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 release of lymphotoxin (LT) from peripheral blood lymphocytes of patients with isoniazid (INH)-induced hepatitis was studied, using L929 fibroblast target cells, as was the cytotoxic effect of these lymphocytes on murine hepatoma cells (L1469) and L929 fibroblasts, using a 3H-proline cytotoxicity assay. Evidence for LT release was found in five out of six patients, following stimulation of the peripheral blood lymphocytes with INH or isonicotinic acid (INA) conjugated to human serum albumin. In the direct cytotoxicity assay, cytotoxic effects on the hepatoma cells were enhanced by preincubation of the target cells with INH in five out of six patients tested. Although specificity with regard to the drug was demonstrable, tissue specificity was less certain in that enhanced killing of the fibroblast cell line was also found to occur following preincubation of the L929 cells with INH.
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PMID:Lymphocyte-mediated cytotoxicity in isoniazid-associated hepatitis. 31 34

In a retrospective study of patients developing hepatitis or persistent serum glutamic oxaloacetic transaminase (SGOT) elevations while receiving isoniazid, it was found that the lymphocyte transformation test (LTT) was positive in nineteen cases (95%) in response to stimulation by isoniazid, isonicotinic acid and conjugates of these compounds with human serum albumin. However, no significant amount of antibody against isoniazid was detected in the sera of these patients by a sensitive radioimmunoassay. By contrast, no positive LTT was seen in normal controls or in patients receiving isoniazid without evidence of liver damage, while in patients with transient SGOT abnormalities, the LTT was positive only at the time of liver dysfunction. There was no correlation between the degree of lymphocyte transformation and the severity of liver damage. However, there were differences in the patterns of response to the four stimulatory preparations used. Thus patients with overt hepatitis most frequently responded to isoniazid, while individuals with only SGOT abnormalities showed stimulation in the LTT more often with a conjugate of isonicotinic acid and human serum albumin. It appears, therefore, that the presence of isoniazid-induced liver damage is associated with the presence of cellular hypersensitivity to the drug. The differences in lymphocyte reactivity in the two groups might indicate a potential means of predicting which individuals are at increased risk of developing overt hepatitis when exhibiting evidence of minor liver dysfunction while receiving isoniazid.
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PMID:Evaluation of isoniazid-associated hepatitis by immunological tests. 66 95

Sixty seven patients with coexistent tuberculosis and hepatitis were given a 3 drug regimen of streptomycin (SM), isonicotinic acid hydrazide (INH) and ethambutol (ETB) and observed for a period of 15 days. Total bilirubin as well as SGPT were repeated weekly and these showed a significant drop in a majority of patients when observed over this period. No patient developed any signs of fulminant hepatic failure. We conclude that a regimen of SM, INH and ETB can be given to patients who suffer from combined pathologies of pulmonary tuberculosis and active hepatitis without incurring the danger of increasing hepatocellular dysfunction/damage.
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PMID:Anti-tubercular treatment in patients with hepatitis. 181 72

The results of the experiments with use of isoniazid and its metabolites showed that in the liver of rats isoniazid induced albuminous degeneration with stroma inflammation and hepatocyte necrosis, monoacetylhydrazine induced fatty hepatosis, acetylisoniazid induced fatty hepatosis with stroma inflammation and hepatocyte necrosis and isonicotinic acid induced granular degeneration. Piracetam proved to be efficient in fatty hepatosis. Riboxin and dibunol were efficient in hepatitis. The drugs used clinically as liver protectors, i.e. cobamamide, pyridoxal phosphate and methionine had no protective action in liver affections induced by isoniazid whereas catergen, lipamide, dipromonium and methindione even aggravated such affections.
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PMID:[Drug prophylaxis of liver lesions induced by isoniazid and its metabolites]. 274 56

The effect of daily administration of rifampin on the direct conversion of isoniazid to isonicotinic acid and hydrazine by isoniazid hydrolase was investigated in 6 slow and 8 rapid acetylators of isoniazid. The proportion of isoniazid metabolized through this direct pathway during the first 6 h was estimated from the ratio of total isonicotinic acid formed to acetylisoniazid in urine after administration of isoniazid or acetylisoniazid. In slow acetylators, this proportion was approximately 3% when isoniazid alone was administered and approximately 6% during the maximal phase of induction caused by the daily administration of rifampin in addition to isoniazid (p less than 0.001); in rapid acetylators, the proportions were considerably less (less than 1 and 2.5%, respectively), suggesting that isoniazid hydrolase was induced by rifampin. The increased formation of hydrazine, a known hepatotoxic agent in animals, could explain the substantially higher frequency of the occurrence of hepatitis in slow than in rapid acetylators among tuberculous patients treated with daily rifampin and isoniazid.
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PMID:Rifampin-induced release of hydrazine from isoniazid. A possible cause of hepatitis during treatment of tuberculosis with regimens containing isoniazid and rifampin. 371 59

