP, presumably due to effects on oxidative stress.
Carcinogenesis 2003 Jun
PMID:Prevention of dual promoting effects of pentachlorophenol, an environmental pollutant, on diethylnitrosamine-induced hepato- and cholangiocarcinogenesis in mice by green tea infusion. 1280 50

Hepatitis B virus (HBV) infection is the main factor, which induces hepatocellular carcinoma (HCC) in Qidong high-risk area, China. To prevent HBV infection is the most important strategy to inhibit the HCC carcinogenesis. A large project was performed in Qidong area to protect newborn babies from the HBV infection that 80,000 children born between 1984 and 1990 were vaccinated. After three times of follow-up studies, 15 screened children were found to have symptoms of illness showing persistent elevation of serum glutamic-pyruvic transaminase (ALT). From these previously collected data, we found that the ALT levels of five vaccinees with negative hepatitis B surface antigen (HBsAg) were significantly higher than those of 10 vaccinees with positive HBsAg. Furthermore, with the passage of time, the difference of ALT levels between the two groups (HBsAg negative and positive groups) diminishes. After cloning and sequencing of the HBsAg "a" epitope coding sequences, we found that mutations in "a" epitope were correlated with the absence of detectable anti-HBsAg, while no mutations were seen in the anti-HBsAg positive infections. We also found that majority of point mutations were occurred in the coding sequences of the first loop structure in "a" epitope. The structure of double loop conformation in "a" epitope was conservative, and important for HBV antigenicity. These changes in a double loop conformation would escape neutralization by vaccine-induced antibody.
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PMID:Hepatitis B virus (HBV) vaccine-induced escape mutants of HBV S gene among children from Qidong area, China. 1468 48

For cells on the path to carcinogenesis, the key to unlimited growth potential lies in overcoming the steady loss of telomeric sequence commonly referred to as the 'end-replication problem' that occurs with each cell division. Most human tumors have reactivated telomerase, a specialized reverse transcriptase that directs RNA-templated addition of telomeric repeats on to chromosomal termini. However, approximately 10% of tumors maintain their telomeres through a recombination-based mechanism, termed alternative lengthening of telomeres or ALT. Here we demonstrate that telomeric DNA undergoes a high rate of a particular type of recombination visualized cytogenetically as sister chromatid exchange (SCE), and that this rate is dependent on genotype. A novel model of ALT is presented in which it is argued that telomeric exchanges, if they are unequal and occur at a sufficiently high frequency, will allow cells to proliferate indefinitely without polymerase-mediated extension of telomeric sequence.
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PMID:Frequent recombination in telomeric DNA may extend the proliferative life of telomerase-negative cells. 1525 49

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