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PubMed1976

Mode of action and quantitative structure-activity correlations of tuberculostatic drugs of the isonicotinic acid hydrazide type.

Quantitative structure-activity studies have been performed for a series of 2-substituted isonicotinic acid hydrazides by correlating electronic, steric, and lipophilic properties of the substituents with the biological activity date (MIC) from serial dilution tests with Mycobacterium tuberculosis (strain H 37 Rv). The reaction rates for the quaternization of 2-substituted pyridines with methyl iodide were also determined. The rate constants show a similar dependence on the steric and electronic effects of the substituents as the antibacterial activities of the corresponding pyridine-4-carboxylic acid hydrazides. The obtained correlations give evidence that the reactivity of the pyridine nitrogen atom is essential for the biological activity of 2-substituted isonicotinic acid hydrazides and seem to support the hypothesis that isonicotinic acid derivatives are incorporated into an NAD analogue.

Antitubercular Agents↗
PubMed2006

Catalase-peroxidase of Mycobacterium bovis BCG converts isoniazid to isonicotinamide, but not to isonicotinic acid: differentiation parameter between enzymes of Mycobacterium bovis BCG and Mycobacterium tuberculosis.

Isonicotinic acid hydrazide (Isoniazid, INH) is one of the major drugs worldwide used in the chemotherapy of tuberculosis. Many investigators have emphasized that INH activation is associated with mycobacterial catalase-peroxidase (katG). However, INH activation mechanism is not completely understood. In this study, katG of M. bovis BCG was separated and purified into two katGs, katG I (named as relatively higher molecular weight than katG II) and katG II, indicating that there is some difference in protein structure between two katGs. The molecular weight of the enzymes of katG I and katG II was estimated to be approximately 150,000 Da by gel filtration, and its subunit was 75,000 Da as determined by SDS-PAGE, indicating that purified enzyme was composed of two identical subunits. The specific activity of the purified enzyme katG I was 991.1 (units/mg). The enzymes were then investigated in INH activation by using gas chromatography mass spectrometry (GC-MS). The analysis of GC-MS showed that the katG I from M. bovis BCG directly converted INH (Mr, 137) to isonicotinamide (Mr, 122), not to isonicotinic acid (Mr, 123), in the presence or absence of H2O2. Therefore, this is the first report that katG I, one of two katGs with almost same molecular weight existed in M. bovis BCG, converts INH to isonicotinamide and this study may give us important new light on the activation mechanism of INH by KatG between M. bovis BCG and M. tuberculosis.

Bacterial Proteins↗
PubMed1975

Determination of isonicotinic acid hydrazide in serum.

A method for the determination of isonicotinic acid hydrazide is given. The hydrazide is complexed with cupric ions and condensated with an aromatic aldehyde substituted in ortho-position with a hydroxyl group. The method is adapted to the AutoAnalyzer equipment of first and second generation. Pilot measurements on the pharmacokinetic behaviour of isonicotinic acid hydrazide are presented.

Aged↗
PubMed1990

Inhibition of leukotriene omega-oxidation by isonicotinic acid hydrazide (isoniazid).

Metabolism of leukotrienes via omega-oxidation represents a major degradative and inactivating pathway of these biologically active icosanoids. Isonicotinic acid hydrazide (isoniazid) inhibited this process in rats in vivo, in the isolated perfused rat liver, and in hepatic microsomes. The in vivo catabolism of leukotriene E4 via N-acetyl-leukotriene E4 to its omega-oxidized metabolites was inhibited by 50% or 71% using single intravenous isoniazid doses of 0.6 mmol or 1.0 mmol/kg body mass, respectively. Isoniazid interfered with leukotriene catabolism at the initial omega-oxidation step, resulting in an accumulation of N-acetyl-leukotriene E4. Analogous although weaker inhibition of leukotriene omega-oxidation in vivo was observed by pretreatment with isonicotinic acid 2-isopropylhydrazide and monoacetyl hydrazine. In the isolated perfused liver, isoniazid at concentrations varying over 0.2-10 mM decreased the omega-oxidation of cysteinyl leukotrienes dose-dependently by up to 94%. omega-Oxidation of both leukotriene E4 and leukotriene B4 by rat liver microsomes was inhibited by isoniazid, isonicotinic acid 2-isopropylhydrazide, and monoacetyl hydrazine with half-maximal concentrations in the range of 5-15 mM. Our measurements indicate that the impairment of leukotriene omega-oxidation by isoniazid involves both cytochrome-P450-dependent enzyme systems responsible for omega-oxidation of leukotriene E4 and leukotriene B4. In effect, under isoniazid treatment one can expect a prolongation of the proinflammatory actions of endogenously produced leukotrienes.

