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)

The effect of cytokine-independent hepatitis on cytochrome P450 (CYP) gene expression remains unknown. Treatment of mice with anti-Fas antibodies (150 microg/kg, i.v.) caused elevated plasma alanine aminotransferase activity at 4 and 24 h after treatment. Under normal reverse-transcription polymerase chain reaction (RT-PCR) amplification conditions, no effect of anti-Fas antibody-induced hepatitis on hepatic CYP 2E1 and 3A gene expression was observed. But lower cycle RT-PCR amplification revealed slight suppression of hepatic CYP 2E1 gene expression. The present results showed that cytokine-independent hepatitis induced by anti-Fas anti-bodies had only a minimal effect on the suppression of CYP gene expression in the liver.
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PMID:Minimal effect of cytokine-independent hepatitis induced by anti-Fas antibodies on hepatic cytochrome P450 gene expression in mice. 1099 39

Thioacetamide administration to rats (20 mg/100 g) caused the development of toxic hepatitis which was accompanied by the increase of hepatic ALA-synthase and D-ALA that led to accumulating free porphyrines in the liver. At the same time an increase in activity of heme oxigenase was also found. A decrease in heme synthesis correlated with a decrease in content of cytochrome P450 and b5 in microsomal hepatic fraction of experimental animals.
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PMID:[Changes in the activity of enzymes of heme synthesis and catabolism, and level of microsomal hemoproteins during the liver acute intoxication by thioacetamide]. 1145 Apr 45

A substantial body of evidence provides support (but not definitive proof of efficacy) for the use of antiretroviral agents as postexposure prophylaxis for occupational exposures to HIV in the healthcare workplace. Despite the lack of definitive evidence of the efficacy of these agents in this setting, over the past decade this intervention has become the standard of care for healthcare workers who sustain occupational exposures to HIV. Administration of these agents--even for a relatively short 28-day postexposure course--is often fraught with difficulty. All of the agents currently used for postexposure prophylaxis regimens have substantial adverse effects, and significant adverse effects occur in more than two-thirds of individuals electing prophylaxis. This manuscript reiterates current US Federal Government guidelines for the administration of postexposure prophylaxis, specifically noting that zidovudine plus lamivudine (with or without a protease inhibitor) remains the recommended regimen. The paper summarises the significant toxicities associated with nucleoside reverse transcriptase inhibitors (primarily nausea, vomiting, diarrhoea and bone marrow suppression), non-nucleoside reverse transcriptase inhibitors (rash, fever, gastrointestinal symptoms and hepatitis, including hepatic decompensation necessitating liver transplantation) and protease inhibitors (nausea, vomiting, diarrhoea, abdominal pain, hyperglycaemia, hyperlipidaemia, headache and anorexia). As a class, the antiretroviral agents have an extraordinary number of drug interactions. The non-nucleoside reverse transcriptase inhibitors and the protease inhibitors are metabolised through the cytochrome P450 pathway, and the effects of concomitant administration of protease inhibitors with other agents in the same class are discussed, as well as the effects of concomitant administration of protease inhibitors with non-nucleoside agents. The potential for numerous and medically risky drug interactions emphasises the importance of planning antiretroviral prophylaxis in consultation with practitioners or clinical pharmacists who are skilled in the use of these agents and knowledgeable about the potential for significant drug interactions that could either reduce the benefit of prophylaxis or increase the potential for toxicity. Another common problem encountered by individuals managing postexposure prophylaxis programmes relates to the administration of chemoprophylaxis to a pregnant healthcare worker who has sustained an occupational exposure to HIV. We address what is known about the potential for toxicity and emphasise the recently published warning concerning the deaths of pregnant women and their offspring from lactic acidosis while receiving regimens containing stavudine and didanosine.
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PMID:Tolerability of postexposure antiretroviral prophylaxis for occupational exposures to HIV. 1148 Apr 91

Simvastatin, a hydroxymethyl glutarate coenzyme A (HMG-CoA) reductase inhibitor, is a commonly used cholesterol lowering agent. The long-term safety profile of simvastatin, established over ten-years of clinical use, is excellent. Both rhabdomyolysis and hepatitis, however, are recognized toxic effects of this medication, and generally occur when the patients are taking more than 40 mg of simvastatin a day. Potent inhibitors of the cytochrome P450 3A4 (CYP3A4) enzyme increase the incidence of simvastatin toxicity. Calcium channel blockers are weak inhibitors of the CYP3A4 enzyme. Diltiazem is known to increase the serum concentration of simvastatin. Many patients who take both simvastatin and diltiazem require lower doses of simvastatin to achieve the recommended reduction in cholesterol. Since diltiazem is known to increase plasma levels of lovastatin, a similar phenomenon may occur with simvastatin. Our patient had been stable for three years on simvastatin therapy. His rhabdomyolysis and hepatitis coincided with the addition of diltiazem. This is the first report of the combined toxicities of rhabdomyolysis and hepatitis being induced by the addition of diltiazem to simvastatin therapy. This patient serves as a reminder to the clinician of the potential interaction of these two commonly used drugs.
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PMID:Simvastatin-diltiazem drug interaction resulting in rhabdomyolysis and hepatitis. 1155 Apr 1

