Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019158 (hepatitis)
 30,205 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Xanthine oxidase (XO) is a highly versatile flavoprotein enzyme, ubiquitous among species (from bacteria to human) and within the various tissues of mammals. The enzyme catalyses the oxidative hydroxylation of purine substrates at the molybdenum centre (the reductive half-reaction) and subsequent reduction of O(2) at the flavin centre with generation of reactive oxygen species (ROS), either superoxide anion radical or hydrogen peroxide (the oxidative half-reaction). Many diseases, or at least symptoms of diseases, arise from a deficiency or excess of a specific metabolite in the body. For an example of an excess of a particular metabolite that produces a disease state is the excess of uric acid which can led to gout. Inhibition of XO decreases the uric acid levels, and results in an antihyperuricemic effect. Allopurinol, first synthesised as a potential anticancer agent, is nowadays a clinically useful xanthine oxidase inhibitor used in the treatment of gout. There is overwhelming acceptance that xanthine oxidase serum levels are significantly increased in various pathological states like hepatitis, inflammation, ischemia-reperfusion, carcinogenesis and aging and that ROS generated in the enzymatic process are involved in oxidative damage. Thus, it may be possible that the inhibition of this enzymatic pathway would be beneficial. In this review the State of the Art will be presented, which includes a summary of the progress made over the past years in the knowledge of the structure and mechanism of the enzyme, associated pathological states, and in the efforts made towards the development of new xanthine oxidase inhibitors.
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PMID:Progress towards the discovery of xanthine oxidase inhibitors. 1186 Mar 55

Transgenic mice expressing the c-Myc oncogene driven by woodchuck hepatitis virus (WHV) regulatory sequences develop hepatocellular carcinoma with a high frequency. To investigate genetic lesions that cooperate with Myc in liver carcinogenesis, we conducted a genome-wide scan for loss of heterozygosity (LOH) and mutational analysis of beta-catenin in 37 hepatocellular adenomas and carcinomas from C57BL/6 x castaneus F1 transgenic mice. In a subset of these tumors, chromosome imbalances were examined by comparative genomic hybridization (CGH). Allelotyping with 99 microsatellite markers spanning all autosomes revealed allelic imbalances at one or more chromosomes in 83.8% of cases. The overall fractional allelic loss was rather low, with a mean index of 0.066. However, significant LOH rates involved chromosomes 4 (21.6% of tumors), 14, 9 and 1 (11 to 16%). Interstitial LOH on chromosome 4 was mapped at band C4-C7 that contains the INK4a/ARF and INK4b loci, and on chromosome 14 at band B-D including the RB locus. In man, the homologous chromosomal regions 9p21, 13q14 and 8p21-23 are frequently deleted in liver cancer. LOH at chromosomes 1 and 14, and beta-catenin mutations (12.5% of cases) were seen only in HCCs. All tumors examined were found to be aneuploid. CGH analysis of 10 representative cases revealed recurrent gains at chromosomes 16 and 19, but losses or deletions involving mostly chromosomes 4 and 14 generally prevailed over gains. Thus, Myc activation in the liver might select for inactivation of tumor suppressor genes on regions of chromosomes 4 and 14 in a context of low genomic instability. Myc transgenic mice provide a useful model for better defining crosstalks between oncogene and tumor suppressor pathways in liver tumorigenesis.
