UMLS:C0008370 - FACTA Search

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Query: UMLS:C0008370 (cholestasis)
9,378 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

alpha-naphthylisothiocyanate (ANIT) administration to rats results in periportal hepatic inflammation and injury. Glutathione (GSH) appears to be necessary for the liver injury to occur. The leukotrienes (LTs) are metabolites of arachidonic acid and potent mediators of inflammation that have been implicated in certain liver injury models. Inasmuch as GSH is a cofactor for the synthesis of cysteinyl-LTs and since inflammation is a prominent component of ANIT injury, we hypothesized that LTs are involved in producing the hepatic insult that results from ANIT administration. To test this hypothesis, rats were treated with one of several inhibitors of LT biosynthesis, A63162, Zileuton or MK-886. Each of these agents prevented the formation of LTB4 in Ca++ ionophore-stimulated whole blood from rats treated with the inhibitors. A63162 attenuated the hepatic parenchymal injury caused by ANIT and resulted in a modest decrease in ANIT-induced cholestasis. In contrast, neither Zileuton nor MK-886 attenuated liver injury. AT-125 (Acivicin) inhibits gamma-glutamyl transferase (GGT), the enzyme that catalyzes the formation of LTD4 from LTC4. AT-125 pretreatment did not prevent ANIT-induced hepatic parenchymal insult. It did, however, ameliorate the cholestasis caused by ANIT. In conclusion, the partial protection afforded by A63162 and AT-125 likely results from effects unrelated to the formation of LTs, since Zileuton and MK-886 inhibited LT synthesis without affording protection. The lack of protection by Zileuton and MK-886 in the face of LT synthesis inhibition suggests that LTs are not necessary for the expression of injury after ANIT administration.
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PMID:Leukotrienes and alpha-naphthylisothiocyanate-induced liver injury. 762 71

One of the rat liver "Class 3" cytosolic aldehyde dehydrogenases (EC 1.2.1.3), ALDH3c, is known to be markedly induced by polycyclic aromatic hydrocarbons and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; dioxin). In the present study we examined whether hepatic ALDH3c induction is a general response to toxicity. Treatment of Wistar rats for 4 days with known toxic doses of hepatotoxic agents--carbon tetrachloride, dimethylnitrosamine, diethylnitrosamine, aflatoxin B1, and D-ethionine--did not induce ALDH3c enzyme activity. Whereas dimethylaminoazobenzene at 100 mg/kg/day for 4 days did not increase ALDH3c, a 10-fold lower dose of dimethylaminoazobenzene for 4 days produced a 20-fold increase in ALDH3c activity. Treatment with phorone, diethylmaleate or L-buthionine-S,R-sulfoximine--which deplete reduced glutathione (GSH) by different mechanisms--did not affect ALDH3c activity. One dose of benzo[a]pyrene for 24 hr increased ALDH3c activity by 25-fold. Treatment with both the GSH-depleting chemicals and benzo[a]pyrene inhibited ALDH3c induction by 45% to 75%, suggesting a role for GSH during ALDH3c induction. After ALDH3c activity had already been induced by benzo[a]pyrene, however, the GSH-depleting chemicals did not affect ALDH3c activity. No changes in ALDH3c activity were seen 24 or 48 hr after partial hepatectomy, on the fifth day following surgical cholestasis, or after guanethidine-induced sympathectomy. These data indicate that hepatic ALDH3c inducibility in the rat is not a general or direct response to chemical toxicity, or to conditions of GSH depletion or other forms of stress.
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PMID:Lack of response of the rat liver "class 3" cytosolic aldehyde dehydrogenase to toxic chemicals, glutathione depletion, and other forms of stress. 808 Apr 57

The effect of peptidoleukotrienes (LT) on the efflux of glutathione (GSH) from the perfused rat liver was investigated. LTD4, C4 and E4 were infused at a final concentration of 20 nM into the portal vein of rat livers perfused with Krebs-Henseleit buffer. Perfusion pressure, efflux of glucose and release of LDH increased during the infusion of LTC4 and D4 and returned to baseline upon cessation of the infusion of LT. In contrast, the efflux of GSH did not change during the infusion of LT, but increased from 15 +/- 2 to 26 +/- 4 nmol/min.g liver 20 min after cessation of the infusion of LTC4. LTE4 did not increase the efflux of LDH, glucose, lactate, or GSH. During the LTC4- and LTD4-induced rise in perfusion pressure bile-flow decreased transiently by one third. The biliary excretion of GSH, however, decreased by an average of 75% and recovered more slowly than the cholestasis. In the presence of the selective LTD4 receptor antagonist LY171883 the effects of LTC4 and LTD4 were largely abolished. The delayed effects of LT on GSH efflux suggest that LT shift the efflux of GSH from the canalicular towards the sinusoidal side of the hepatocyte independent of other effects of LT on hepatic function. The sustained increase in efflux of GSH resulting from LT will raise the extracellular concentration of this antioxidant, such that more GSH is available at sites of inflammation to detoxify reactive oxygen species released by activated inflammatory cells.
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PMID:Peptidoleukotrienes increase the efflux of glutathione from perfused rat liver. 824 80

