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)

Alteration of the components of the mixed-function oxidase system, including cytochrome P450, cytochrome b5, cytochrome P450 reductase, and cytochrome b5 reductase, was examined in liver microsomes prepared from needle biopsy samples of 12 patients with intrahepatic cholestasis. The rate of p-nitroanisole O-demethylation in the microsomes was also measured as the activity of cytochrome P450-dependent drug oxidation. The cytochrome P450 content (0.29 +/- 0.05 nmol/mg microsomal protein) in the patients was significantly lower than that in the 11 control subjects (0.41 +/- 0.09). The rate of p-nitroanisole O-demethylation was also significantly lower in the patients. However, the cytochrome b5 content and the activities of the reduced forms of nicotinamide adenine dinucleotide phosphate- and nicotinamide adenine dinucleotide-cytochrome c reductases did not differ between the two groups. Thus, selective reduction of cytochrome P450 seems to play a major role in the impairment of microsomal drug oxidation during intrahepatic cholestasis. Moreover, the reduction of cytochrome P450 was correlated with the serum concentrations of total bilirubin and bile acid but not with the serum glutamic oxaloacetic transaminase value. These observations suggest that the reduction of cytochrome P450 might be related to the severity of cholestasis.
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PMID:Selective reduction of hepatic cytochrome P450 content in patients with intrahepatic cholestasis. A mechanism for impairment of microsomal drug oxidation. 379 66

The accumulation of hydrophobic bile acids plays a role in the induction of apoptosis and necrosis of hepatocytes during cholestasis. The aim of this study was to determine in freshly isolated rat hepatocytes the roles of oxidant stress and the mitochondrial permeability transition (MPT) in bile acid-induced apoptosis. Hepatocytes isolated from adult male Sprague-Dawley rats were incubated for 4 hours in buffer containing the hydrophobic bile acid, glycochenodeoxycholic acid (GCDC, 0-500 micromol/L) or the hydrophilic bile acid, glycocholic acid (GCA), and either the antioxidants, alpha tocopherol, ebselen, or idebenone (a coenzyme Q analogue); or the MPT blockers, cyclosporin A, or bongkrekic acid, or a caspase-8 inhibitor. Apoptosis was assessed hourly by nuclear morphologic changes of fixed cells by DAPI fluorescence microscopy and reactive oxygen species (ROS) generation by dichlorofluorescein fluorescence of hepatocytes. The percent of cells undergoing apoptosis increased in a time- and concentration-dependent manner in cells exposed to GCDC, and to a much lesser extent to GCA. ROS generation preceded the onset of apoptosis. MPT blockers, caspase-8 inhibition, and antioxidants prevented apoptosis and reduced ROS generation by hepatocytes. Flow cytometry analysis showed that MPT occurred within 1 hour of exposure of cells to 100 micromol/L GCDC, prior to onset of significant apoptosis. In conclusion, ROS generation, MPT induction, and cytochrome c release are critical steps in the induction of apoptosis by bile acids. Antioxidants may reduce liver injury caused by low levels of bile acids by preventing the generation of oxidant stress and subsequent stimulation of the MPT and release of cytochrome c from mitochondria.
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PMID:Bile acid-induced rat hepatocyte apoptosis is inhibited by antioxidants and blockers of the mitochondrial permeability transition. 1123 Jul 42

