Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0008370 (cholestasis)
 9,378 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

2-Nitropropane (2-NP) is mutagenic in a number of short-term mutagenicity assays in vitro and in vivo, and is a potent hepatocarcinogen in rats. A structural isomer, 1-nitropropane (1-NP), is mutagenic in V79 cells and can induce unscheduled DNA synthesis in rat hepatocytes, yet did not induce tumors in rats following chronic exposure. We examined the correlation of cell proliferation and hepatocarcinogenesis induced by this mutagenic noncarcinogen-carcinogen pair in a rat liver proliferation model. Rats were exposed to gavage doses of 0.5, 1, or 2 mmol/kg of 1-NP or 2-NP daily for 10 days; the highest two dose groups were similar to the doses used in the carcinogenesis bioassay. Cell proliferation was quantitated by incorporation of bromodeoxyuridine, detected immunohistochemically, into newly synthesized DNA. Animals exposed to the vehicle exhibited a labeling index (LI) of approximately 1.9% and animals exposed to CCL4 had a LI of approximately 30%. Rats exposed to the hepatocarcinogen 2-NP exhibited a dose-related increase in LI to 6.3 and 11% at the 1 and 2 mmol/kg doses, respectively, and no increase above control at the 0.5 mmol/kg exposure level. Animals exposed to the noncarcinogenic isomer 1-NP showed no statistically significant increase in LI above controls at any dose level tested. Serum chemistries were consistent with mild to moderate decreases in hepatocellular function, cholestasis, and necrosis following 2-NP exposure, but only minimal effects were observed, probably due to slight dehydration resulting from 1-NP exposure. These data indicate a positive association between increased cell proliferation and hepatocarcinogenesis induced by these two nitropropane isomers.
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PMID:Relationship of hepatocarcinogenicity and hepatocellular proliferation induced by mutagenic noncarcinogens vs carcinogens. II. 1- vs 2-nitropropane. 194 17

We used an in situ hybridization technique using single-stranded RNA probes to study the expression pattern of gamma-glutamyl transpeptidase (GGT) in rat liver and kidney during development. The results were compared to those obtained with an immunoperoxidase technique and with Northern blot analysis of GGT mRNA. In the kidney, northern blot revealed a 20-fold increase of GGT mRNA between day 18 of gestation and adulthood. Protein and mRNA localization clearly identified the proximal tubules as the site of synthesis of GGT. In the liver, the expression was lower than in the kidney and Northern blot showed a dramatic decrease of expression after birth. Using immunohistochemistry, the protein was detected within parenchymal cells in embryo and hepatocyte membranes and bile ducts in adults. Using in situ hybridization, GGT mRNA was only detected on days 1 and 2 after birth and exclusively in hepatocytes. Immunoperoxidase may be more sensitive than in situ hybridization to study the expression of minor liver protein such as GGT. However, the study of GGT expression using in situ hybridization is possible in cases of increased expression such as alcoholism, cholestasis, and carcinogenesis.
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PMID:Pattern of expression of gamma-glutamyl transpeptidase in rat liver and kidney during development: study by immunochemistry and in situ hybridization. 197 21

