Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.6.1.1 (aspartate aminotransferase)
 21,665 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The paper investigates the relationships between hydrophobic parameters and antituberculotic activity of 2-alkylthio-6-benzamidobenzothiazoles, tested on INH-resistant strain of Mycobacterium tuberculosis. In the group of compounds with linear alkyl substituents in position 2, the tuberculostatic effect is increasing with decrease of lipophility of alkyls. Branching of the alkyls strongly increases the activity. The hepatotoxicity of compounds under study was investigated by means of the activity of serum aminotransferases (ALT, AST) in Wistar type rats. The hepatotoxicity of compounds seemed to be smaller than that of the thiobenzamides.
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PMID:[Relation between chemical structure, antitubercular activity and hepatotoxicity of 2-alkylthio-6-benzamidobenzothiazoles]. 312 40

Glutamic oxaloacetic transaminase (EC 2.6.1.1), has been prepared from the liver of Hausa he-goat (Capra hircus). 2. Gel filtration of the liver extract presents evidence of two molecular species of the enzyme; one species (Fraction A) has a specific activity of 280 U/mg protein and the other (Fraction B) has a specific activity of 338 U/mg protein. 3. Fraction A has optimum activity at pH 6.8 and Fraction B is optimally active at pH 5.5. The observed variation in activity with pH variation may be due to ionisation of some group(s) on the enzyme. 4. Characteristic spectral changes typical of INH/GOT interactions at low and high pH values are presented. 5. Typical Dixon's plot indicates a competitive inhibition of the enzyme by INH. Ki and Km of 0.04 and 2.5 mM for Fraction A and Ki and Km of 0.098 and 4.7 mH for Fraction B have been calculated from the data. 6. These results have been discussed in the light of the properties of the enzyme from other sources.
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PMID:Isoniazid inhibition of liver glutamic oxaloacetic transaminase from the goat Capra hircus. 682 99

The role of oxidative stress as a mechanism of hepatic injury caused by isoniazid (INH) was investigated in young growing rats. The interaction of moderate and severe degree of protein-energy malnutrition (PEM) was also investigated. Hepatic injury was produced by giving 50 mg/kg/day of INH for 2 weeks. Liver showed kupffer cell hyperplasia along with patchy sinusoidal congestion in hematoxylin (H) and eosin (E) staining. However, diffuse microglobules of oil red O' positive fat globules could be demonstrated in frozen sections stained with oil red O'. The concomitant elevation of serum ALT/AST added support to the histopathologic injury. Electronmicroscopic analysis revealed the proliferation of rough endoplasmic reticulum in INH-treated groups. The glutathione and related thiols were decreased significantly by INH both in blood and liver tissues, indicating a decrease in protective mechanism. Glutathione reductase activity was elevated concomitantly in both the tissues. A significant decrease in the activity of glutathione peroxidase and catalase is again indicative of diminished capacity to handle the disposal of hydrogen peroxide (H2O2) and lipid peroxides. All these alterations indicated that the damage to the liver cell could well be operating through the inefficient disposal of superoxides (O-2) and H2O2. A profound decrease in the protective mechanism further aggravated the picture in moderate and severe PEM, which was observed with INH alone.
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PMID:Study of oxidative stress in isoniazid-induced hepatic injury in young rats with and without protein-energy malnutrition. 902 73