Bile acids cause liver injury during cholestasis by inducing hepatocyte apoptosis by both Fas-dependent and -independent mechanisms. However, the Fas-independent apoptosis also appears to be death receptor-mediated. Because death receptor-mediated apoptosis in hepatocytes requires proapoptotic Bcl-2 BH3 domain only protein Bid, we postulated that Fas-independent but death receptor-mediated bile acid cytotoxicity would be Bid-dependent. We used Fas-deficient lymphoproliferative (lpr) mouse hepatocytes for these studies, and inhibited Bid expression using an antisense approach. Glychochenodeoxycholate (GCDC) was used to induce apoptosis. Bid cleavage and translocation to mitochondria was observed in GCDC-treated cells as assessed by immunoblot analysis and confocal imaging of Bid-green fluorescent protein, respectively. Bid translocation to mitochondria was associated with cytochrome c release. A Bid antisense 2'-MOE modified oligonucleotide inhibited Bid expression in hepatocytes and markedly attenuated hepatocytes apoptosis by GCDC. Treatment of lpr mice with Bid antisense also ameliorated liver injury following bile duct ligation of the mice, a model of extrahepatic cholestasis. These results suggest that bile acid cytotoxicity is Bid-dependent despite the absence of Fas. Bid antisense therapy is a promising approach for the treatment of cholestatic liver injury.
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PMID:Bid antisense attenuates bile acid-induced apoptosis and cholestatic liver injury. 1171 70

Elevated serum and tissue bilirubin concentrations that occur in pathological conditions such as cholestasis, jaundice, and other liver diseases are known to stimulate cytotoxic responses. In preliminary studies, we noted that bilirubin seemed to cause apoptosis in murine hepatoma Hepa 1c1c7 wild-type (WT) cells. Consequently, we investigated apoptosis caused by bilirubin in WT, mutant C12 [aryl hydrocarbon receptor (AHR)-deficient], and C4 (AHR nuclear translocator-deficient) Hepa 1c1c7 cells. Three independent measures of apoptosis were used to quantify the effects of exogenous bilirubin (0, 1, 10, 25, 50, or 100 microM). Caspase-3 activity and cytochrome c release from mitochondria increased at 3 h post-treatment, before increased caspase-8 activity at 6 h, and nuclear condensation by 24 h after treatment with bilirubin. No differences in whole-cell lipid peroxidation were observed between the cell types; however, intracellular reactive oxygen species (ROS) production was greater in WT cells than C12 or C4 cells 3 h after bilirubin exposure. Pretreatment of cells for 1 h with 1 or 10 microM alpha-naphthoflavone, an AHR antagonist, before bilirubin exposure resulted in decreased caspase-3 activity at 6 h and nuclear condensation at 24 h in WT cells. These results indicate that bilirubin, a potential AHR ligand, causes apoptosis in murine Hepa 1c1c7 WT cells by a mechanism(s) partially involving the AHR, disruption of membrane integrity, and increased intracellular ROS production.
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PMID:Apoptosis in murine hepatoma hepa 1c1c7 wild-type, C12, and C4 cells mediated by bilirubin. 1213 Jun 76

The pathogenesis of cholestasis, bilirubin encephalopathy, and Alzheimer's disease appears to result from accumulation of diverse cytotoxic agents, which in turn may cause apoptotic cell death. In addition, mitochondria has lately been considered as a central executioner of programmed cell death, through the release of caspase activating factors. The aims of this study were to: (a) investigate mitochondrial perturbation during incubation of isolated mitochondria with unconjugated bilirubin (Bb), amyloid beta-peptide (A beta), and glycochenodeoxycholate (GCDC); (b) characterize membrane perturbation in isolated mitochondria induced by each toxic agent, and determine whether the mitochondrial permeabilization is required for cytochrome c redistribution. Mitochondria were isolated from rat liver and brain. Swelling and cytochrome c release were evaluated by spectrophotometry and western blot, respectively. The results showed that Bb as well as A beta and GCDC act directly at the mitochondrial level causing increased organelle volume, permeabilization, as well as cytochrome c release from the intermembrane space in a dose-dependent manner (P < 0.01). Moreover, cyclosporine A inhibited mitochondrial permeability, particularly after Bb- and GCDC-induced swelling (P < 0.01). Cytochrome c efflux was invariably prevented by cyclosporine A (P < 0.05). In conclusion, the results indicate that Bb-, A beta-, and GCDC-induced toxicity, culminating in apoptosis, may result from enhanced mitochondrial permeability, followed by cytochrome c efflux, which can be explained at least in part by the megapore opening.
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PMID:[Release of cytochrome C with the interaction of bilirubin, amyloid beta-peptide and glycochenodeoxycholate from isolated mitochondria]. 1252 20

