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)

A method for the measurement of reactive oxygen species (ROS) in human hepatic tissue has been developed. The method is based on the EPR detection of the nitroxide radical produced by reaction of the hydroxylamine spin-probe bis(1-hydroxy-2,2,6,6-tetramethyl-4-piperidinyl)decandioate with ROS generated under pseudo-physiologic conditions in fine needle biopsies of healthy (10 controls) and diseased (22 patients) human liver. Measures of malonaldehyde in 9 liver biopsies (3 controls and 6 patients) have also been obtained by high pressure liquid chromatography and values parallel those obtained by the spin-probe technique. The amount of ROS found in healthy human liver (median = 1.8 x 10(-11) mol/mg) was significantly lower than values found in liver affected by hepatitis B (median=5.8 x 10(-10) mol/mg; p < 0.02) or by hepatitis C (median = 2.7 x 10(-9) mol/mg; p < 0.003) as well as compared to some other non-viral liver diseases (NVLD): autoimmune hepatitis, primary biliary cirrhosis, primary schlerosing cholangitis (median = 9.8 x 10(-9) mol/mg; p < 0.005). NVLD also showed significantly higher ROS levels compared to hepatitis B (p < 0.04) and hepatitis C (p < 0.04). The mechanism, potentiality and limitations of our method are discussed.
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PMID:Measurement of oxidative stress in human liver by EPR spin-probe technique. 1088 24

Oxidative stress is involved in the development of anorexia. In the present study, we examined the possible involvement of anorexia in oxygen radical-induced hepatitis. A low dose of carbon tetrachloride (1 ml/kg of a 1:1 solution with olive oil) was orally administered to rats with and without food restriction. In rats with food restriction, carbon tetrachloride treatment induced hepatitis and reduced the body weight gain. In contrast, carbon tetrachloride treatment did not induce hepatitis in rats without food restriction, but the body weight was decreased. In these rats, the loss of body weight was accompanied by a decrease in food intake. The present results indicate that the administration of a low dose of carbon tetrachloride to rats without food restriction induced anorexia independently of hepatitis.
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PMID:Carbon tetrachloride treatment induces anorexia independently of hepatitis in rats. 1089 63

We describe a case of adult chickenpox which was complicated by severe varicella pneumonia, mild hepatitis and thrombocytopenia. The hepatitis and the thrombocytopenia were asymptomatic clinically and were diagnosed on biochemistry and blood count results. These eventually improved without specific interventions. The pneumonia, however, deteriorated rapidly despite the early commencement of oxygen supplementation, acyclovir and antibiotic. Subsequently, systemic corticosteroid therapy was initiated and the patient was ventilated in the intensive care unit. The patient eventually recovered.
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PMID:Adult varicella pneumonia that responded to combined acyclovir and steroid therapy. 1097 42

The mutant strain Long-Evans Cinnamon (LEC) rat, which accumulates copper in the liver because of a mutation in the Atp7b gene, encoding a copper-ATPase, is a model of Wilson disease. It spontaneously develops hepatitis, and subsequently hepatocellular carcinoma and cholangiofibrosis. Excess intracellular copper has been thought to induce DNA damage through reactive oxygen species produced by Cu (II)/Cu (I) redox cycling, and also by direct interaction with DNA. We have developed lacI transgenic Wilson disease (WND-B) rats by mating LEC with Big Blue F344 rats carrying a lambda shuttle vector harboring the lacI gene. lacI mutations of the livers of C-B heterozygous (Atp7b w/m, lacI) and WND-B homozygous (Atp7b m/m, lacI) rats at 6, 24, and 40 weeks of ages were analyzed. Mutant frequencies in the WND-B rats were 2.0 +/- 0.7 x 10(-5), 5.3 +/- 0.9 x 10(-5), and 5.3 +/- 1.0 x 10(-5), respectively, significantly higher than those of C-B rats. Nucleotide sequence analysis revealed that the frequency of deletion mutations of more than two nucleotides were much higher, 15% in WND-B rats, but only 2% in C-B rats. In addition, the average size of deletion was larger in the former. Loss of oligonucleotide-repeat units was specific and relatively frequent in WND-B rats. This type of mutation might be implicated in the induction of DNA strand scissions by reactive oxygen species. These findings suggest that the increase in mutant frequencies and/or the specific type of mutation according to copper accumulation play a crucial role in hepatocarcinogenesis in LEC rats.
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PMID:Increased mutant frequency and altered mutation spectrum of the lacI transgene in Wilson disease rats with hepatitis. 1101 32