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PMID:Recurrent allelic deletions at mouse chromosomes 4 and 14 in Myc-induced liver tumors. 1189 80

Peroxisomes are essential and ubiquitous cell organelles having a key role in mammalian lipid and oxygen metabolism. The presence of flavine oxidases makes them an important intracellular source of H(2)O(2): an obligate product of peroxisomal redox reactions and a key reactive oxygen species. Peroxisomes proliferate in response to external signals triggered by peroxisome-proliferator-activated receptor signalling pathways. Peroxisome-derived oxidative stress as a consequence of this proliferation is increasingly recognized to participate in pathologies ranging from carcinogenesis in rodents to alcoholic and non-alcoholic steatosis hepatitis in humans. To date, no sensitive approach exists to record H(2)O(2) turnover of peroxisomes in real time. Here, we introduce a sensitive chemiluminescence method that allows the monitoring of H(2)O(2) generation and degradation in real time in suspensions of intact peroxisomes. Importantly, removal, as well as release of, H(2)O(2) can be assessed at nanomolar, non-toxic concentrations in the same sample. Owing to the kinetic properties of catalase and oxidases, H(2)O(2) forms fast steady-state concentrations in the presence of various peroxisomal substrates. Substrate screening suggests that urate, glycolate and activated fatty acids are the most important sources for H(2)O(2) in rodents. Kinetic studies imply further that peroxisomes contribute significantly to the beta-oxidation of medium-chain fatty acids, in addition to their essential role in the breakdown of long and very long ones. These observations establish a direct quantitative release of H(2)O(2) from intact peroxisomes. The experimental approach offers new possibilities for functionally studying H(2)O(2) metabolism, substrate transport and turnover in peroxisomes of eukaryotic cells.
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PMID:Sensitive and real-time determination of H2O2 release from intact peroxisomes. 1196 48

A persistent immune response to hepatitis viruses is a well-recognized risk factor for hepatocellular carcinoma. However, the molecular and cellular basis for the procarcinogenic potential of the immune response is not well defined. Here, using a unique animal model of chronic hepatitis that induces hepatocellular carcinogenesis, we demonstrate that neutralization of the activity of Fas ligand prevented hepatocyte apoptosis, proliferation, liver inflammation, and the eventual development of hepatocellular carcinoma. The results indicate that Fas ligand is involved not only in direct hepatocyte killing but also in the process of inflammation and hepatocellular carcinogenesis in chronic hepatitis. This is the first demonstration that amelioration of chronic inflammation by some treatment actually caused reduction of cancer development.
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PMID:Prevention of hepatocellular carcinoma development associated with chronic hepatitis by anti-fas ligand antibody therapy. 1239 Oct 22

Cadmium is known to be a potent carcinogenic and mutagenic metal. However, we demonstrated that dietary supplementation with 50 ppm cadmium inhibits spontaneous carcinogenesis in C3H/HeN and spontaneous hepatitis in A/J mice. We found that the frequencies of spontaneous hepatocarcinogenesis in C3H/HeN mice and of spontaneous hepatitis in A/J mice fed low-dose cadmium for 54 weeks were significantly lower than those in the respective control groups. A cadmium-induced increase in metallothionein production itself and/or metallothionein-associated increases in hepatic zinc concentrations may be involved in the observed preventive effects of cadmium. Our results suggest that low doses of cadmium in the diet or environment may play a beneficial role in the prevention of hepatic disease in humans and animals.
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PMID:Dietary cadmium inhibits spontaneous hepatocarcinogenesis in C3H/HeN mice and hepatitis in A/J mice, but not in C57BL/6 mice. 1258 87

Ten million new cancer patients are diagnosed each year worldwide. Many specific causes of cancer are known, ranging from factors related to lifestyle, diet and chronic infections to occupational exposures. Primary and secondary prevention continue to be of major importance in cancer control globally. The global burden of cancer, especially the part attributable to infectious diseases, disproportionally affects populations in developing countries. Inadequate access to treatment (pharmaceuticals and other modern technology) plays a role in perpetuating this disparity. Drugs and vaccines may not be accessible because of excessive cost or because development of the required products has been neglected. The remarkable advances in molecular understanding of the carcinogenesis process over the past 25 years have transformed the approaches to cancer control. Promising new tools in preventive oncology, such as immunization (vaccines) and chemoprevention, have emerged. Vaccines are currently being tested in trials e.g., against hepatitis B virus and human papillomaviruses. Chemoprevention has been successfully achieved in animal experiments, and has been validated in several clinical trials. The current agents and strategies should not be regarded as a panacea; more effective and safer vaccines and chemopreventive agents are needed. Future enhanced efforts on an international basis are needed to coordinate the prevention and intervention research efforts in a cost-efficient and affordable manner. Cancer prevention deserves continuing high priority in terms of both research and application, also in the developing countries. New ventures may be built on possible expansion of IARC's role in prevention and intervention research into a "Global Science Force" by following the examples of e.g., the Gambia Hepatitis Intervention Study and the cervix cancer screening trials in India. WHO's support with its regional offices would be beneficial, together with further national funding and support, and research collaboration and funding from more wealthy countries.