Cholestatic liver injury results from the accumulation of toxic bile salts within the liver. The aim of the present study was to examine the temporal changes in expression and immunolocalization of protein associated with apoptosis in cholestatic rat liver. Rats were anesthetized and cholestasis was induced by double ligation of the common bile duct and sectioning between the ligatures. The animals were euthanized at day 3 and at weeks 1, 2, 4, and 6 after bile duct ligation (BDL). Apoptotic cell death was increased fivefold after 3 days of BDL, decreased over 2 weeks, and remained constant thereafter as has been demonstrated by TUNEL staining. Western blot analysis for Bax, Bcl-2, cytochrome c, and p53 were performed. Results show that total cellular Bax protein was increased 3 days after BDL and decreased over time thereafter. We observed the translocation of Bax to mitochondria and subsequent release of cytochrome c. According to our immunohistochemical data, nuclear p53 increased 3 days after BDL, but cytoplasmic sequestration of p53 was observed after 1 week. The expression of c-Myc was inhibited by 3 days, but increased at later stages following BDL. Bcl-2 was increased over time in BDL rats. Our data suggest toxic bile salts-induced hepatocellular apoptosis is related to differential expression of Bcl-2 family member protein and release of cytochrome c. Cellular localization of p53 plays an important role in apoptotic death of hepatocytes in BDL rats.
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PMID:Changes in expression and immunolocalization of protein associated with toxic bile salts-induced apoptosis in rat hepatocytes. 1259 Mar 63

Although a lysosomal, cathepsin B-dependent (Ctsb-dependent) pathway of apoptosis has been described, the contribution of this pathway to tissue damage remains unclear. Our aim was to ascertain if Ctsb inactivation attenuates liver injury, inflammation, and fibrogenesis after bile duct ligation (BDL). In 3-day BDL mice, hepatocyte apoptosis, mitochondrial cytochrome c release, and serum alanine aminotransferase (ALT) values were reduced in Ctsb-/- versus Ctsb+/+ animals. Likewise, R-3032 (a Ctsb inhibitor) also reduced these parameters in BDL WT mice. Both genetic and pharmacologic inhibition of Ctsb in the BDL mouse reduced (a). hepatic inflammation, as assessed by transcripts for CXC chemokines and neutrophil infiltration, and (b). fibrogenesis, as assessed by transcripts for stellate cell activation and sirius red staining for hepatic collagen deposition. These differences could not be ascribed to alterations in cholestasis. These findings support a prominent role for the lysosomal pathway of apoptosis in tissue injury and link apoptosis to inflammation and fibrogenesis. Ctsb inhibition may be therapeutic in liver diseases.
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PMID:Cathepsin B inactivation attenuates hepatic injury and fibrosis during cholestasis. 1286 4

Hydrophobic bile acids are implicated in the pathogenesis of cholestatic liver disorders through mechanisms involving oxidative stress and mitochondrial dysfunction. Antioxidants ameliorate bile acid-induced cytotoxicity in rat hepatocyte suspensions. The purpose of the current study was to evaluate the potential protective role of beta-carotene (betaC), a putative fat-soluble antioxidant that is reduced in patients with cholestasis, against bile acid-induced hepatotoxicity. In freshly isolated rat hepatocyte suspensions that were exposed to the toxic hydrophobic bile acid glycochenodeoxycholic acid (100 or 500 microM), betaC (100 microM) decreased generation of reactive oxygen species by >50%, similar to the inhibition afforded by alpha-tocopherol. Commensurate with this antioxidant effect, 100 microM betaC also protected hepatocytes against both glycochenodeoxycholic acid-induced cellular necrosis and apoptosis, which was associated with reduction in caspase 3 activation, inhibition of mitochondrial cytochrome c release in rat hepatocytes, and prevention of the mitochondrial permeability transition in both liver mitochondria and rat hepatocytes. A lower concentration of betaC (50 microM) produced similar antioxidant and anti-apoptotic protection but with less inhibition against cell necrosis, suggesting that the higher concentration of betaC may have conferred additional cytoprotection not directly related to its antioxidant function. These results demonstrate that the antioxidant effects of betaC may provide hepatoprotection against cholestatic liver injury by preventing bile acid-induced oxidative stress and mitochondrial perturbations.
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PMID:Beta-carotene prevents bile acid-induced cytotoxicity in the rat hepatocyte: Evidence for an antioxidant and anti-apoptotic role of beta-carotene in vitro. 1476 12