An in vivo model of liver hyperplastic noduligenesis was induced in rats by long-term administration of thioacetamide (TAM) (50 mg/kg/day i.p.). Three doses of 50 mg/kg of an antitumoral Rh(III) complex were administered at 14, 9 and 5 days before the end of TAM treatment. Plasma and urine were obtained from either TAM or Rh(III) complex or TAM plus Rh(III) complex treated rats to determine the interactions of both substances with the biochemical parameters related to liver function. The rise in alkaline phosphatase (ALP), leucine aminopeptidase (LAP), gamma-glutamyl transferase (GGT) and the unchanged activities in the aspartate and alanine aminotransferases (AST, ALT) in plasma of TAM-treated rats indicated that the disease induced by this substance can be considered as a chronic obstructive biliary disease with indices of cell proliferation and tumors. The increased concentration of bilirubin both in the plasma and urine of TAM-treated rats suggested liver cholestasis and hepatobiliary obstruction. The very low values of creatinine clearance indicated that there was some degree of kidney failure due to the effect of TAM. The increased concentration of ammonia both in plasma and urine were probably a consequence of the decreased flux in the urea cycle in the liver. The Rh(III) complex alone did not produce significant changes in the plasma enzyme activities. The only significant changes were found in the concentrations of uric acid and ammonia in the urine. When the Rh(III) complex was administered to TAM-treated rats, significant restoration of the following parameters were observed: plasma enzymatic activities, blood bilirubin and ammonia, uric acid and creatinine in the urine and the creatinine clearance. These results suggest that the altered liver function induced by TAM can be restored by Rh(III) complex. The mechanisms by which this complex acts to counteract the TAM-induced changes are not yet established.
Carcinogenesis 1987 Nov
PMID:Effect of a rhodium complex on alterations of hepatic function in thioacetamide-induced hyperplastic noduligenesis in rats. 288 38

General tests of hepatotoxicity must be selected to identify all seven different types of exposure effect--cytotoxicity, cholestasis, fibrosis, vascular injury, metabolic dysfunction, impairment of the reticuloendothelial system, and carcinogenesis--whereas specific tests need only identify one or more. The liver's multifunctional character requires using sets of tests that include blood, urine, breath, isotopic, sonic, radiological, histological, and genetic tests. In this paper, traditional studies (eg, enzymes, proteins) are reviewed for medical screening and biological monitoring for specificity, sensitivity, selectivity, and cost-effectiveness. Status of newer tests (eg, clearance, radioisotopic assay, scans) will be reviewed, and developing tests (eg, molecular, genetic) for occupational use will be introduced. Practical application of these tests will be reviewed regarding clinical evaluations, interpretation, and triage. Finally, the medical-socioeconomic implications at initial medical screening and during subsequent monitoring will be illustrated.
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PMID:Tests for hepatotoxicity: usefulness in screening workers. 377 39

Hyperplastic nodular cirrhosis was induced in rats by long-term (6 month) i.p. administration of thioacetamide at doses of 2.66 mmol/kg body wt, three times per week. The survival rate of animals at the end of the treatment was 90%. To follow the temporal changes samples at 0, 7, 15, 30, 45, 60, 90, 150 and 180 days from rats during thioacetamide intoxication and from chronological controls were obtained. The cirrhogenic ability of this treatment was assessed on the basis of morphological changes: the development of macronodular cirrhosis and the appearance of fibrous septa of collagen through portal spaces. Parameters of liver injury and cholestasis were obtained by assaying the serum activities of isocitrate dehydrogenase and gamma-glutamyltransferase. Enzymes and metabolites related to glutathione redox systems, as well as other antioxidant enzymes, were tested. Catalase and glutathione peroxidase, the two enzymes involved in the elimination of peroxides, and glutathione reductase decreased significantly at the end of the 6 months of intoxication, while Cu-Zn and Mn superoxide dismutases increased progressively during the long-term thioacetamide treatment. Protein thiol levels profile showed a biphasic change increasing from the 7th day and were insensitive to the 30% depletion of intracellular glutathione (GSH). To study the relationship of the intracellular thiols on the mechanisms of cell proliferation and differentiation during the cirrhogenic process, DNA content was assayed by flow cytometry in isolated hepatocytes, and DNA ploidy and distribution between G0-G1, S and G2 + M phases were determined. Remarkable changes in relation to a sharp increase in diploid population from 7 to 180 days (24.5%-->85.5%), a pronounced decrease in polyploid populations (tetraploid+octoploid) in the same period (73.7%-->12.3%), and elevations in the populations in S phase (S1 + S2) were observed in thioacetamide-treated rats. The results obtained indicate that hepatocytes isolated from thioacetamide-treated rats showed a marked tendency to diploidy, an enhancement in DNA replication parallel to the hepatic content of protein sulphydryl groups and a significant decline in antioxidant enzyme activities. The increase in protein thiols was independent of GSH level and of the thiol redox state.
Carcinogenesis 1995 Jul
PMID:Relationship between antioxidant systems, intracellular thiols and DNA ploidy in liver of rats during experimental cirrhogenesis. 761 93