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PMID:Social Responsibility in Cancer Prevention Research: IARC as a 'Global Science Force' 1271 86

Methyl carbamate is used as a chemical intermediate by the textile industry for the manufacture of dimethylol methyl carbamate-based resins that are applied on polyester/cotton blend fabrics as durable-press finishes. Experimental Design: Toxicology and carcinogenesis studies of methylyl carbamate (98% pure) were conducted by exposing groups of F344/N rats and B6C3F1 mice by gavage in water in a single dose and by repeated administration for 16 days, 13 weeks, 6 months, 12 months, 18 months, and 2 years. In addition, short-term mutagenicity studies in bacteria, mammalian cells, and Drosophila and of unscheduled DNA synthesis in rat liver cells were conducted. Single-Administration Studies: In the single-administration studies, 5/5 male and 5/5 female rats that received 8,000 mg/kg methyl carbamate and 2/5 male and 5/5 female that received 4,000 mg/kg died before the end of the 15-day observational period. Five of five male and 5/5 female mice that received 8,000 mg/kg and 1/5 females that received 4,000 mg/kg died before the end of the 15-day observational period. No compound-related morphologic effects were observed in rats or mice that received 2,000 mg/kg. Sixteen-Day Studies: In the 16-day studies, all rats dosed at 2,000 or 4,000 mg/kg died, and 3/5 male rats that received 1,000 mg/kg died. Male mice that received 2,000 or 4,000 mg/kg, female mice that received 4,000 mg/kg, and 1/5 female mice that received 2,000 mg/kg died. No compound-related gross pathologic or histopathologic effects were seen in male or female rats (groups of five each) that received 500 mg/kg or in mice that received 1,000 mg/kg. Thirteen-Week Studies: In the 13-week studies, groups of 10 male and 10 female rats and mice received up to 800 mg/kg (male rats), 1,000 mg/kg (female rats), 1,500 mg/kg (male mice), or 2,000 mg/kg (female mice). Four of 10 male rats that received 800 mg/kg and 1/10 female rats that received 1,000 mg/kg died of compound-related causes before the end of the studies. Toxic hepatitis, splenic pigmentation, bone marrow atrophy, and testicular atrophy were observed in the two highest dose groups of rats. One of the female mice that received 2,000 mg/kg died. The dosed female mice had significantly greater liver weights than did the vehicle controls. Experimental Design of Six-, Twelve-, and Eighteen-Month and Two-Year Studies: Based on the findings in the short-term studies, 2-year studies of methyl carbamate were conducted by administering 0, 100, or 200 mg/kg methyl carbamate in distilled water by gavage, 5 days per week for 103 weeks, to groups of 50 F344/N rats of each sex for 103 weeks. Groups of 50 B6C3F1 mice of each sex were administered 0, 500, or 1,000 mg/kg methyl carbamate on the same schedule. Additional groups of 30 rats of each sex were administered 0 or 400 mg/kg methyl carbamate, and additional groups of 30 mice of each sex were administered 0 or 1,000 mg/kg methyl carbamate in distilled water by gavage, 5 days per week. Ten animals from each group were killed at 6, 12, or 18 months so that the progression of lesions could be followed. Results of the Six-, Twelve-, and Eighteen-Month and Two-Year Studies: In the 6-month studies, all vehicle control and dosed (400 mg/kg) rats survived. Cytologic alterations and atypical proliferative changes were observed in the liver of all dosed male and female rats, and neoplastic nodules of the liver were observed in 6/10 dosed male and 5/10 dosed female rats. In the 12-month studies, all vehicle control male and female rats and dosed female rats survived. One of 10 dosed male rats died. Neoplastic nodules of the liver were observed in 7/10 dosed male and 9/10 dosed female rats, and hepatocellular carcinomas were observed in 8/10 dosed male and 6/10 dosed female rats. In the 18-month studies, 1/10 dosed male and 8/10 