The accumulation of glycochenodeoxycholate (GCDC) induced hepatocyte apoptosis in cholestasis. However, many hepatocytes still survived GCDC-induced apoptosis. The molecular mechanism for the survival of hepatocytes remains unclear. In the present study, isolated rat hepatocytes were cultured in William's E medium and treated with 50 microM GCDC. DNA, RNA, cell lysate, and nuclear proteins were collected at different intervals for DNA fragmentation assay, reverse transcription PCR, Western blotting, and gel mobility shift assay, respectively. GCDC-induced active caspases were detected as early as 2 h by Western blotting and kinetic caspase assay, whereas hepatocyte apoptosis was found at 4 h by DNA fragmentation and terminal deoxynucleotidyl transferase-mediated dUPT nick-end labeling assay. When GCDC was removed, the increased caspases as well as NF-kappaB could be restored to control level. A1/Bfl-1 and inducible nitric oxide synthase (iNOS) were up-regulated in 2 h of GCDC stimulation. After GCDC was removed, hepatocytes decreased expression of A1/Bfl-1, but not iNOS, to the control level. NF-kappaB activation coincided with the change of A1/Bfl-1. Survivin, cIAP1, cIAP2, XIAP, and A1/Bfl-1, but not iNOS, were down-regulated by pan-caspase inhibitor benzyloxycarbonyl-VAD-fluoromethyl ketone. In addition, benzyloxycarbonyl-VAD-fluoromethyl ketone inhibited release of cytochrome c and suppressed NF-kappaB activation. Our data suggested that caspase pathway is an important regulatory factor during hepatocyte apoptosis. GCDC-induced caspase response is reversible, which may activate anti-apoptotic genes to protect hepatocytes from apoptosis.
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PMID:Reversibility of caspase activation and its role during glycochenodeoxycholate-induced hepatocyte apoptosis. 1576 49

The accumulation of hydrophobic bile acids in the liver is considered to play a pivotal role in the induction of apoptosis of hepatocytes during cholestasis. Thus, factors that affect apoptosis may be used to modulate liver fibrosis. Yin-Chen-Hao-Tang (YCHT) decoctions have been recognised as a hepatoprotective agent for jaundice and various types of liver diseases. We used an experimental rat model of bile-duct ligation (BDL) to test whether YCHT plays a regulatory role in the pathogenesis of hepatic apoptosis. BDL-plus-YCHT groups received 250 or 500 mg kg (-1) YCHT by gavage once daily for 27 days. YCHT significantly ameliorated the portal hypertensive state and serum TNF-alpha compared with the vehicle-treated control group. In BDL-plus-YCHT-treated rats, hepatic glutathione contents were significantly higher than than in BDL-only rats. BDL caused a prominent liver apoptosis that was supported by an increase in Bax and cytochrome c protein and increased expression of Bax and Bcl-2 messenger RNA. The normalising effect of YCHT on expression of Bax and Bcl-2 mRNA was dependent on the dose of YCHT, 500 mg kg (-1) having the greater effect on both Bax and Bcl-2 of mRNA levels. Additionally, YCHT treatment down-regulated both hepatic caspase-3 and -8 activities of BDL rats. This study demonstrates the anti-apoptotic properties of YCHT and suggests a potential application of YCHT in the clinical management of hepatic disease resulting from biliary obstruction.
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PMID:Yin-Chen-Hao-Tang ameliorates obstruction-induced hepatic apoptosis in rats. 1743 Jun 43


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