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PubMed2000

Redox potential measurements of the Mycobacterium tuberculosis heme protein KatG and the isoniazid-resistant enzyme KatG(S315T): insights into isoniazid activation.

Mycobacterium tuberculosis KatG is a multifunctional heme enzyme responsible for activation of the antibiotic isoniazid. A KatG(S315T) point mutation is found in >50% of isoniazid-resistant clinical isolates. Since isoniazid activation is thought to involve an oxidation reaction, the redox potential of KatG was determined using cyclic voltammetry, square wave voltammetry, and spectroelectrochemical titrations. Isoniazid activation may proceed via a cytochrome P450-like mechanism. Therefore, the possibility that substrate binding by KatG leads to an increase in the heme redox potential and the possibility that KatG(S315T) confers isoniazid resistance by altering the redox potential were examined. Effects of the heme spin state on the reduction potentials of KatG and KatG(S315T) were also determined. Assessment of the Fe(3+)/Fe(2+) couple gave a midpoint potential of ca. -50 mV for both KatG and KatG(S315T). In contrast to cytochrome P450s, addition of substrate had no significant effect on either the KatG or KatG(S315T) redox potential. Conversion of the heme to a low-spin configuration resulted in a -150 to -200 mV shift of the KatG and KatG(S315T) redox potentials. These results suggest that isoniazid resistance conferred by KatG(S315T) is not mediated through changes in the heme redox potential. The redox potentials of isoniazid were also determined using cyclic and square wave voltammetry, and the results provide evidence that the ferric KatG and KatG(S315T) midpoint potentials are too low to promote isoniazid oxidation without formation of a high-valent enzyme intermediate such as compounds I and II or oxyferrous KatG.

Amino Acid Substitution↗
PubMed2002

Treatment of isoniazid-resistant tuberculosis with isoniazid, rifampin, ethambutol, and pyrazinamide for 6 months.

SETTING: In 1992 the Seattle-King County Department of Public Health Tuberculosis Clinic began to treat patients with isoniazid-resistant tuberculosis with a regimen of isoniazid, rifampin, pyrazinamide, and ethambutol daily for 6 months. OBJECTIVE: To conduct a review of clinical and bacteriological outcomes of treatment for patients who received the four-drug, 6-month regimen for isoniazid-resistant tuberculosis. DESIGN: A retrospective review of medical records of TB cases meeting the study criteria, a Mycobacterium tuberculosis isolate resistant to isoniazid, and intent to treat with a 6-month course of isoniazid, rifampin, pyrazinamide, and ethambutol. RESULTS: Through December 1999, 44 consecutive patients with isoniazid-resistant, rifampin-susceptible tuberculosis were started on the four-drug, 6-month daily regimen. Among 42 patients followed until completion of therapy, three required changes in the regimen due to side effects. There was one case of drug-induced hepatotoxicity. Among 39 patients with pulmonary involvement, 37 converted sputum cultures from positive to negative within 2 months of starting treatment. There were no treatment failures. On passive follow-up of at least 2 years on all patients, two patients relapsed. The single patient with bacteriological relapse did not develop further drug resistance. CONCLUSION: The regimen of isoniazid, rifampin, pyrazinamide, and ethambutol given daily for 6 months produced successful outcomes when used in a public health tuberculosis clinic as routine therapy for isoniazid-resistant tuberculosis.

Adolescent↗
PubMed1995

Relative bioavailability of rifampicin, isoniazid and ethambutol from a combination tablet vs. concomitant administration of a capsule containing rifampicin and a tablet containing isoniazid and ethambutol.

Twenty male volunteers who were slow metabolisers of isoniazid, completed this single-blind, single-dose, randomised, cross-over study to compare the bioavailability of rifampicin (CAS 13292-46-1), isoniazid (CAS 54-85-3) and ethambutol (CAS 1070-11-7) from Myrin tablets (test preparation) with the bioavailability of these drugs from a combination of capsules containing rifampicin and tablets containing isoniazid and ethambutol (reference). There were 2 treatment periods and on clinic days volunteers were given either the reference (300 mig rifampicin plus 200 mg isoniazid and 600 mg ethambutol HCl), or the test preparation (300 mg rifampicin, 150 mg isoniazid and 600 mg ethambutol HCl). Serial blood samples were drawn from the volunteers and rifampicin, isoniazid and ethambutol assays were performed. The results of this study indicate that the test preparation is equivalent to the reference with respect to both the rate and the extent of absorption of rifampicin, isoniazid (after adjustment for the different doses of isoniazid and ethambutol).