Animals↗
PubMed1979

Mutagenic effects of isonicotinic acid hydracide in Fanconi's anemia.

Isonicotinic acid hydracide (INH) increases substantially the chromosomal instability in Fanconi's anemia (FA) cells. The same concentrations of INH do not significantly break chromosomes in heterozygous or normal cells. INH does not induce alkylation or cross-links in the DNA, like other mutagens known to increase breakage in FA cells. Possible mechanisms of the effect of INH are discussed. One consequence of this experiment is the possibility of an exact and doubtless prenatal diagnosis of a homozygous FA fetus.

Adolescent↗
PubMed1982

Altered glycine decarboxylation inhibition in isonicotinic Acid hydrazide-resistant mutant callus lines and in regenerated plants and seed progeny.

Isonicotinic acid hydrazide (INH), an inhibitor of the photorespiratory pathway blocking the conversion of glycine to serine and CO(2), has been used as a selective agent to obtain INH-resistant tobacco (Nicotiana tabacum) callus cells. Of 22 cell lines that were INH-resistant, none were different from wild-type cells in their ability to take up [(3)H]INH or to oxidize INH to isonicotinic acid. In 7 of the 22 cell lines, INH resistance was associated with decreased inhibition of NAD-dependent glycine decarboxylation activity in isolated mitochondrial preparations. In the cell line that was most extensively investigated (I 24), this biochemical phenotype (exhibiting a 3-fold higher K(i) with INH) was observed in leaf mitochondria of regenerated plants and of plants produced from them by self-fertilization. After crosses between resistant and sensitive plants, the decreased inhibition of glycine decarboxylation was observed among F(2) and backcross progeny only in those plants previously identified as INH-resistant by callus growth tests. In contrast, in siblings identified as INH-sensitive, glycine decarboxylation was inhibited by INH at the wild-type level. This demonstration of the transfer of an altered enzyme property from callus to regenerated plants and through seed progeny fulfills an important requirement for the use of somatic cell genetics to produce biochemical mutants of higher plants.

Journal Article↗
PubMed1972

The determination of isoniazid and its metabolites acetylisoniazid, monoacetylhydrazine, diacetylhydrazine, isonicotinic acid and isonicotinylglycine in serum and urine.

1. A solvent system was devised for the extraction of isoniazid and its metabolites acetylisoniazid, monoacetylhydrazine, diacetylhydrazine, isonicotinic acid and isonicotinylglycine from serum and urine. 2. Specific chemical and fluorimetric methods were developed for the determination of the extracted isoniazid and acetylisoniazid, and chemical methods for the determination of monoacetylhydrazine, diacetylhydrazine, isonicotinic acid and isonicotinylglycine. 3. When applied to serum, these methods were capable of measuring concentrations of down to about 0.005mug of isoniazid/ml, 0.05mug of acetylisoniazid/ml, 0.2mug of monoacetylhydrazine/ml, 0.2mug of diacetylhydrazine/ml, 0.02mug of isonicotinic acid/ml and 0.1mug of isonicotinylglycine/ml. 4. In urine, these methods were capable of measuring concentrations of down to about 0.05mug of isoniazid/ml, 0.2mug of acetylisoniazid/ml, 1mug of diacetylhydrazine/ml, 0.1mug of isonicotinic acid/ml and 0.2mug of isonicotinylglycine/ml. 5. The stability of these compounds was studied in serum and urine and a method devised to decrease their decomposition in serum.