dosed female and all vehicle control rats survived. Hepatocellular carcinomas were observed in 9/10 dosed male and 8/10 dosed female rats. Compound-related neoplastic changes were not observed in mice in the 6-, 12-, or 18-month studies. In the 2-year studar studies, mean body weights of high dose (200 mg/kg) male rats were generally 5%-9% lower than those of the vehicle controls after week 20. Mean body weights of high dose female rats were 5%-8% lower than those of the vehicle controls after week 56. Survival of dosed and vehicle control rats was similar (male: vehicle control, 19/50; low dose, 26/50; high dose, 29/50; female: 29/50; 36/50; 35/50). The mean body weights of high dose (1,000 mg/kg) male mice were about 8%-18% lower than those of the vehicle controls after week 24. The mean body weights of high dose (1,000 mg/kg) female mice were about 16% lower than those of the vehicle controls after week 16 and 30% lower after week 64. Survival of dosed and vehicle control mice was similar (male: 28/50; 35/50; 28/50; female: 38/50; 36/50; 32/50). Chronic focal inflammation and cytologic alteration of the liver were observed at increased incidences in high dose rats of each sex. Hyperplasia of hepatocytes was observed atincreased incidences in dosed male and high dose female rats. Neoplastic nodules or hepatocellular carcinomas (combined) in female rats occurred with a significant positive trend (0/50; 0/50; 6/49; P<0.01); the incidence of neoplastic nodules or hepatocellular carcinomas (combined) in high dose female rats was greater (P<0.03) than that in the vehicle controls. Incidences of liver neoplasms in dosed male rats were not significantly increased (4/50; 0/50; 7/49). Inflammation of the harderian gland was observed at increased incidences in dosed rats (male: 4/50; 11/50; 16/50; female: 7/50; 16/50; 30/50). The lesions were considered to be chemically related. In the 2-year studies in rats, significant decreases in tumor incidences included the following: leukemia (both sexes), pituitary gland (male), adrenal gland (male), and mammary gland (female). In the 2-year mouse studies, multinucleate giant cells in the liver were observed at increased incidences in dosed male mice (14/50; 31/50; 31/49). Adenomatous hyperplasia and histiocytosis of the lung were observed at increased incidences in high dose mice (adenomatous hyperplasia--male: 13/50; 19/50; 24/49; female: 7/49; 10/50; 18/50; histiocytosis--male: 11/50; 7/50; 21/49; female: 9/49; 10/50; 21/50). Genetic Toxicology: Methyl carbamate was not mutagenic in Salmonella typhimurium strains TA97, TA98, TA100, or TA1535 when tested with or without metabolic activation in a preincubation protocol at doses up to 10 mg/plate. Methyl carbamate did not induce forward mutations in the mouse L5178Y/TK± lymphoma assay with or without metabolicactivation at doses up to 5 mg/ml. Unscheduled DNA synthesis was not detected in rat hepatocytes after in vitro treatment with methyl carbamate at concentrations of 1.0-1,000 ug/ml. When tested in Drosophila at doses of 25,000-50,000 ppm, methyl carbamate did not induce sex-linked recessive lethal mutations. Results of tests for induction of chromosomal aberrations and sister chromatid exchanges by methyl carbamate in cultured Chinese hamster ovary cells were also negative at doses up to 5 mg/ml. Data Audit: An audit of the experimental data was conducted for the 6-, 12-, and 18-month and 2-year studies of methyl carbamate. No data discrepancies were found that influenced the final interpretation. Conclusions: Under the conditions of these 6-, 12-, and 18-month and 2-year gavage studies, there was clear evidence of carcinogenic activity for male and female F344/N rats given methyl carbamate as indicated by increased incidences of hepatocellular neoplastic nodules and hepatocellular carcinomas. There was no evidence of carcinogenic activity for male and female B6C3F1 mice given methyl carbamate at doses of 500 or 1,000 mg/kg. Methyl carbamate also induced inflammation of the harderian gland in male and female rats and adenomatous hyperplasia and histiocytosis of the lung in male and female mice. Synonyms: carbamic acid, methyl ester; methylurethan; methylurethane; urethylane
