Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.6.1.2 (alanine aminotransferase)
 26,722 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Since Oct. 1981 a new systemic antifungal drug Ketoconazole is available in the Federal Republic of Germany that has proven effective even in severe cases with fungal infections. This case-study will call attention on a rare but important side effect, namely Ketoconazole induced hepatitis. As an acute icteric viral hepatitis, type Non-A-Non-B-hepatitis possibly misdiagnosed only a carefully compiled history of the recent intake of drugs points at the real cause of hepatitis. In our case-report we observed a considerable increase in serum enzymes, especially GOT, GPT and GLDH after a drug-challenge with two tablets. We recommend so-called liver functions tests 2 to 3 weeks after beginning of therapy and further-on in monthly intervals. Histologically at that time toxic hydropic changes of the liver cells and a mesenchymal reaction with portal and intralobular mainly eosinophilic infiltration could be established. The serum enzymes came to normal only after 12 weeks.
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PMID:[Ketoconazole-induced hepatitis. Case report]. 614 74

In this work, 100 living related donor kidney transplant recipients under cyclosporin (CsA) therapy were randomly distributed to two groups. Group 1 were administered ketoconazole, with group 2 serving as the control. Ketoconazole was given orally, 100 mg/day, while the dose of CsA was adjusted for a CsA whole blood trough level of 100-150 ng/ml. Patients and controls were assessed regularly in an outpatient clinic for 12 months and compared statistically for CsA dose, graft and liver functions, cholesterol, blood sugar, CsA nephrotoxicity, acute rejection episodes, chronic rejection and fungal skin infections. Statistical analysis showed a significant reduction in the CsA dose in the ketoconazole-treated group (73-76%), along with significantly lower alanine aminotransferase, aspartate aminotransferase, bilirubin, and serum creatinine values. CsA chronic nephrotoxicity and chronic rejections were also significantly lower in the ketoconazole-treated group, as was fungal skin infection (6.6 vs 63.2%). From this study, we conclude that addition of a low dose of ketoconazole to CsA-treated kidney transplant recipients not only saves costs, but may also have a favorable effect on graft function, chronic CsA nephrotoxicity, chronic rejection and fungal skin infection.
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PMID:Coadministration of ketoconazole to cyclosporin-treated kidney transplant recipients: a prospective randomized study. 854 71

Dauricine is the major bioactive component isolated from the roots of Menispermum dauricum D.C. and has shown promising pharmacological activities with a great potential for clinic use. However, the adverse effects and toxicity of the alkaloid are unfortunately ignored. The objective of the current study was to evaluate the toxicity of dauricine in vitro and in vivo. Mice (CD-1) were treated intraperitoneally with dauricine at various doses, and sera and lung lavage fluids were collected after 24 h of treatment. No changes in serum aspartate aminotransferase, alanine aminotransferase, and blood urea nitrogen were noticed, whereas a dose-dependent increase in lactate dehydrogenase activity was observed in lung lavage fluids. Ethidium-based staining studies showed that remarkable cells lost membrane integrity in the lungs of the animals treated with dauricine at 150 mg/kg. Histopathological evaluation of lungs of mice showed that dauricine at the same dose caused significant alveolar edema and hemorrhage. Exposure to dauricine at 40 muM for 24 h resulted in up to 60% cell death in human lung cell lines BEAS-2B, WI-38, and A549. Ketoconazole showed protective effect on the pulmonary injury in mice given dauricine. A quinone methide metabolite of dauricine was identified in mouse lung microsomal incubations, and the presence of ketoconazole in the microsomal incubations suppressed the formation of the quinone methide metabolite. In conclusion, dauricine produced pulmonary injury in CD-1 mice. The pulmonary toxicity appears to depend on the metabolism of dauricine mediated by CYP3A. The electrophilic quinone methide metabolite probably plays an important role in the pulmonary toxicity induced by dauricine.
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PMID:Pulmonary toxicity and metabolic activation of dauricine in CD-1 mice. 2000 63

We will present a 42-year-old woman with acute myeloid leukemia and pulmonary aspergillosis. She was treated with several antifungal agents, including three triazoles. Voriconazole, posaconazole, and isavuconazole all led to hepatocellular liver injury. Voriconazole administration led to a peak alanine aminotransferase (ALT) value of 1,793 U/L (normal range, 9-59 U/L). After posaconazole and isavuconazole treatment, ALT rose over 500 U/L. The typical course of events, exclusion of differential diagnoses, and normalization of the liver function tests (LFTs) after stopping the triazoles were highly suspicious for a drug-induced liver injury (DILI). Interestingly, our patient carries a rare HLA B allele (HLA B*35:02), which occurs in less than 1% of the population and is known to be associated with minocycline-induced liver injury. Over the course of 4 months, the patient received two induction chemotherapies and afterward underwent a successful allogenic hematopoietic stem cell transplantation. Her liver function recovered rapidly and favorable clinical findings concerning the aspergillosis led to a de-escalation of the antifungal treatment to prophylactic dose fluconazole. Delayed hepatotoxicity suggested a dose dependency and a cumulative effect. The question of a common pathophysiology and a cross-toxicity was raised. At the present time, only a few case reports describe cross-toxicity or its absence after rechallenge with different azoles. The pathophysiology is not well understood. Ketoconazole was found to impair rat mitochondrial function in vitro. Further investigations showed cell membrane toxicity and ATP depletion in isolated human liver cancer cells. Our case report suggests a cross-toxicity, dose-dependency, and a possible genetic predisposition of triazole-induced liver injury.
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PMID:Hepatotoxicity Due to Azole Antimycotic Agents in a HLA B*35:02-Positive Patient. 3124 59