Cytochrome P450 2E1 (P450 2E1) is active in both the detoxification and activation of small organic molecules. The effects of 2-(allylthio)pyrazine (2-AP) on P450 2E1-catalytic activity and the expression of rat hepatic P450 2E1 were examined. 2-AP competitively inhibited 4-nitrophenol hydroxylase activity in vitro (Ki, 12 microM). 2-AP treatment of rats (200 mg/kg/day, p.o., 1-3 days old) resulted in 20-30% decreases in the rates of P450 2E1-specific metabolic activities. Immunoblot analysis also revealed that hepatic microsomes isolated from 2-AP-treated rats showed substantial decreases in P450 2E1 level. 2-AP-suppressed isoniazid (INH)-inducible hepatic P450 2E1 levels, as shown by both metabolic activities and immunoblot analyses. Thus, 2-AP was effective in suppressing both constitutive and inducible P450 2E1 expression. Northern blot analysis showed that 2-AP transiently suppressed the hepatic P450 2E1 mRNA level, suggesting that suppression in P450 2E1 expression by 2-AP may be mediated in part by transcriptional inactivation. Hepatoprotective effects of 2-AP against toxicants were monitored in mice. 2-AP pretreatment prior to the administration of lethal doses of acetaminophen (AAP) or INH substantially reduced toxicant-induced mortality. Whereas serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were markedly elevated after AAP administration (i.e. 9-20-fold), 2-AP pretreatment of animals before AAP administration resulted in >95% decreases in elevated serum aminotransferase activities. 2-AP was also effective against CCl4-induced hepatotoxicity. Whereas CCl4 treatment caused 35-70-fold increases in aminotransferase activities, treatment of mice with 2-AP (>10 mg/kg) resulted in the blocking of CCl4-induced liver toxicity. The hepatoprotective effect of 2-AP was in part due to 2-AP-induced elevation of hepatic GSH levels. Whereas AAP or CCl4 treatment resulted in 70-80% reduction in hepatic GSH levels, pretreatment of mice with 2-AP caused a 40-210% elevation in hepatic GSH levels, as compared with either AAP or CCl4 alone. 2-AP pretreatment also reduced AAP- or CCl4-induced increases in lipid peroxidation in a dose-dependent manner. The results of these metabolic activities and of immunoblot and RNA blot analyses demonstrate that 2-AP is efficacious in suppressing constitutive and inducible P450 2E1 expression and effective in protecting against toxicant-induced liver toxicity.
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PMID:Inhibition of cytochrome P450 2E1 expression by 2-(allylthio)pyrazine, a potential chemoprotective agent: hepatoprotective effects. 906 29

The notification rate of tuberculosis in Japan was 31.0 per 100,000 in 2000. The rate was especially high among the elderly population, reaching 85.5 per 100,000 among those over 65 years of age. We conducted a study of preventive therapy in middle-aged and elderly persons selected from the population-based screening by the mass miniature radiography. The eligible criteria were 50-79 years of age, fibrous lesion which were compatible with healed tuberculosis and showed no change for at least one year, no previous treatment for tuberculosis, normal liver function tests, and no serious disease at the time of study. The eligible criteria for liver function tests in this study was less than 50 IU/L of AST and ALT value, and less than 1.5 mg/dl of T-bil level. A total of 13,219 people underwent TB screening in 4 cities in 1997 and 2 cities in 1998. Among them, 440 persons fulfilled the above criteria based on the screening records and chest X-ray films. The municipal offices sent letters to 418 people, except 22 whose addresses were unknown, to obtain permission to use their addresses and results of screening in our study. Permission was obtained from 137 persons and we sent them invitation letters for cost-free physical checkup service. Ninety-five persons visited us, and we offered them physical checkup and explained about our study. After obtaining the informed consent, we performed chest X-ray and sputum examination for 3 consecutive days. Finally 29 people were enrolled in the study. They were divided into 4 groups by sex and age, and were randomly assigned to one of two treatment groups. One group took 300 mg of INH per day for 6 months and the other group was only followed up by chest X-ray. Fourteen out of 29 persons began to take INH and received monthly liver function test. All the subjects were scheduled to follow by medical checkup every 6 months for 5 years. The proportion of taking INH tablets was estimated to range from 94% to 100%, based on the calendar for record of taking medication and the number of remaining tablets each month. Six (42.9%) of 14 persons reported adverse reactions. Two of 6 persons complained some of diarrhea, vomiting and gastrointestinal disturbance within 2 weeks, and discontinued taking INH, although none of them showed abnormal liver function tests. Two of 6 persons who reported some kinds of symptoms and 2 of 8 persons who did not complain of any symptoms showed abnormal liver function tests. The abnormal liver function tests had developed from 2 months after the beginning of INH taking in most of the persons and the abnormality improved after the completion of 6-month treatment. We have followed them for a maximum duration of 2.5 years, and 3 cases dropped out from the study. These defaulted cases had completed 6 months of INH. One person (69 y.o. male) was diagnosed as active TB by his chest X-ray film at the 6th month medical checkup, although it was not confirmed bacteriologically. One person (62 y.o. female) had the mastectomy for breast cancer 7 months before the entry to this study and relapsed at the 8th month after the entry. One person (73 y.o. female) was diagnosed as lung cancer at the medical checkup on 2.5 years. Besides them, 4 persons were suspected of worsening the abnormal shadows on chest X-ray films; one was from the INH group and three were from the follow-up group. However none of them was diagnosed clinically and bacteriologically as active tuberculosis.
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PMID:[Preventive therapy in middle-aged and elderly persons selected from the population-based screening by mass miniature radiography--methodological aspect and adverse reactions]. 1244 Jan 39