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

Disulfiram is widely used in the treatment of chronic alcoholism. Adverse drug reactions with fatal outcome following disulfiram therapy are infrequent, and hepatic failure accounts for most of them. Since disulfiram is a cytochrome P450 (CYP450) enzyme system inhibitor, numerous interactions with several drugs metabolized in the liver have been reported. Like disulfiram, clarithromycin inhibits a CYP450 isoenzyme, but, despite its widespread use for the treatment of respiratory tract infections, no interactions with disulfiram have been described as yet. We report a case of fatal toxic epidermal necrolysis (Lyell disease) and fulminant hepatitis shortly after starting treatment with clarithromycin in a patient who was receiving disulfiram. This is the first case of such a severe dermatosis in a patient receiving either disulfiram or clarithromycin therapy. The temporal relationship between drug administration and clinical symptoms in this case suggests a probable interaction between the 2 drugs.
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PMID:Fulminant hepatitis and fatal toxic epidermal necrolysis (Lyell disease) coincident with clarithromycin administration in an alcoholic patient receiving disulfiram therapy. 1186 83

Genetic alterations associated with human hepatocellular carcinoma (HCC) have been reported previously, but are not sufficient to specify differences of HCCs from precancerous diseases of the liver, such as hepatitis, hepatic fibrosis, and cirrhosis. In the present study, we performed differential gene display analysis (DGDA) to clarify the specific genetic alterations associated with gene expression changes in the course of development of HCC from chronic viral hepatitis. Four pairs of surgically resected HCCs and hepatitis tissues were investigated. We found 1,028 expression sequence tags (ESTs) that were decreased or increased in HCC tissues compared with hepatitis tissues in the same patient. Nucleotide sequencing showed that they included 55 EST clones in the GenBank database, which were considered candidates for specific messenger RNA (mRNA) expression alterations in HCCs. After excluding 9 ESTs that code mitochondrial DNA, we performed quantitative real-time reverse-transcription polymerase chain reaction (RT-PCR) for the 46 remaining EST clones. We found 8 mRNAs underexpressed in primary HCC tissues in 20 patients in higher percentages than found in previous studies, including 18 cases (90%) for aldolase B (ALDOB), 15 cases (75%) for carbamyl phosphate synthetase 1 (CPS1), albumin (ALB), plasminogen (PLG), and EST 51549, 13 cases (65%) for cytochrome P450 subfamily 2E1 (CYP2E1), 12 cases (60%) for human retinol-binding protein 4 (RBP4), and 11 cases (55%) for human organic anion transporter C (OATP-C) gene. In conclusion, underexpression of key gene products may be important in the development and/or progression of HCC.
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PMID:Underexpression of mRNA in human hepatocellular carcinoma focusing on eight loci. 1214 53

Murine hepatic cytochrome P450 2a5 (Cyp2a5) is induced during hepatotoxicity and hepatitis, however, the specific regulatory mechanisms have not been determined. We compared the influence of acute inflammation elicited in vivo by bacterial endotoxin lipopolysaccharide (LPS) and liver injury caused by the hepatotoxin pyrazole on hepatic Cyp2a5 expression in mice. Pyrazole treatment resulted in statistically significant increases in levels of Cyp2a5 mRNA, protein and catalytic activity by 540, 273 and 711%, respectively (P<0.05). In LPS-treated livers Cyp2a5 expression was significantly reduced compared to controls at the mRNA (46%) protein (35%), and activity (23%) levels (P<0.05). Treatment of mice with recombinant murine interleukin-1 beta and interleukin-6 had no significant effect on Cyp2a5 mRNA and protein levels. Liver injury, as assessed by serum alanine aminotransferase, was greater with pyrazole than with LPS treatment (609 vs 354% of control levels respectively). ER stress, determined by hepatic glucose regulated protein 78 (grp78) levels, was greater with pyrazole (185% of controls) than with LPS (128% of controls). In pyrazole-treated liver, overexpression of immunoreactive grp78 protein revealed that ER stress was localized to pericentral hepatocytes in which Cyp2a5 was induced. Evidence of glycogen loss and membrane damage in these cells was suggestive of oxidative damage. Moreover, vitamin E attenuated Cyp2a5 induction by pyrazole in vivo. These results suggest that induction of Cyp2a5 that has been observed in mouse models of hepatitis and hepatoxicity may be related to oxidative injury to the endoplasmic reticulum of pericentral hepatocytes rather than exposure to pro-inflammatory cytokines.
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PMID:Effects of lipopolysaccharide-stimulated inflammation and pyrazole-mediated hepatocellular injury on mouse hepatic Cyp2a5 expression. 1249 23

HIV/AIDS has become a chronic disease thanks to the availability of antiretroviral drugs. Many of these antiretroviral drugs are available in India. Many more will soon become available. The cost of these drugs is being reduced gradually and their use is increasing. However, there are both short term and long term side effects. This review focuses on the common potential toxicities of antiretroviral drugs and their management. The potential toxicities include gastrointestinal effects, hepatitis, hypersensitivity reactions, cytochrome P450 interactions, mitochondrial toxicity and lipodystrophy syndrome as well as more drug-specific adverse effects.
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PMID:Antiretroviral therapy: are we aware of adverse effects? 1251 2

The different types of hepatotoxicity can be induced by drugs. Approximately 2%-5% of patients require hospitalization for jaundice. Drug-induced hepatic lesions are responsible for 10% of hepatitis cases in adults. Most hepatotoxic drug reactions are idiosyncratic and classified either as immunologic (hipersensitivity) or metabolic. In contrast to intrinsic hepatotoxins, these reactions are not dose-dependent nor predictable. The enzyme system responsible for drug biotransformation in liver is cytochrome P450, a large multigene family of enzymes with 300 members. Clinical presentation in patients who develop drug hepatotoxicity can be asymptomatic with mild biochemical abnormalities, resembling acute hepatitis or chronic autoimmune hepatitis, veno-occlusive disease and cirrhosis. Withdrawal of the drug usually leads to reversal of the lesion. A spectrum of drug induced hepatotoxicity, diagnosis and treatment is reviewed.
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PMID:[Clinical aspects and therapy of toxic hepatitis]. 1458 64


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