Hepatic complications in athletes and bodybuilders after abusing anabolic-androgenic steroids (AAS) have been reported. Hepatic injury, including cholestasis, peliosis hepatis, hyperplasia, and tumors, have been attributed to abuse of the 17 alpha-alkylated AAS. Some of these pathological conditions have been reversed when individuals were converted to nonalkylated AAS regimens. The purpose of this study was to determine and compare the direct toxic effects of commonly abused AAS (both 17 alpha-alkylated and nonalkylated) in primary hepatic cell cultures. Primary cultures, established from 60-day-old Sprague-Dawley rats, were exposed to doses of 1 x 10(-8), 1 x 10(-6), and 1 x 10(-4)M 19-nortestosterone, fluoxymesterone, testosterone cypionate, stanozolol, danazol, oxymetholone, testosterone, estradiol, and methyltestosterone for 1, 4, and 24 hr. Lactate dehydrogenase (LDH) release, neutral red (NR) retention, and glutathione (GSH) depletion were evaluated to determine plasma membrane damage, cell viability, and possible oxidative injury, respectively. Those cultures exposed to the 17 alpha-alkylated AAS, methyltestosterone and stanozolol, at doses of 1 x 10(-4) M for 24 hr and the 17 alpha-alkylated AAS, oxymetholone, at 1 x 10(-4) M for 4 and 24 hr showed significant increased in LDH release and decreases in NR retention while there were no significant differences with the nonalkylated steroids (testosterone cypionate, 19-nortestosterone, testosterone, and estradiol). GSH depletion was evaluated in cultures treated with 1 x 10(-8), 1 x 10(-6), and 1 x 10(-4) M concentrations of methyltestosterone, stanozolol, and oxymetholone for 1, 2, 4, and 6 hr. Cultures exposed to 1 x 10(-4) M oxymetholone were significantly depleted of GSH at 2, 4, and 6 hr; cultures exposed to 1 x 10(-4) M methyltestosterone were significantly depleted of GSH at 4 and 6 hr; and cultures exposed to stanozolol were not significantly depleted of GSH at any of the time periods tested. These data indicate that the 17 alpha-alkylated steroids (methyltestosterone, oxymetholone, and stanozolol) are directly toxic to hepatocytes, whereas the nonalkylated steroids (testosterone cypionate, 19-nortestosterone, testosterone, and estradiol) show no effects at similar doses. These data demonstrate a trend toward a structural-activity relationship to AAS-induced toxicity in primary cultures of rat hepatocytes.
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PMID:Toxic effects of anabolic-androgenic steroids in primary rat hepatic cell cultures. 852 26

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.
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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 threshold for hepatotoxicity and cholestasis induced by methylene dianiline (DAPM) in rats is between 25 and 75 mg/kg (Bailie et al., Environ. Health Perspect., 124, 25-30, 1993). Our objectives were to determine if a minimally toxic dose of DAPM provided a model system for studies of selective injury to biliary epithelial cells (BEC) in vivo. Thus, we examined the effects of 50 mg DAPM/kg on (1) biliary constituents, (2) liver constituents likely involved in DAPM biotransformation/detoxification, and (3) early morphological and histochemical changes in the liver. Male Sprague Dawley rats had biliary cannulas positioned under pentobarbital anesthesia. After 1 h of control bile collection, rats received 50 mg DAPM/kg po in 35% ethanol or 35% ethanol only. Bile was collected for another 6 h. Histochemical, ultrastructural, and biochemical liver alterations were assessed at 3 h or at 3 and 6 h. DAPM had minimal effects on biliary bile salt and bilirubin excretion over 6 h. Biliary glucose and protein excretion were increased approximately 2-fold starting in Hour 1, while inorganic phosphate excretion was not increased until Hour 2. Biliary glutathione excretion initially increased (Hour 1) but then declined steadily for 5 h. Microsomal cytochrome P-450 activities were transiently decreased at 3 h but had returned to control values by 6 h. Liver glutathione (GSH and GSSG) was not affected by DAPM at 3 or 6 h. Necrosis of intrahepatic bile ducts was severe at 6 h with moderate injury in smaller bile ducts. Ultrastructural alterations were observed in BEC mitochondria and microvilli at 3 h with no apparent alterations in hepatocyte mitochondria or tight junctions between cells. In addition, histochemical staining of liver sections and assays of mitochondrial enzyme activities in vitro at 3 h revealed no loss of mitochondrial function in hepatocytes. These results provide strong evidence for defining DAPM as a selective bile duct toxicant.
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PMID:A minimally toxic dose of methylene dianiline injures biliary epithelial cells in rats. 965 73