In North America, liver disease due to alcohol consumption is an important cause of death in adults, although its pathogenesis remains obscure. Despite the fact that resident hepatic macrophages are known to contribute to early alcohol-induced liver injury via oxidative stress, the exact source of free radicals has remained a mystery. To test the hypothesis that NADPH oxidase is the major source of oxidants due to ethanol, we used p47(phox) knockout mice, which lack a critical subunit of this major source of reactive oxygen species in activated phagocytes. Mice were treated with ethanol chronically, using a Tsukamoto-French protocol, for 4 weeks. In wild-type mice, ethanol caused severe liver injury via a mechanism involving gut-derived endotoxin, CD14 receptor, production of electron spin resonance-detectable free radicals, activation of the transcription factor NF-kappaB, and release of cytotoxic TNF-alpha from activated Kupffer cells. In NADPH oxidase-deficient mice, neither an increase in free radical production, activation of NF-kappaB, an increase in TNF-alpha mRNA, nor liver pathology was observed. These data strongly support the hypothesis that free radicals from NADPH oxidase in hepatic Kupffer cells play a predominant role in the pathogenesis of early alcohol-induced hepatitis by activating NF-kappaB, which activates production of cytotoxic TNF-alpha.
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PMID:NADPH oxidase-derived free radicals are key oxidants in alcohol-induced liver disease. 1101 74

The definable causes of nonalcoholic steatohepatitis (NASH) include jejunoileal bypass surgery (JIB), other causes of rapid and profound weight loss in obese subjects, total parenteral nutrition, drugs, industrial toxins, copper toxicity, and disorders characterized by extreme insulin resistance. However, the etiopathogenesis in most cases of NASH appears multifactorial. Obesity, type 2 diabetes, and hypertriglyceridemia are often associated with hepatic steatosis, and although this does not invariably lead to NASH, the fatty liver is vulnerable to hepatocellular injury initiated by reactive oxygen species (ROS). It is critical to understand not only the triggers for hepatitis (injury and inflammation) in NASH but also how this is perpetuated as chronic liver disease. The present focus is on whether the biochemical processes that generate oxidative stress lead to hepatocyte injury and secondary recruitment of inflammation or whether inflammation is the primary mediator of liver cell injury. Insulin resistance is a reproducible pathogenic factor in NASH. It favors accumulation of free fatty acids in the liver and predisposes to oxidative stress by stimulating microsomal lipid peroxidases and by the direct effects of high insulin levels in decreasing mitochondrial beta-oxidation. CYP2E1 is normally suppressed by insulin but is invariably increased in the livers of patients with NASH. In rodent dietary models of steatohepatitis, CYP2E1 is the catalyst of microsomal lipid peroxidation, while in Cyp 2e1 nullizygous mice, CYP4A proteins are induced and function as alternative microsomal lipid peroxidases. Other studies implicate activation of peroxisome proliferator-activated receptor-alpha (PPAR alpha) as leading to NASH; PPAR alpha is a transcription factor that governs both microsomal (via CYP4A) and peroxisomal (beta-oxidation) pathways of lipid oxidation and ultimately production of ROS. Increased lipid peroxidation is a crucial difference between the livers of rodents with experimental NASH and those of ob/ob genetically obese mice that have uncomplicated steatosis. Administration of endotoxin, through the release of tumor necrosis factor-alpha (TNF-alpha), provokes liver inflammation with hepatocyte injury in the steatotic liver. This may be particularly relevant in JIB and has been suggested as a pathogenic mechanism in primary NASH. It has been proposed that inheriting one or more copies of the hemochromatosis gene, C282Y, promotes fibrotic progression in NASH because of increased hepatic iron deposition, but recent studies have failed to confirm this. The relationship between the severity of hepatitis in NASH and progression to cirrhosis implies that products of the inflammatory infiltrate play a role in fibrogenesis. In summary, NASH can be regarded as the hepatic consequence of the metabolic syndrome (or syndrome X). Attention should now shift from steatosis, a generally benign process that is less evident in the advanced stages of cirrhosis, to the mechanisms for hepatocellular injury, inflammation, and hepatic fibrosis. In particular, the genetic, molecular, and cellular factors that ordain and moderate fibrosis in the context of steatohepatitis will be of greatest relevance to effective therapy and clinical outcome.
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PMID:Etiopathogenesis of nonalcoholic steatohepatitis. 1129 94