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PMID:NTP Toxicology and Carcinogenesis Studies of Methyl Carbamate (CAS No. 598-55-0) in F344/N Rats and B6C3F1 Mice (Gavage Studies). 1273 8

A carcinogenesis bioassay of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a contaminant in several phenoxy herbicides, was conducted by administering TCDD by gavage to Osborne-Mendel rats and B6C3F1 mice for 104 weeks. Fifty rats and mice of each sex were given TCDD suspended in a vehicle of 9:1 corn oil-acetone 2 days per week for 104 weeks at doses of 0.01, 0.05, or 0.5 &mgr;g/kg/wk for rats and male mice and 0.04, 0.2, or 2.0 &mgr;g/kg/wk for female mice. Seventy-five rats and 75 mice of each sex served as vehicle controls. One untreated control group containing 25 rats and 25 mice of each sex was present in the TCDD treatment room, and one untreated control group containing 25 rats and 25 mice of each sex was present in the vehicle-control room. All surviving animals were killed at 105 to 108 weeks. In rats, a dose-related depression in mean body weight gain was observed in the males after week 55 of the bioassay and in the females after week 45. In mice, the mean body weight gain in the dosed groups was comparable to that of the vehicle-control groups. In male rats, increased incidences of follicular-cell adenomas in the thyroid were dose related and were significantly (P=0.001) higher in the high-dose group than in the vehicle controls (1/69, 1%; 5/48, 10%; 6/50, 12%; 10/50, 20%). Similarly in the female rats, an increase (though not statistically significant) was seen in the high-dose group (3/73, 4%; 2/45, 4%; 1/49, 2%; 6/47, 13%). In female rats, the incidence of neoplastic nodules of the liver in the high-dose group was significantly (P=0.006) higher than that in the vehicle control group (5/75, 7%; 1/49, 2%; 3/50, 6%; 12/49, 24%). In male and female mice, incidences of hepatocellular carcinomas were dose related and the incidences in the high-dose groups were significantly (P=0.002 and 0.014, respectively) higher than those in the corresponding vehicle control groups (males: 8/73, 11%; 9/49, 18%; 9/49, 16%; 17/50, 34%; females: 1/73, 1%; 2/50, 4%; 2/48, 4%; 6/47, 13%). In female mice, follicular-cell adenomas in the thyroid occurred at dose-related incidences, and were significantly (P=0.009) higher in the high-dose groups than those in the vehicle controls (0/69, 0%; 3/50, 6%; 1/47, 2%; 5/46, 11%). Increased incidences of toxic hepatitis related to the administration of the test chemical were detected among high-dose rats and high-dose mice of each sex. Under the conditions of this bioassay, 2,3,7,8-tetrachlorodibenzo-p-dioxin was carcinogenic for Osborne-Mendel rats, including follicular-cell thyroid adenomas in males and neoplastic nodules of the liver in females. TCDD was also carcinogenic for B6C3F1 mice, including hepatocellular carcinomas in male and females and follicular-cell thyroid adenomas in females. Levels of Evidence of Carcinogenicity: Male Rats: Positive Female Rats: Positive Male Mice: Positive Female Mice: Positive Synonyms: 2,3,7,8-TCDD; TCDD
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PMID:Carcinogenesis Bioassay of 2,3,7,8-Tetrachlorodibenzo-p-dioxin (CAS No. 1746-01-6) in Osborne-Mendel Rats and B6C3F1 Mice (Gavage Study). 1277 26