Ketoconazole is a first orally available anti-fungal drug which has been reported as a potent inhibitor of human cytochrome P-450. The present study was designed to examine the heptoprotective effect of ketoconazole in both in vitro and in vivo liver injury models. Hepatocyte injury was induced by 8mM CCl4 while hepatic fibrosis model was established by injecting 1 ml/kg CCl4 followed by treatment with ketoconazole. Effect of ketoconazole treatment on injured hepatocytes was determined by lactate dehydrogenase release and trypan blue assay. Analysis of ketoconazole treatment and prevention on liver fibrosis was assessed by sirius red staining, masson trichome staining, PCR and liver function tests for bilirubin and alanine transaminase (ALAT).A significant reduction (P<0.05) in LDH release and reduced number of dead cells was observed in hepatocytes treated with ketoconazole. Sirus red and masson trichome stainings showed reduced levels of collagen in both treated and preventive groups and down regulation of alpha smooth muscle actin was observed with up-regulations of MMP-2, CK-8 and CK-18. Hepatic functional assessment demonstrated reduced serum levels of bilirubin and ALAT. Treatment of fibrotic liver with ketoconazole improves hepatic microenvironment and enhanced reduction of liver injury after fibrosis. Cytochrome P-450 inhibitors seems a favored therapeutic option in attenuation of liver fibrosis.
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PMID:Hepatoprotective effect of ketoconazole in chronic liver injury model. 3127 17

Columbin, a furanoid compound, is the major bioactive ingredient of Tinospora sagittata (Oliv.) Gagnep, a traditional Chinese medicine that has been reported to cause liver injury in the clinic. The aim of this study was to investigate the hepatotoxicity caused by columbin and its underlying mechanism. Our results indicated that columbin could result in a dose-dependent increase of mice serum alanine aminotransferase and aspartate aminotransferase after oral treatment with columbin, as well as local spotty necrosis in the liver of mice treated with columbin. No hepatotoxicity was observed in mouse treated with the same dose of tetrahydrocolumbin. Pretreatment with ketoconazole preserved the mice from columbin-induced hepatotoxicity. Further studies suggested that bioactivation of the furan ring played an indispensable role in columbin-caused hepatotoxicity. In vitro and in vivo metabolism studies demonstrated that columbin could be metabolized into the cis-butene-1,4-dial intermediate, which readily reacted with glutathione and N-acetyllysine to form stable adducts. Ketoconazole displayed strong inhibitory effect on the generation of M4 and M5 both in vitro and in vivo. Further recombinant human CYP450 screening demonstrated that CYP3A4 was the major enzyme responsible for columbin bioactivation. The present study demonstrated that columbin was hepatotoxic and CYP3A4-mediated bioactivation of the furan ring would serve as an underlying mechanism for columbin-induced hepatotoxicity.
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PMID:Cytochrome P450 Enzyme-Mediated Bioactivation as an Underlying Mechanism of Columbin-Induced Hepatotoxicity. 3216 8

Fraxinellone, a furanoid, is one of the bioactive and potentially hepatotoxic constituents from Dictamnus dasycarpus Turcz, which is extensively spread throughout Asian countries. This herb was reported to cause liver injury in clinical application. However, the mechanism behind is still not fully understood. This study mainly focused on the hepatotoxicity of fraxinellone and the underlying mechanism. The current study demonstrated that fraxinellone resulted in a significant elevation of serum alanine aminotransferase and aspartate aminotransferase in a dose-dependent manner in mice after oral administration. Pretreatment with ketoconazole for three successive days could significantly alleviate the hepatotoxicity of fraxinellone. Considering that fraxinellone has a structural alert of furan ring, it is believed that the hepatotoxicity caused by fraxinellone required cytochrome P450-mediated bioactivation. Bioactivation studies were subsequently carried out in vitro and in vivo. Fraxinellone was metabolized into cis-enedial intermediate, an electrophile that was prone to react with glutathione or N-acetyl-lysine through 1,2- or 1,4-addition to form stable conjugates. Ketoconazole significantly inhibited the formation of the glutathione conjugates (M1 and M2) in microsomal incubation and similar finding was obtained in vivo. Phenotyping study indicated that CYP3A4 was the principal enzyme responsible for the bioactivation of fraxinellone. This study suggested that CYP3A4-mediated bioactivation plays an indispensable role in fraxinellone-induced hepatotoxicity. The work performed herein enables us to better understand the hepatotoxicity of fraxinellone as well as the mechanism behind.
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PMID:Cytochrome P450-Mediated Bioactivation: Implication for the Liver Injury Induced by Fraxinellone, A Bioactive Constituent from Dictamni Cortex. 3248 42