Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Incubation of rat brain synaptosomes and mitochondria with LPO inducers (Fe2+ and ascorbate) was accompanied by a decrease of deamination of serotonin (substrate of MAO-A) in mitochondria, but not in synaptosomes, with simultaneous stimulation of GABA and GLCA deamination, apparently owing to modification of catalytic properties of brain membrane-bound MAO. Oxidation of PEA (substrate of MAO-B) was insignificantly altered in both fractions. Reactions of deamination of serotonin, GABA, and GLCA (but not PEA), were highly sensitive to a selective inhibitor of MAO-A pyrazidol (pyrlindole). Isoniazid and hydrazides of quinoline carbonic acids (inhibitors of both modified MAO and copper-containing amine oxidases) strongly inhibited deamination of GABA and GLCA. During epileptiformic seizures in rats, genetically selected for high incidence of audiogenic epilepsia, stimulation in brain synaptosomes and mitochondria of LPO was observed. This was accompanied by a marked decrease in serotonin and PEA deamination, with a simultaneous increase in GABA and GLCA deamination in both fractions. The data obtained suggest that appearance of GABA-deaminating activity owing to modification of catalytic properties of MAO, might be an essential pathogenetic component in the development of epileptic seizures.
Mol Chem Neuropathol
PMID:The role of lipid peroxidation in the possible involvement of membrane-bound monoamine oxidases in gamma-aminobutyric acid and glucosamine deamination in rat brain. Focus on chemical pathogenesis of experimental audiogenic epilepsy. 152 Apr 3

Isoniazid (INH) resistance of the Mycobacterium tuberculosis Complex (MtbC) is associated with both loss of catalase activity and mutation of the inhA gene. However, the relative contributions of these changes to resistance and to the loss of virulence for guinea-pigs is unknown. In this study, a virulent strain of Mycobacterium bovis, a member of the MtbC, was exposed to increasing concentrations of INH. Two INH-resistant strains were produced which had lost catalase activity. Strain WAg405, which had a higher resistance to INH, also had a mutation in the inhA gene. This demonstrated that loss of catalase activity and mutation of inhA had a cumulative effect on INH resistance. When a functional katG gene was integrated into the genome of WAg405 the INH resistance was greatly reduced. This indicated that most of the resistance had been caused by loss of catalase activity. While the parent INH-sensitive strain was virulent for guinea-pigs, the INH-resistant strains were significantly less virulent. Integration of a functional katG gene into the most resistant strain restored full virulence. This clearly established that katG is a virulence factor for M. bovis and that mutation of the inhA gene has no effect on virulence.
Mol Microbiol 1995 Mar
PMID:Effect of inhA and katG on isoniazid resistance and virulence of Mycobacterium bovis. 762 58

Isoniazid-resistant isolates of Mycobacterium tuberculosis were transformed with a plasmid vector carrying the functional catalase-peroxidase (katG) gene. Expression of katG restored full drug susceptibility in isolates initially resistant to concentrations ranging from 3.2 to > 50 micrograms ml-1. Transformation with the corresponding katG gene from Escherichia coli resulted in low-level expression of catalase and peroxidase activities and conferred partial isoniazid sensitivity.
Mol Microbiol 1993 May
PMID:Transformation with katG restores isoniazid-sensitivity in Mycobacterium tuberculosis isolates resistant to a range of drug concentrations. 839 39

Isoniazid (INH), which acts by inhibiting mycolic acid biosynthesis, is very potent against the tuberculous mycobacteria. It is about 100-fold less effective against Mycobacterium avium. This difference has often been attributed to a decreased permeability of the cell wall. We measured the rate of conversion of radiolabelled INH to 4-pyridylmethanol by whole cells and cell-free extracts and estimated the permeability barrier imposed by the cell wall to INH influx in Mycobacterium tuberculosis and M. avium. There was no significant difference in the relative permeability to INH between these two species. However, the total conversion rate in M. tuberculosis was found to be four times greater. Examination of in vitro-generated mutants revealed that the major resistance mechanism for both species is loss of the catalase-peroxidase KatG. Analysis of lipid and protein biosynthetic profiles demonstrated that the molecular target of activated INH was identical for both species. M. avium, however, formed colonies at INH concentrations inhibitory for mycolic acid biosynthesis. These mycolate-deficient M. avium exhibited altered colony morphologies, modified cell wall ultrastructure and were 10-fold more sensitive to treatment with hydrophobic antibiotics, such as rifampin. These findings may significantly impact the design of new therapeutic regimens for the treatment of infections with atypical mycobacteria.
Mol Microbiol 1998 Mar
PMID:Mechanisms involved in the intrinsic isoniazid resistance of Mycobacterium avium. 957 Apr 7