White suckers from polluted regions of western Lake Ontario have an increased prevalence of cholangiocellular and hepatocellular and hepatocellular neoplasms associated with an idiopathic chronic cholangiohepatitis. We examined the hypothesis that bile duct obstructions and cholestasis in these fish might increase the susceptibility of liver to administered benzo[a]pyrene (B[a]P). Cytosolic glutathione S-transferase (GST) activity (CDNB) was reduced in obstructed liver to 45% of activity in adjacent unobstructed liver. At micromolar concentrations, chenodeoxycholic acid, deoxycholic acid, bilirubin and haematin each inhibited GST activity of hepatic cytosolic and S-hexylglutatione-affinity-purified GST preparations from unobstructed liver. Liver cytosol and affinity-purified hepatic GSTs from normal white sucker liver reduced DNA binding of 3H-benzo[a]-pyrene-7,8-diol-9,10-epoxide (3H-BPDE) after preincubation in vitro in the presence of 5 mM GSH. Under these conditions, cytosol from adjacent unobstructed liver had a moderately stronger protective activity against DNA binding by BPDE (16.4 +/- 1.3 pmol BPDE/mg DNA) than did cytosol from obstructed liver (20.6 +/- 1.6 pmol BPDE/mg DNA). Suckers with obstructed livers identified by laparotomy were orally administered 3H-benzo[a]pyrene (3H-B[a]P) (0.2 mmol/kg) or unlabelled B[a]P (2.0 mg/kg) and the level of B[a]P macromolecular binding was analyzed in liver tissue by liquid scintillation counting and by immunohistochemistry with antibodies to BPDE-DNA adducts. Covalent binding of 3H-B[a]P to hepatic protein was 30% less in adjacent unobstructed liver compared to obstructed liver; however, there was no significant difference in the levels of 3H-B[a]P bound to DNA in the obstructed lobes compared with non-obstructed adjacent liver. These studies demonstrate that some endogenous non-substrate ligands that accumulate during cholestasis can reduce hepatic GST activity in white suckers. While these changes are insufficient to influence total 3H-B[a]P-DNA adducts in obstructed liver, the preferential localization of BPDE-DNA adducts in GST-deficient hyperplastic biliary tracts suggests that cholangiohepatitis might increase susceptibility to cholangiolar neoplasia in fish exposed to genotoxic polycyclic aromatic hydrocarbons.
Carcinogenesis 1995 Dec
PMID:Influences of chronic cholangiohepatitis and cholestasis on hepatic metabolism of benzo[a]pyrene in white suckers (Catostomus commersoni) from industrially polluted areas of Lake Ontario. 860 65

The incidence of carcinoma arising in the wall of a congenital bile duct cyst is high and there is no doubt that these lesions represent a precancerous state of the biliary tract. In almost all cases congenital bile duct cysts are related to anomalous arrangements of the pancreaticobiliary duct system which seems to play a crucial role in the development of cystic bile ducts and biliary carcinogenesis. Bile stasis together with reflux of pancreatic juice causing longstanding inflammation and activation of bile acids might be the factors in carcinogenesis of the exposed bile duct epithelium in the cystic wall. In the case of primary or secondary extrahepatic bile duct cysts, primary excision is mandatory because of the high risk to develop biliary cancer with even nowadays poor prognosis despite advantages in biliary surgery during the last years. We report a case of a young woman in which bile duct cancer was found arising in the wall of a congenital bile duct cyst. Despite radical surgery the outcome was poor proving the high malignant potential of bile duct cancer. The question of possible tumor seeding in hepatobiliary surgery is discussed as a way of inducing hepatobiliary metastatic tumors.
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PMID:Congenital bile duct cyst: a premalignant lesion of the biliary tract associated with adenocarcinoma--a case report. 876 28