Adolescent↗
PubMedDate not supplied

Elevated serum aminotransferase induced by isoniazid in relation to isoniazid acetylator phenotype.

Of 143 patients with pulmonary tuberculosis receiving isoniazid therapy, 52 (36%) had a transient elevation in serum aminotransferases. Among 74 patients taking isoniazid, rifampicin and streptomycin, 35 (47%) had such an increase, while of 69 patients taking isoniazid, amino-salicylic acid and streptomycin, 17 (24%) did; this difference was significant. Isoniazid therapy could be continued in all patients with the abnormal test results. In 36 of the patients receiving isoniazid, rifampicin and streptomycin, isoniazid and its metabolites were studied in the serum and urine using high-performance liquid chromatography after the oral administration of 10 mg per kg of isoniazid. We had chosen for this test 18 patients with normal aminotransferase levels and 18 with abnormal levels. There were 14 rapid acetylators in the patients with abnormal aminotransferase levels and 7 rapid acetylators in the patients with normal levels; this difference was significant. These results indicate that liver dysfunction is more often caused by an isoniazid/rifampicin regimen, and patients who are rapid acetylators are more susceptible.

Acetylation↗
PubMed1980

High-performance liquid chromatographic determination of isoniazid and 1-isonicotinyl-2-lactosylhydrazine in isoniazid tablet formulations.

A high-performance liquid chromatographic procedure is presented for the simultaneous determination of isoniazid and 1-isonicotinyl-2-lactosylhydrazine (I) in isoniazid tablet formulations. An aliquot of a diluted aqueous tablet extract is introduced onto a microparticulate cyanopropyl bonded-phase column using a valve-loop injector and chromatographed using a mobile phase of acetonitrile--0.01 M, pH 3.5 aqueous acetate buffer (5:95). Compound I can be determined at levels as low as 0.5% of the isoniazid label claim. The relative standard deviations are 0.4 and 0.7% for the simultaneous determination of isoniazid and I, respectively. Seven commercial tablet formulations contained 93.8--97.0% of the labeled isoniazid amounts and 0.3--5.8% of I, expressed as equivalent isoniazid relative to the labeled isoniazid level.

Chromatography, High Pressure Liquid↗
PubMed1980

Prevention of isoniazid tumorigenicity by antitoxicants of isoniazid in Swiss mice.

Effect of isoniazid on blood ammonia levels and protein biosynthesis in tissues of Swiss mice was studied. Isoniazid treatment resulted in an elevation of the blood ammonia. It inhibited the protein biosynthesis in lung and kidney tissues of Swiss mice after 24 h of treatment. Simultaneous administration of L-arginine or L-sodium glutamate or pyridoxine hydrochloride or folic acid prevented the inhibition. Further, effect of these antitoxicants of isoniazid was studied on its tumorigenicity. Mice were fed isoniazid (1.1 mg/mouse/day) and the antitoxicant (1.1 mg/mouse/day) and killed when they appeared moribund. Incidence of tumor in mice receiving L-arginine or L-sodium glutamate along with isoniazid did not show any significant difference when compared with the mice treated with isoniazid alone. On the other hand, observations with folic acid gave full protection against tumorigenic action of isoniazid while pyridoxine hydrochloride displayed partial protection.

Adenocarcinoma↗
PubMed2001

Evidence for isoniazid-dependent free radical generation catalyzed by Mycobacterium tuberculosis KatG and the isoniazid-resistant mutant KatG(S315T).

The antitubercular agent isoniazid can be activated by Mycobacterium tuberculosis KatG using either a peroxidase compound I/II or a superoxide-dependent oxyferrous pathway. The identity of activated isoniazid is unknown, but it has been suggested that it may be a free radical intermediate. In this work, EPR spin trapping experiments detected isoniazid-derived radicals generated during KatG-mediated oxidation via the peroxidase compound I/II pathway. On the basis of hyperfine splitting patterns and oxygen dependence, these radicals were identified as the acyl, acyl peroxo, and pyridyl radicals of isoniazid. Isoniazid-resistant KatG(S315T) produced the same radicals found with KatG, while the less potent antitubercular agent nicotinic acid hydrazide produced the corresponding nicotinyl radicals. The time course of radical production was similar for KatG and KatG(S315T), while a lower steady-state level of radicals was produced from nicotinic acid hydrazide. These results support an earlier finding that the peroxidase pathway does not correlate with isoniazid resistance conferred by KatG(S315T). Trace amounts of radicals were detected via the superoxide-dependent pathway. The low level of isoniazid-derived radicals found in the superoxide-dependent pathway may be due to scavenging by superoxide.