Conditions have been determined under which the C1 inactivator (C1-INA) can be pasteurized to reduce the risk of transfusion hepatitis associated with its use for replacement therapy in patients with genetic or acquired deficiencies. Recovery of 90% of the biological and immunological activity of a C1-INA concentrate was achieved following heat treatment for 10 h at 60 degrees C in the presence of 3 M potassium citrate. Crossed immunoelectrophoresis in heparinized agarose was used to demonstrate the ability of the pasteurized C1-INA to bind heparin and to form a precipitation pattern with antibody which was almost indistinguishable from that of an unheated control. High pressure liquid chromatography and enhancement of the fluorescence of 1,8-anilinonaphthalene sulfonate were used to show that other proteins present in the concentrate were also stabilized.
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PMID:Pasteurization of C1 inactivator in the presence of citrate salts. 673 Apr 23

Isoniazid (INH) treatment can cause serious liver injury and autoimmunity. There are now several lines of evidence that INH-induced liver injury is immune mediated, but this type of liver injury has not been reproduced in animals, possibly because immune tolerance is the dominant response of the liver. In this study, we immunized mice with isonicotinic acid (INA)-modified proteins and Freund's adjuvant, which led to mild experimental autoimmune hepatitis (EAH) with an increase in cells staining positive for F4/80, CD11b, CD8, CD4, CD45R, and KI67. We expected that subsequent treatment of mice with oral INH would lead to more serious immune-mediated liver injury, but paradoxically it markedly attenuated the EAH caused by immunization with INA-modified hepatic proteins. In addition, patients of the slow acetylator phenotype are at increased risk of INH-induced liver injury. Treatment of arylamine N-acetyltransferase-deficient Nat1/2(-/-) mice with INH for up to 5 weeks produced mild increases in glutamate and sorbitol dehydrogenase activities, but not severe liver injury. Female Nat1/2(-/-) mice treated with INH for 1, 3, or 7 days developed steatosis, an increase in Oil Red O staining, and abnormal mitochondrial morphology in the liver. A decrease in M1 and an increase in M2a and M2b macrophages was observed in female Nat1/2(-/-) mice treated with INH for 1, 3, or 7 days; these changes returned to baseline levels by day 35. These data indicate that INH has immunosuppressive effects, even though it is also known to induce autoantibody production and a lupus-like autoimmune syndrome in humans.
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PMID:Paradoxical attenuation of autoimmune hepatitis by oral isoniazid in wild-type and N-acetyltransferase-deficient mice. 2462 63

Isoniazid (INH) has been a first-line drug for the treatment of tuberculosis for more than 40 years. INH is well-tolerated by most patients, but some patients develop hepatitis that can be severe in rare cases or after overdose. The mechanisms underlying the hepatotoxicity of INH are not known, but covalent binding of reactive metabolites is known to occur in animals and is suspected in human cases. A major unresolved question is the identity of the liver proteins that are modified by INH metabolites. Treating mice with INH leads to accumulation of isonicotinoyl-lysine residues on numerous proteins in the hepatic S9 fraction. Analysis of this fraction by SDS-PAGE followed by tryptic digestion of bands and LC-MS/MS revealed a single adducted peptide derived from d-dopachrome decarboxylase. When a tryptic digest of whole S9 was applied to anti-INH antibody immobilized on beads, only 12 peptides were retained, 5 of which clearly contained isonicotinoyl-lysine adducts and could be confidently assigned to 5 liver proteins. In another experiment, undigested S9 fractions from INA-treated and untreated (UT) mice were adsorbed in parallel on anti-INA beads and the retained proteins were digested and analyzed by LC-MS/MS. The INA-S9 digest showed 1 adducted peptide that was associated with a unique protein whose identity was corroborated by numerous nonadducted peptides in the digest and 13 other proteins identified only by multiple nonadducted peptides. None of these 14 proteins was associated with any peptides present in the UT-S9 fraction. Overall, we identified 7 mouse liver proteins that became adducted by INH metabolites in vivo. Of these 7 INH target proteins, only 2 have been previously reported as targets of any reactive metabolite in vivo.
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PMID:Protein Targets of Isoniazid-Reactive Metabolites in Mouse Liver in Vivo. 2709 13