The mesenteric hemodynamic response to circulatory shock is characteristic and profound; this vasoconstrictive response disproportionately affects both the mesenteric organs and the organism as a whole. Vasoconstriction of post-capillary mesenteric venules and veins, mediated largely by the alpha-adrenergic receptors of the sympathetic nervous system, can effect an "autotransfusion" of up to 30% of the total circulating blood volume, supporting cardiac filling pressures ("preload"), and thereby sustaining cardiac output at virtually no cost in nutrient flow to the mesenteric organs. Under conditions of decreased cardiac output caused by cardiogenic or hypovolemic shock, selective vasoconstriction of the afferent mesenteric arterioles serves to sustain total systemic vascular resistance ("afterload"), thereby maintaining systemic arterial pressure and sustaining the perfusion of non-mesenteric organs at the expense of mesenteric organ perfusion (Cannon's "flight or fight" response). This markedly disproportionate response of the mesenteric resistance vessels is largely independent of the sympathetic nervous system and variably related to vasopressin, but mediated primarily by the renin-angiotensin axis. The extreme of this response can lead to gastric stress erosions, nonocclusive mesenteric ischemia, ischemic colitis, ischemic hepatitis, ischemic cholecystitis, and/or ischemic pancreatitis. Septic shock can produce decreased or increased mesenteric perfusion, but is characterized by an increased oxygen consumption that exceeds the capacity of mesenteric oxygen delivery, resulting in net ischemia and consequent tissue injury. Mesenteric organ injury from ischemia/reperfusion due to any form of shock can lead to a triggering of systemic inflammatory response syndrome, and ultimately to multiple organ dysfunction syndrome. The mesenteric vasculature is therefore a major target and a primary determinant of the systemic response to circulatory shock.
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PMID:The mesenteric hemodynamic response to circulatory shock: an overview. 1133 91