Aerobiosis↗
PubMed2002

Differential role of CYP2E1 binders and isoniazid on CYP2E1 protein modification in NADPH-dependent microsomal oxidative reactions: free radical scavenging ability of isoniazid.

We evaluated the effect of "weak" CYP2E1 binders (ethanol, acetone and glycerol) "tight" CYP2E1 binders (4-methylpyrazole, imidazole, isoniazid and pyridine) and CCl4 (suicide substrate of CYP2E1) on the NADPH-dependent production of microsomal reactive oxygen species (ROS), lipid peroxidation (LPO), and subsequent modification of microsomal and CYP2E1 proteins. The oxidation of 2',7'-dichlorofluorescin diacetate (DCFHDA) was used as an index of formation of microsomal ROS and LPO-derived reactive species. Microsomal LPO was determined by malondialdehyde (MDA) HPLC measurement. Addition of NADPH to rat liver microsomes initiated DCFHDA oxidation and MDA formation, leading to further selective modification of microsomal proteins and proteases-independent degradation of CYP2E1 protein. Iron chelators prevented these processes whereas hydroxyl radical scavengers showed weak effects, suggesting an important role of LPO. Among the tested CYP2E1 binders, only isoniazid strongly inhibited NADPH-dependent DCFHDA oxidation, LPO and modification of microsomal proteins. Other CYP2E1 binders showed weak inhibitory effects of these processes. Concerning NADPH-dependent modification of CYP2E1 protein, all of the tested CYP2E1 binders, except glycerol, prevented this process with a different potency (isoniazid > 4-methylpyrazole = imidazole = pyridine 3 >> acetone > ethanol). "Tight" binders were more effective than "weak" binders. The CCl4 stimulated the DCFHDA oxidation, LPO and CYP2E1 protein modification. Among the tested CYP2E1 binders, only isoniazid effectively scavenged 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radicals. In microsomes isolated from CYP2E1 transfected HepG2 cells, isoniazid inhibited the CYP2E1-dependent DCFHDA oxidation whereas other CYP2E1 binders did not inhibit this reaction although these compounds strongly inhibited CYP2E1 activity. The present study demonstrates that CYP2E1 binders and isoniazid differentially inhibit LPO-catalyzed oxidative modification of CYP2E1 protein in NADPH-dependent microsomal reactions. It seems that CYP2E1 binders protect CYP2E1 from the oxidative modification mainly by binding to the active site of the enzyme, rather than by blocking the reactive species production. The strong protective effect of isoniazid can be attributed to its ability to scavenge free radicals. These effects of CYP2E1 binders are considered to contribute to the regulation of hepatic CYP2E1 protein levels via stabilization of the protein.

Animals↗
PubMed2004

Oxidation of isoniazid by quinolinium dichromate in an aqueous acid medium and kinetic determination of isoniazid in pure and pharmaceutical formulations.

The kinetics of oxidation of isoniazid in acidic medium was studied spectrophotometrically. The reaction between QDC and isoniazid in acid medium exhibits (4:1) stoichiometry (QDC:isoniazid). The reaction showed first order kinetics in quinolinium dichromate (QDC) concentration and an order of less than unity in isoniazid (INH) and acid concentrations. The oxidation reaction proceeds via a protonated QDC species, which forms a complex with isoniazid. The latter decomposes in a slow step to give a free radical derived from isoniazid and an intermediate chromium(V), which is followed, by subsequent fast steps to give the products. The reaction constants involved in the mechanism are evaluated. Isoniazid was analyzed by kinetic methods in pure and pharmaceutical formulations.

Algorithms↗
PubMed1975

Failure of isoniazid prophylaxis after exposure to isoniazid-resistant tuberculosis.

We report the failure of isoniazid chemoprophylaxis to prevent the development of active pulmonary tuberculosis and tuberculin conversion in contacts of patients infected with isoniazid-resistant strains of Mycobacterium tuberculosis. Although failure of isoniazid chemoprophylaxis has been reported rarely in contracts of isoniazid-resistant tuberculosis, the cases reported here as well as previous observations by others suggest that isoniazid chemoprophylaxis for contracts of patients with isoniazid-resistant tuberculosis may not be effective and that other agents must be considered. Initial chemotherapy of active pulmonary tuberculosis in contacts of known drug-resistant patients should be based on drug susceptibility studies in the index case.

Adolescent↗