Isoniazid (INH) has neurotoxic effects such as seizure, poor concentration, subtle reduction in memory, anxiety, depression and psychosis. INH-induced toxic effects are thought to be through increased oxidative stress, and these effects have been shown to be prevented by antioxidant therapies in various organs. Increased oxidative stress may be playing a role in these neurotoxic effects. N-methyl D-aspartat receptors (NMDA) are a member of the ionotropic group of glutamate receptors. These receptors are involved in a wide variety of processes in the central nervous system including synaptogenesis, synaptic plasticity, memory and learning. Erdosteine is a potent antioxidant and mucolytic agent. We aimed to investigate adverse effects of INH on rat hippocampal NMDAR receptors, and to elucidate whether erdosteine prevents possible adverse effects of INH. In the present study, compared to control group, NMDAR2A (NR2A) receptors were significantly decreased and malondialdehyde (MDA), end product of lipid peroxidation, production was significantly increased in INH-treated group. On the other hand, administration of erdosteine to INH-treated group significantly increased NR2A receptors and decreased MDA production. In conclusion, decreasing NR2A receptors in hippocampus and increasing lipid peroxidation correlates with the degree of oxidative effects of INH and erdosteine protects above effect of INH on NR2A receptors and membrane damage due to lipid peroxidation by its antioxidant properties.
Mol Cell Biochem 2005 Sep
PMID:The effects of isoniazid on hippocampal NMDA receptors: protective role of erdosteine. 1613 24

Isoniazid is a key drug used in the treatment of tuberculosis. Isoniazid is a pro-drug, which, after activation by the katG-encoded catalase peroxidase, reacts nonenzymatically with NAD(+) and NADP(+) to generate several isonicotinoyl adducts of these pyridine nucleotides. One of these, the acyclic 4S isomer of isoniazid-NAD, targets the inhA-encoded enoyl-ACP reductase, an enzyme essential for mycolic acid biosynthesis in Mycobacterium tuberculosis. Here we show that the acyclic 4R isomer of isoniazid-NADP inhibits the M. tuberculosis dihydrofolate reductase (DHFR), an enzyme essential for nucleic acid synthesis. This biologically relevant form of the isoniazid adduct is a subnanomolar bisubstrate inhibitor of M. tuberculosis DHFR. Expression of M. tuberculosis DHFR in Mycobacterium smegmatis mc(2)155 protects cells against growth inhibition by isoniazid by sequestering the drug. Thus, M. tuberculosis DHFR is the first new target for isoniazid identified in the last decade.
Nat Struct Mol Biol 2006 May
PMID:Mycobacterium tuberculosis dihydrofolate reductase is a target for isoniazid. 1664 61

In this paper, molecularly imprinted polymer (MIP) of isoniazid is synthesized through thermal radical copolymerization of metharylic acid (MAA) and ethylene glycol dimethacrylate (EGDMA) in the presence of isoniazid template molecules. A novel flow injection chemiluminescence sensor for isoniazid determination is developed by packing the isoniazid-MIP into the flow cell as recognition elements. Isoniazid could be selectively adsorbed by the MIPs and the adsorbed isoniazid was sensed by its great enhancing effect on the weak CL reaction between luminol and periodate which were mixed in the flow cell. The enhanced CL intensity is linear in the range 2x10(-9) to 2x10(-7) g/mL and the detection limit is 7x10(-10) g/mL (3sigma) isoniazid with a relative standard deviation 2.8% (n=9) for 8x10(-8) g/mL. The sensor is reversible and reusable. It has a great improvement in sensitivity and selectivity for CL analysis. As a result, the sensor has been successfully applied to determination of isoniazid in human urine. At the same time, the binding characteristic of the polymer to isoniazid was evaluated by batch method and the dynamic method, respectively.
Spectrochim Acta A Mol Biomol Spectrosc 2007 Feb
PMID:Flow-injection chemiluminescence sensor for determination of isoniazid in urine sample based on molecularly imprinted polymer. 1684 43