To investigate the secular change in the incidence rate of drug-induced hepatitis (DIH) due to anti-tuberculosis chemotherapy including isoniazid (INH) and rifampicin (RFP), but not including pyrazinamide (PZA), we retrospectively studied the incidence rates of DIH in patients treated with chemotherapy including INH and RFP in four periods 1980-83, 87-88, 91-92, and 1998-2000. The criteria for selection of the patients were as follows. 1. The serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were measured before, and one month (20-40 days) and 2 months (45-75 days) after starting anti-tuberculosis chemotherapy. When the serum AST and ALT were measured twice or more during period 20-40 days or 45-75 days after starting anti-tuberculosis chemotherapy, the data obtained nearest to 30 or 60 days after were chosen as those of one or two months after starting chemotherapy, respectively. 2. The serum AST and ALT were within normal range before starting anti-tuberculosis chemotherapy. The normal range of serum AST and ALT were < or = 40 K-A and < or = 35 K-A (in 1980-83) or < or = 31 IU/l and 34 IU/l (in 1987-2000), respectively. 3. Chronic active hepatitis and cirrhosis patients were excluded. 4. All alive after completion of anti-tuberculosis chemotherapy. The numbers of the subjects who fulfilled the above criteria were 113, 135, 128 and 154 in 1980-83, 1987-88, 1991-92 and 1998-2000, respectively. DIH was defined serologically by serum AST > or = 40 K-A and/or ALT > or = 35 K-A (in 1980-83), or AST > or = 40 IU/l and/or ALT > or = 40 IU/l (1987-2000). The DIH incidence rate of the subjects classified by the year of treatment and age were examined, and the contributions of the risk factors for DIH, such as age, sex, alcoholics, previous liver disease history, HBs ag positivity, anti-HCV ab positivity, and hypoalbuminenia were studied, and none except the age over 80 y.o. was found to be a risk factor to DIH, in our subjects. In patients with the age over 80 y.o., daily doses of antituberculosis drugs RFP, INH and ethambutol (EB) were significantly higher in patients with DIH than those without DIH, but body weight and serum albumin level were not significantly different between these two groups. There was no risk factor to DIH in our patients less than 80 y.o. and this could be explained by the above-mentioned criteria of study patients selection. To exclude the age dependence of the incidence rate of DIH in our subjects, the incidence rates of DIH were calculated in patients less than 80 y.o. by the period of treatment, and they were 10/111 (9.0%), 23/131 (17.6%), 26/123 (21.1%) and 32/117 (27.4%) in 1980-83, 87-88, 91-92, and 1998-2000, respectively. The secular increase of the incidence rate of DIH was statistically significant (p = 0.01). It is quite clear that this secular increase was not at all attributable to the above-mentioned risk factors. It is suspected that human liver has become more easily affected with INH and RFP in recent years. It is suggested that the new chemical compounds present in our increasingly complicated human milieu give heavier burdens on human liver, weaken the liver function, and enhance the capacity of INH and RFP to cause DIH.
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PMID:[Secular increase in the incidence rate of drug-induced hepatitis due to anti-tuberculosis chemotherapy including isoniazid and rifampicin]. 1273 93