alpha-Naphthylisothiocyanate (ANIT) induces intrahepatic cholestasis in rats, involving damage to biliary epithelial cells; our study aims to investigate whether disruption of biliary function in hepatocytes can contribute to early stages of ANIT-induced intrahepatic cholestasis. Isolated rat hepatocyte couplets were used to investigate biliary function in vitro by canalicular vacuolar accumulation (cVA) of a fluorescent bile acid analogue, cholyl-lysyl-fluorescein (CLF), within the canalicular vacuole between the two cells. After a 2-h exposure to ANIT, there was a concentration-dependent inhibition of cVA (cVA-IC50; 25 microM), but no cytotoxicity (LDH leakage or [ATP] decline) within this ANIT concentration range. There was no loss of cellular [GSH] at low ANIT concentrations, but, at 50 microM ANIT, a small but significant loss of [GSH] had occurred. Diethylmaleate (DEM) partially depleted cellular [GSH], but addition of 10 microM ANIT had no further effect on GSH depletion. Reduction in cVA was seen in DEM-treated cells; addition of ANIT to these cells reduced cVA further, but the magnitude of this further reduction was no greater than that caused by ANIT alone, indicating that glutathione depletion does not enhance the effect of ANIT. F-actin distribution (by phalloidin-FITC staining) showed an increased frequency of morphological change in the canalicular vacuoles but only a small, non-significant (0.05 < p < 0.1) increase in proportion of the F-actin in the region of the pericanalicular web. The results are in accord with a disruption of hepatocyte canalicular secretion within two h in vitro, at low, non-cytotoxic concentrations of ANIT, and the possible involvement of a thiocabamoyl-GSH conjugate of ANIT (GS-ANIT) in this effect.
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PMID:ANIT-induced disruption of biliary function in rat hepatocyte couplets. 1022 Aug 58

Carmustine [1 ,3-bis(2-chloroethyl)-1-nitrosurea (BCNU)] is an antitumour agent, however, its usefulness has been limited by a side effect; which involves pericholangitis and intrahepatic cholestasis. The primary effects of cholestasis is well known; bile flow retention, intracellular Ca++ accumulation and acidosis although it may lead to hepatotoxicity by dose-dependent manner. Recent studies provide evidence that lipoperoxidation (LPO) and alterations in the antioxidant system may significantly contribute to BCNU induced hepatotoxicity. Trimetazidine, (1-[2,3,4-Trimethoxy-benzyl] piperazine HCl; TMZ) introduced as an antianginal compound, is found to exhibit various cytoprotective features by preserving cellular ATP levels, limiting intracellular acidosis and inorganic phosphate as well as Na+ and Ca++ accumulation in ischemic cardiac injury. No study was undertaken to investigate the cytoprotective role of TMZ in cholestatic injury till today; therefore we initiated this study to investigate if its cytoprotective features also exhibit in the liver and to characterize further the cholestatic response to BCNU administration. Male rats were randomly seperated to control (CONT) (n = 15), BCNU administered (BCNU) (n = 16) and BCNU+TMZ administered (BCNU+TMZ) (n = 12) groups. The control rats received a single dosage of 2 ml/kg of corn oil (i.p.) while the BCNU group received a single dosage of BCNU (20 mg/kg, i.p.) in corn oil. In the BCNU + TMZ group 2,5 mg/kg/day (i.p.) of TMZ was administered for three days. This group also received BCNU (20 mg/kg, i.p.) in corn oil, 12 hours after the initial dose of TMZ. The cholestatic effect of BCNU was monitored by stasis markers such as ALP, GGT and total bilirubin levels. Hepatic TBARS analysis was determined with the modified method of OKHAWA et al. based on the reaction of lipid peroxides with thiobarbituric acid. Oxidized (GSSG) and reduced (GSH) glutathione levels were measured by the modified enzymatic recycling method of TEARE et al. Statistical tests were performed using Kruskal Wallis one-way Anova test and posthoc analysis by Newman-Keuls test. The BCNU group and the BCNU + TMZ group showed significant increases (p = 0.029) in hepatic TBARS levels compared to the CONT group; however the difference between the BCNU and BCNU + TMZ groups in regard to TBARS was not significant. BCNU and BCNU + TMZ groups manifested a significant decrease (p = 0.0005) in GSH levels as compared to controls. GSH/GSSG ratios in the BCNU and BCNU + TMZ group also manifested a significant decrease (p = 0.0013) as compared to the CONT group. TMZ administration caused a significant increase in total GSH levels (p = 0.0026) in BCNU + TMZ group when compared to the BCNU group. Our results support the hypothesis that BCNU induced cholestasis partly involves LPO revealed by the distinct increase in the content of TBARS in the liver after BCNU administration. BCNU is a potent inhibitor of GSSG reductase altering the preservation of the thiol redox balance in the system. As a result, supranormal concentrations of intracellular GSSG would accumulate in the hepatocyte and the extrusion of this oxidized compound would require active transport leading to ATP hydrolysis. This would deplete the energy stores of the cell which would accelerate further the possible prooxidant status. Although administration of TMZ did not provoke any significant alterations in LPO, it preserved the total GSH levels of the cell probably by improving the energy status of the cell by protection of ATP-producing processes at the mitochondrial level and provision of the necessary substrates for GSH synthesis. This protective role in the antioxidant system normalizes the altered GSH levels by BCNU and hence proposes TMZ to be a promising agent in the cholestatic injury.
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PMID:Cytoprotective effects of trimetazidine in carmustine cholestasis. 1044 91