The levels of dehydroepiandrosterone (DHEA) and its sulfate (DHEA-S) peak in human in their twenties, then decrease gradually with age. The physiological importance of DHEA was not clear until recent research reports showing that DHEA has beneficial effects on preventing diabetes, malignancy, inflammation, osteoporosis, and collagen disease. We summarize our results concerning diabetes, hepatitis, and colon cancer. In 1982, Coleman et al. [Diabetes 31 (1982) 830] reported that DHEA decreased hyperglycemia in diabetic db/db mice, which become insulin resistant. We measured hepatic gluconeogenic enzymes in an attempt to elucidate the mechanical mechanism of DHEA action. The activity and gene expression of hepatic gluconeogenic enzyme such as glucose-6-phosphatase (G6Pase) was increased in db/db mice despite hyperinsulinemia compared to control db/+m mice. DHEA, like troglitazone, decreased these levels in db/db mice. We also showed that DHEA improved the insulin resistance caused by aging or obesity using the glucose clamp technique in another animal model. In humans, the serum DHEA concentration was shown to be associated with hyperinsulinemia in diabetes. It also became clear that DHEA increased insulin secretion in old-aged db/db mice. DHEA increases not only insulin sensitivity due to the effects in the liver and muscle, but also insulin secretion. As an effect of DHEA on T-cell mediated hepatitis induced by concanavalin A (ConA), DHEA reduced hepatic injury by inhibiting several inflammatory mediators and apoptosis. As an effect of DHEA on carcinogenesis, DHEA would be a potential chemopreventative agent against colon cancer because it decreases the number of azoxymethane (AOM) induced aberrant crypt foci, which is a possible precursor to adenoma and cancer in a murine model.Thus, since DHEA has many beneficial effects experimentally, we should consider administration of DHEA in the future, and common mechanisms among these actions of DHEA should be elucidated in further studies.
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PMID:Prevention of diabetes, hepatic injury, and colon cancer with dehydroepiandrosterone. 1294 37

The Long-Evans Cinnamon (LEC) rat, an animal model for Wilson's disease, is an inbred mutant strain, which because of the genetic copper metabolism disorder develops hepatitis approximately 4 months after birth, followed by chronic hepatitis later in life, and eventually all of the surviving animals from liver injury and hepatitis develop spontaneous hepatocellular carcinomas. This animal model also shows that the generation of reactive oxygen species and the accumulation of oxidative damage in the liver DNA has significantly increased over the lifetime of LEC versus the wild-type Long-Evans Agouti (LEA) rats. Thus, the LEC rats having this genetically induced oxidative condition are proved to be very useful model for the study of endogenous DNA lesions and their relation to spontaneous carcinogenesis. In this study, we tested the hypothesis that differences do exist between these two rat strains in respect to their capacity to repair oxidative DNA base modification, which could explain the elevation of endogenous oxidative damage in the LEC rat liver DNA. We found that both the activity and expression at the protein and RNA levels of major DNA glycosylases, endonuclease III and 8-oxoguanine DNA-glycosylase, which initiate the excision and repair of oxidized bases, were significantly altered during the acute (16-18 weeks) and early chronic (24 weeks) phases of hepatitis. Enzyme levels were restored in the later period of chronic hepatitis (week 40) in the LEC rat liver as compared with the age-matched LEA rats. This early reduction in the capacity to repair oxidative DNA base damage could have contributed to the accumulation of mutagenic adducts in liver DNA. These findings show for the first time in an animal model that acute hepatitis impairs the repair of oxidative DNA base damage and strongly suggest that the repair of endogenous DNA adducts plays a critical role in the development of spontaneous hepatocellular carcinoma in LEC rats.
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PMID:Evidence of alterations in base excision repair of oxidative DNA damage during spontaneous hepatocarcinogenesis in Long Evans Cinnamon rats. 1463 94


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