Isoniazid (INH) still remains a first-line drug both for treatment and prophylaxis of tuberculosis, but various organs toxicity frequently develops in patients receiving this drug. We aimed to investigate possible toxic effects of INH on rat red blood cells (RBCs), and to elucidate whether Caffeic acid phenethyl ester (CAPE) prevents a possible toxic effect of INH. Experimental groups were designed as follows: control group, INH group, INH + CAPE group. Compared with the control, the INH caused a significant increase in superoxide dismutase (SOD) activity and malondialdehyde (MDA) levels, and a decrease in glutathione peroxidase (GSH-Px) and catalase (CAT), which are recently used to monitor the development and extent of damage due to oxidative stresses. CAPE administration to INH group ameliorated above changes due to INH.
Mol Cell Biochem 2006 Oct
PMID:Ameliorating role of caffeic acid phenethyl ester (CAPE) against isoniazid-induced oxidative damage in red blood cells. 1696 38

Three of the most frequent antitubercular agents employed against Mycobacterium tuberculosis are: Rifampicin, Isoniazid and Pyrazinamide. It has been proven that the use of these antitubercular agents together, shortens the treatment period from 12-18 months to 6 months [1]. In this work we use a new Density Functional Theory chemistry model called CHIH-DFT (Chihuahua-Heterocycles-Density Functional Theory) that reflects the mixture of Hartree Fock exchange and DFT exchange, according to a mixing parameter based on empirical rules suited for heterocyclic systems. This new chemistry model was used to calculate the molecular structure of these antitubercular compounds, as well as their infrared, UV spectra, chemical reactivity and electronic properties. The UV and infrared spectra were obtained by experimental techniques. The calculated molecular structure, UV and IR spectra values from CHIH-DFT were compared with experimentally obtained values and theoretical studies. These results are in good agreement with experimental and theoretical studies. We also predicted using the relative electrophilicity and relative nucleophilicity concepts as defined by Roy et al. [2] the chemical active sites for the three antitubercular compounds as well as their electronegativity, ionization potential, electron affinity, hardness, dipole moment, E(HOMO)-E(LUMO) gap energy, etc.
J Mol Model 2007 Apr
PMID:CHIH-DFT determination of the molecular structure infrared spectra, UV spectra and chemical reactivity of three antitubercular compounds: Rifampicin, Isoniazid and Pyrazinamide. 1726 Jan 47

Isoniazid (INH) continues to be a sheet anchor in treatment of tuberculosis, however its chronic administration is known to cause hepatotoxicity through a poorly defined mechanism. Ellucidation of mechanism underlying INH induced hepatotoxicity may be beneficial in devising ways to counteract toxic manifestations. In view of this concentration dependent effects INH were evaluated in hepatoma cell line (Hep-G2). INH exposure produced cytotoxic effects in Hep-G2 cells in a characteristic dose dependent manner. There was considerable cell detachment, loss of viability and alterations in cellular morphology that were indicative of toxic insult. We observed cell shrinkage at highest concentrations (88 microM) suggesting an involvement of apoptosis. This finding was substantiated by the flow cytometry data and DNA fragmentation analysis which clearly indicated that INH induced cytotoxicity, was being mediated by induction of apoptosis. Furthermore there was mitochondrial dysfunction as indicated by significant inhibition of MTT Reduction as compared to control at all the concentrations and depletion of cellular glutathione (GSH) content along with increased production of Reactive oxygen species (ROS). Collectively these findings led us to conclude that INH induced apoptosis in Hep-G2 cells is mediated by generation of oxidative stress.
Cell Mol Biol (Noisy-le-grand) 2007 Apr 15
PMID:Isoniazid induces oxidative stress, mitochondrial dysfunction and apoptosis in Hep G2 cells. 1751 18


1 2 3 4 Next >>