Accumulation of 8-hydroxy-2'-deoxyguanosine (8-OHdG) in DNA, which may result from the continuous reactive oxygen species (ROS) generation associated with chronic inflammation, has been reported in various human preneoplastic lesions and in cancerous tissues. However, no direct causative relationship between the 8-OHdG formation and carcinogenesis has been thus far demonstrated in humans. Directly proving the causality requires showing that depletion of 8-OHdG levels in tissue by interfering with ROS generation results in a reduction in cancer. Chronic hepatitis C virus (HCV) infection is associated with a high risk of hepatocellular carcinoma (HCC). Several studies on patients with chronic HCV have shown that hepatic iron overload is attributable to liver injury and that iron depletion improved serum aminotransferase levels. Excess iron is known to generate ROS within cells, which causes mutagenic lesions, such as 8-OHdG. In this study, therefore, we have evaluated whether therapeutic iron reduction (phlebotomy and low iron diet) with a long-term follow-up (6 years) would decrease the hepatic 8-OHdG levels and the risk of HCC development in patients with chronic HCV. Patients (34) enrolled were those who had undergone standard IFN therapy but had no sustained response. Quantitative immunohistochemistry using the KS-400 image analyzing system and electrochemical detection was used for 8-OHdG detection. With this treatment, elevated hepatic 8-OHdG levels in patients with chronic hepatitis C (8.3 +/- 4.6/10(5) dG) significantly decreased to almost normal levels (2.2 +/- 0.9/10(5) dG; P < 0.001) with concomitant improvement of hepatitis severity, including fibrosis, whereas HCV titers were unaffected. None of these patients developed HCC. Thus, long-term iron reduction therapy in patients with chronic hepatitis C may potentially lower the risk of progression to HCC.
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PMID:Normalization of elevated hepatic 8-hydroxy-2'-deoxyguanosine levels in chronic hepatitis C patients by phlebotomy and low iron diet. 1175 87

The virucidal properties of photoactive phenothiazine dyes, such as methylene blue, have been known approximately 70 years. The mechanism of virus inactivation involves binding of the dye to nucleic acid, absorption of light, generation of reactive oxygen species, guanine oxidation in the viral genome. The first practical research involving phenothiazine photosensitizers in transfusion medicine was sparked by efforts to prevent transmission of hepatitis from pooled plasma administered during the Korean War. During the last decade, methylene blue was used by some European countries for virus photoinactivation in fresh frozen plasma, whereas other phenothiazine derivatives with greater affinities for nucleic acids and capabilities to inactivate intracellular virus have been investigated for photochemical decontamination of red cell suspensions. The toxicity of methylene blue is well characterized; the drug has been used for many years to treat methemoglobinemia using concentrations orders of magnitude greater than those used for virus photoinactivation, and several filters have been developed to remove the dye from plasma. Future widespread use of phenothiazines for virus photoinactivation in blood components may depend on whether the risk inherent in their use is less than the residual risk from transfusion-transmitted viruses.
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PMID:Virus inactivation in blood components by photoactive phenothiazine dyes. 1178 30

This review addresses recent advances in specific mechanisms of hepatotoxicity. Because of its unique metabolism and relationship to the gastrointestinal tract, the liver is an important target of the toxicity of drugs, xenobiotics, and oxidative stress. In cholestatic disease, endogenously generated bile acids produce hepatocellular apoptosis by stimulating Fas translocation from the cytoplasm to the plasma membrane where self-aggregation occurs to trigger apoptosis. Kupffer cell activation and neutrophil infiltration extend toxic injury. Kupffer cells release reactive oxygen species (ROS), cytokines, and chemokines, which induce neutrophil extravasation and activation. The liver expresses many cytochrome P450 isoforms, including ethanol-induced CYP2E1. CYP2E1 generates ROS, activates many toxicologically important substrates, and may be the central pathway by which ethanol causes oxidative stress. In acetaminophen toxicity, nitric oxide (NO) scavenges superoxide to produce peroxynitrite, which then causes protein nitration and tissue injury. In inducible nitric oxide synthase (iNOS) knockout mice, nitration is prevented, but unscavenged superoxide production then causes toxic lipid peroxidation to occur instead. Microvesicular steatosis, nonalcoholic steatohepatitis (NASH), and cytolytic hepatitis involve mitochondrial dysfunction, including impairment of mitochondrial fatty acid beta-oxidation, inhibition of mitochondrial respiration, and damage to mitochondrial DNA. Induction of the mitochondrial permeability transition (MPT) is another mechanism causing mitochondrial failure, which can lead to necrosis from ATP depletion or caspase-dependent apoptosis if ATP depletion does not occur fully. Because of such diverse mechanisms, hepatotoxicity remains a major reason for drug withdrawal from pharmaceutical development and clinical use.
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PMID:Mechanisms of hepatotoxicity. 1181 20


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