We experienced 4 cases of agranulocytosis due to anti-tuberculosis drugs (rifampicin [RFP], isoniazid [INH], ethambutol [EB], streptomycin [SM] or pyrazinamide [PZA]) among some 6,400 tuberculosis patients who underwent chemotherapy over the past 20 years from 1981 to 2002 in our hospital, and the incidence rate of agranulocytosis was estimated at 0.06%. The 4 cases of agranulocytosis were as follows. CASE 1: A 51-year-old woman with right chest pain and fever was admitted to our hospital on Jan 4, 2001. The white blood cell (WBC) count was 5,200/microliter. The tubercle bacilli were cultured in her sputum. The treatment with INH 0.3, RFP 0.45, EB 0.75, PZA 1.2 g/day, allopurinol and teprenone was started on Jan 13. Pyrazinamide and allopurinol were stopped because of hyper-uric acidemia on Feb 7. Agranulocytosis and eosinophilia (WBC 1,300 [Neut 1%, Ly 57%, Eos 35%]) developed on Feb 13. All drugs were withdrawn and G-CSF drug nartograstim 100 micrograms was injected subcutaneously for 3 days. The WBC recovered to normal level and she was thereafter treated with INH, EB and Levofloxacin (LVFX) without any further trouble. Agranulocytosis in this case was supposed to be due to RFP. CASE 2: A 66-year-old man who had had nephrotic syndrome and hypothyroidism and has been treated with prednisolone 10 mg/day was admitted to our hospital on Aug 9, 2000 because of miliary tuberculosis. The tubercle bacilli were cultured in his sputum and the treatment with INH 0.3, RFP 0.45, and EB 0.75 g/day were started on Aug 10, but it was withdrawn on Aug 17 because of general skin eruption. After re-starting treatment with EB and INH on Aug 24, RFP was added in small dosage (0.05 g) on Oct 12, but agranulomatosis (WBC 2,300/microliter [Neut 2%]) developed on Nov 21, and all drugs were withdrawn again. The G-CSF drug filgrastim was used once subcutaneously, and WBC recovered immediately. He was thereafter treated with INH, EB, LVFX successfully. Agranulocytosis was supposed to be due to RFP. CASE 3: A 60-year-old woman without symptoms had abnormal chest roentgenograph, and consulted with our hospital on Aug 26, 2002. The broncho-alveolar lavage fluid was smear and culture-negative, but PCR-TB positive, and the case was diagnosed as pulmonary tuberculosis. Treatment with INH 0.3, RFP 0.45, EB 0.75, PZA 1.2 g/day, alloprinol 300 mg and rebamipide 300 mg/day was started on Sept. 5, 2002. Late in September, she complained of appetite loss. The laboratory data on Oct 3 revealed WBC 900/microliter (Neut 1%, Ly 94%), aspartate aminotransferase (AST) 199 IU/l, and alanine aminotransferase (ALT) 253 IU/l, showing agranulocytosis and drug-induced hepatitis. The chemotherapy was immediately withdrawn and she was admitted to our hospital on the next day. Glycyrrhizin derivative (SNMC) 40 ml was injected for 5 days, and WBC recovered, and AST and ALT also became normal. CASE 4: A 60-year-old man was admitted to our hospital on March 11, 1981 because pulmonary tuberculosis had recurred. He had been treated with SM, PAS and INH in 1973 for pulmonary tuberculosis. On admission examination of blood count and blood chemistry were normal. Treatment with RFP, INH and SM was started on March 11. He stopped out from the hospital on April 17, but in a few days he returned back with sore throat, lower lip swelling and gingival bleeding. Blood cell count on April 24 showed pancytopenia with RBC 226, Hb 7.5, WBC 800 (Ly 96%, Eos 4%) and Plt 10,000/microliter. The bone-marrow showed NCC (nuceated cell count) of 5,500, and megakaryocyte 0. Thereafter ground glass appearance shadows were seen on the whole lung field, and he died May 26. Autopsy showed generalized aspergillosis. It was strongly suspected that either of RFP, INH or SM was responsible for his pancytopenia. We collected another 10 cases of agranulocytosis due to anti-tuberculosis drugs in the world wide literature, and found men/women ratio 5/8 (in one case gender was not known), the duration of chemotherapy before appearance of agranulocytosis 1-3 months, no change in the lymphocyte count of the peripheral blood, and the accompanying of another allergic signs such as skin eruption, blood eosinophilia or drug-induced hepatitis in some cases, and these findings suggest that the mechanism of agranulocytosis due to anti-tuberculosis drugs was allergic in nature.
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PMID:[Agranulocytosis due to anti-tuberculosis drugs including isoniazid (INH) and rifampicin (RFP)--a report of four cases and review of the literature]. 1467 45