In the present research, we studied the effect of the administration of melatonin or S-adenosyl-L-methionine (S-AMe) on oxidative stress and hepatic cholestasis produced by double ligature of the extra-hepatic biliary duct (LBD) in adult male Wistar rats. Hepatic oxidative stress was evaluated by the changes in the amount of lipid peroxides and by the reduced glutathione content (GSH) in lysates of erythrocytes and homogenates of hepatic tissue. The severity of the cholestasis and hepatic injury were determined by the changes in the plasma enzyme activities of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (AP), g-glutamyl-transpeptidase (GGT), and levels of albumin, total bilirubin (TB) and direct bilirubin (DB). Either melatonin or S-AMe were administered daily 3 days before LBD, and for 10 days after biliary obstruction. LDB caused highly significant increases in plasma enzyme activities and in bilirubin and lipid peroxides levels in erythrocytes and hepatic tissue. At the same time, this procedure produced a notable decrease in the GSH pools in these biological media. Both melatonin and S-AMe administration were effective as antioxidants and hepatoprotective substances, although the protective effects of melatonin were superior; it prevented the GSH decrease and reduced significantly the increases in enzyme activities and lipid peroxidation products produced by biliary ligature. S-AMe did not modify the increased GGT activity nor did it decrease greatly the TB levels (43% melatonin vs. 14% S-AMe). However, S-AMe was effective in preventing the loss of GSH in erythrocytes and hepatic tissue, as was melatonin. The obtained data permit the following conclusions. First, the LDB models cause marked hepatic oxidative stress. Second, the participation of free radicals of oxygen in the pathogenecity and severity of cholestasis produced by the acute obstruction of the extra-hepatic biliary duct is likely. Third, the results confirm the function of S-AMe as an antioxidant and hepatoprotector. Finally, melatonin is far more potent and provides superior protection as compared to S-AMe. Considering the decrease in oxidative stress and the intensity of cholestasis, these findings have interesting clinical implications for melatonin as a possible therapeutic agent in biliary cholestasis and parenchymatous liver injury.
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PMID:Protective effect of melatonin against oxidative stress induced by ligature of extra-hepatic biliary duct in rats: comparison with the effect of S-adenosyl-L-methionine. 1073

Transient haemolysis and shortened erythrocyte lifespan are reported in association with extrahepatic biliary tract obstruction. An increase in lipid peroxidation has been noted as evidence of oxidative damage in red cells due to cholestasis. The influence of surgical relief on the antioxidative capacity of the erythrocyte is less well defined. The ability of erythrocytes to regenerate the antioxidative capacity after side-to-side choledo-choduodenostomy was assessed by measuring the two principal antioxidant enzymes, namely superoxide dismutase (SOD) and catalase (CAT), as well as the glutathione (GSH) content in the red blood cells (RBC) taken from patients with obstructive jaundice. A comparison of patients and healthy volunteers revealed a consistent decrease in enzyme activities (pSOD = 0.01, pCAT = 0.0002) and glutathione concentrations (PGSH = 0.0000) in cholestatic patients. Statistical analysis proved a clear correlation between the surgical relief of common bile duct obstruction and restored antioxidative capacity of red cells. These observations suggest that the red cells from patients with multiple common bile duct stones almost completely regenerated their antioxidative capacity four weeks after side-to-side choledochoduodenostomy.
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PMID:Effects of obstructive jaundice on the antioxidative capacity of human red blood cells. 1083 61

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