Alkaline phosphodiesterase (APDE) is associated with the cellular plasma membrane of many organs. Several isoforms are also detected in normal human serum and their respective amounts vary in liver diseases but their significance is unknown. The aims of this study were: 1) to identify a serum form of B10, an APDE exclusively localized at the apical pole of the plasma membrane of rat hepatocytes and biliary cells; 2) to gain insight into its origin; and 3) to investigate its behavior, in two liver diseases in which an abnormal membrane expression of B10 has been reported, namely cholestasis and cholangiocarcinoma. A soluble form of B10 was immunoprecipitated from normal rat serum, which amounted to 13% of total serum APDE activity. By sodium dodecyl sulfate-polyacrylamide gel electrophoresis, the size of the serum enzyme was 125 kd, which is slightly lower than that found in the plasma membrane (130 kd). In bile, a 120-kd and a 130-kd form was found. A sixfold and fivefold increase of B10 APDE activity was observed in the serum of bile duct-ligated rats and in the Long-Evans Cinnamon (LEC) rats which spontaneously develop cholangiocarcinoma. The molecular size of the form present in serum was unchanged. A threefold increase was also observed in LEC rats which had not yet developed a cholangiocarcinoma. In conclusion, we identified a soluble form of B10 in normal rat serum. The increase in serum B10 in the experimental and pathological conditions investigated does not seem to result from passage of the biliary form to the serum but seems to be caused by increased cleavage of the membrane form. Its rise early during the onset of cholangiocarcinoma suggests that B10 in the serum might be a marker of carcinogenesis and/or be involved in the development of cholangiocarcinoma.
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PMID:Identification of B10, an alkaline phosphodiesterase of the apical plasma membrane of hepatocytes and biliary cells, in rat serum: increased levels following bile duct ligation and during the development of cholangiocarcinoma. 946 58

Ductular reaction refers to an increased number of ductules (the finest ramifications of the biliary tree), accompanied by polymorphonuclear leukocytes and an increase in matrix, leading to periportal fibrosis and eventually biliary cirrhosis. It is a phenomenon that is seen in a variety of liver diseases, such as acute and chronic cholestasis and variable degrees of parenchymal necrosis. Ductular reaction has gained new interest because of its relationship with putative human liver progenitor cells. The existence of progenitor cells in a quiescent organ such as the liver, although still controversial, is important for the understanding of biological processes, such as embryogenesis, carcinogenesis, and regeneration. This article provides a diagnostic algorithm: Starting from the phenomenon of ductular reaction, portal tract and parenchymal changes that give diagnostic clues are systematically described.
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PMID:Ductular reaction and its diagnostic significance. 984 27

Diseases of the liver and biliary tract interested the physicians of The Mount Sinai Hospital from the time the hospital started until the present. Indeed, the institution has become a well-recognized center for the study of the liver and its diseases. During the first 75 years of the hospital, there were many admissions for hepatobiliary diseases, resulting in many case reports. The evolution of the hospital into a teaching hospital brought with it a more systematic method of studying diseases, not only in Pathology under Paul Klemperer, but in clinical chemistry and microbiology as well. Liver biopsy was also attempted. With the arrival of Hans Popper in 1957, the emphasis shifted to coordinated studies of structure and function under normal circumstances and in diseases as they progressed. Soon, Liver Diseases (Hepatology) were split from Gastroenterology, with Fenton Schaffner as the first chief. Over the next 30 years, more than 1000 papers, chapters and books were published. The main areas of research were fibrosis, cholestasis (especially morphology and bile salt metabolism), toxic liver injury, metabolic transformations and carcinogenesis. Primary biliary cirrhosis and viral hepatitis were and continue to be special interests. Fellows from all over the world were trained and many moved on to leadership positions. Although he was active in the development of the liver transplant program, Popper did not live to see its start. A new generation of hepatologists maintains the interest and position of The Mount Sinai Hospital in this important field of medicine.
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PMID:The history of liver disease at The Mount Sinai Hospital. 1067 86


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