In the present study, the biochemical manifestations of liver toxicity caused by co-administration of anti-TB drugs, rifampicin (RIF), isoniazid (INH) and pyrazinamide (PZA), in a sub-chronic mode (12 weeks), were investigated. Significant alterations were revealed in (a) increased levels of alanine aminotrasferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) and a high bilirubin content in serum; (b) elevated lipid peroxidation (LPO), intracellular calcium [Ca(2+)](i) and CYP4502EI activity in liver; and (c) decreased glutathione (GSH) content, glutathione peroxidase (GPx) and catalase activities in liver. Silymarin reversed these abnormal alterations. The biochemical changes were supported by histological observations.
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PMID:Biochemical manifestations of anti-tuberculosis drugs induced hepatotoxicity and the effect of silymarin. 1577 1

This time, we compared conventional method Well pack P (the proportion method on Ogawa egg medium) with automated instrument BACTEC MGIT 960 AST system for Mycobacterium tuberculosis drug susceptibility testing. Fifty-three M. tuberculosis stock strains were used. Concordance rates between the two methods were SM: 94.3%; INH: 100%; RFP: 100%; and EB: 90.5%. All 23 drug-susceptible strains corresponded to four drugs. Discrepant results were observed in six of 30 drug-resistant strain. The mean times for results from the MGIT 960 AST system was 8.7 days. On the other hand, with Well pack P, growth of drug resistant strains was slow, and it was still difficult to judge four weeks later. Although the MGIT 960 AST system has problems, such as its high cost of labor and reagents, and the confirmation of contamination, because it is an automatic instrument, there are no discrepancies due to different technician techniques. The MGIT 960 AST system was found to be a rapid and excellent method.
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PMID:[Basic evaluation of BACTEC MGIT 960 Series for drug susceptibility testing of antimicrobial agents against Mycobacterium tuberculosis]. 1596 80

The infectious disease is one of the most important complications related to the organ transplantation. Patients using immunosuppressive agents often present atypical tuberculosis and the treatment of such case is far more difficult in some cases due to the liver damage and/or the drug interaction. We report a case of pulmonary tuberculosis in a patient of 60-year-old man using tacrolimus after an orthotopic liver transplantation. He had liver transplanted orthotopically for the long-term history of chronic hepatitis B and subsequent liver failure on January 28, 2004. An abnormal shadow was first detected on his chest X-ray film on October, 2004. He was admitted to our hospital after the smear of the gastric juice showed some acid-fast bacilli and tubercle bacilli were confirmed by polymerase chain reaction (PCR). Tuberculin skin test was positive (erythema 10 x 10) and the computed tomography (CT) scan of his chest revealed a nodular opacity with some smaller nodules scattered around in the right upper lobe. We started four anti-tuberculous drugs other than pyrazinamide (PZA) and rifampicin (RFP), which included isoniazid (INH), ethambutol (EB), streptomycin (SM), levofloxacin (LVFX). The liver enzyme was transiently elevated (AST 123 IU/I, ALT 103 IU/I) but improved after desensitization against INH. The blood concentration of tacrolimus preserved between 5 and 7 ng/ml and there was no need to change the dosage.
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PMID:[A case of pulmonary tuberculosis complicated with an orthotopic liver transplantation]. 1671 44


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