Acetates↗
PubMed1976

Antibodies specific to isoniazid and isonicotinic acid.

Rabbit antisera to isoniazid (INH) and its major metabolite, isonicotinic acid (INA), were prepared by immunization with conjugates of these compounds with human serum albumin. The antisera were rendered hapten-specific by exhaustive absorption with the immunizing carrier. Purified anti-hapten antibodies were also isolated with appropriate immunosorbents. As demonstrated by inhibition of the quantitative precipitin curves and of precipitating immune complexes in immunodiffusion tests, the antibodies to the two haptens reacted with either INH or INA, and also with isonicotinamide (INC); these three related molecules share the isonicotinyl group. The relative effectiveness of inhibition by free hapten of precipitating immune complexes consisting of either anti-INH or anti-INA antibodies and the related hapten-protein conjugates was INH greater than INC greater than INA.

Animals↗
PubMed1977

Correlation of isonicotinic acid hydrazide infiltration across the blood-brain barrier to postnatal development in rats.

Changes in the isonicotinic acid hydrazide (INH) concentration in rat blood and brain were studied in correlation to postnatal development in groups of animals aged 21 and 42 days and 3 months. In the first part of the experiments, INH was administered intravenously to all the age groups in a dose of 100 mg/kg. In the second part, the dose was related to extracellular fluid volume, so that the 3-week-old rats were given 154 mg/kg, the 6-week-old animals 129 mg/kg and the 3-month-old animals 100 mg/kg. After a dose of 100 mg/kg, INH levels in the blood of 21-day-old rats were significantly lower than in 42-day-old and adult animals. The brain INH levels did not differ significantly. On relating the dose to the amount of extracellular fluid, there were no significant differences in the blood INH levels, but the levels in the brain of 21- and 42-day-old rats were significantly higher than in 3-month-old animals. Blood volume related to body weight and brain weight did not differ in the various age groups. The authors conclude that the blood-brain barrier for isonicotinic acid hydrazide alters in rats during postnatal development. In young animals (21- and 42-day-old), more INH infiltrates into the CNS than in adult animals.

Age Factors↗
PubMed1987

Occupational asthma caused by isonicotinic acid hydrazide (INH) inhalation.

Occupational asthma caused by isonicotinic acid hydrazide (INH) inhalation occurred in a 26-year-old female hospital pharmacist after symptoms of allergic rhinitis. Intradermal, inhalation, and Prausnitz-Küstner tests were performed with INH dissolved in saline, INH dissolved in the subject's serum and incubated at 25 degrees C for 4 hours, and an INH conjugate with human serum albumin. An INH conjugate with bovine serum albumin was also used in the prick tests alone. All preparations caused rapid positive skin reaction in the patient. Prausnitz-Küstner tests on the subject's mother were also rapidly positive. Furthermore, positive results were obtained not only in the inhalation tests with the three antigens but also in the environmental provocation tests. These results strongly suggested that the asthmatic symptoms of the subject were not caused by physical irritation from INH or other drugs and might be mediated by an IgE antibody specific to INH, a suggestion subsequently confirmed by in vitro enzyme-linked allergosorbent test for the antibody previously reported. This is the first precise description of INH-induced bronchial asthma, and the four kinds of INH preparations used in these tests might be very useful as tools of clinical diagnosis in INH allergy.

Adult↗
PubMed1982

Inhibition of avian myeloblastosis virus reverse transcriptase and virus inactivation by metal complexes of isonicotinic acid hydrazide.

The cupric and ferric complexes of isonicotinic acid hydrazide (INH) inhibit the DNA synthesis catalysed by avian myeloblastosis virus (AMV) reverse transcriptase. The inhibition was to the extent of 95% by 50 microM of cupric-INH complex and 55% by 100 microM of ferric-INH complex. These complexes have been found to bind preferentially to the enzyme than to the template-primer. Kinetic analysis showed that the cupric-INH complex is a non-competitive inhibitor with respect to dTTP. The time course of inhibition has revealed that the complexes are inhibitory even after the initiation of polynucleotide synthesis. In vivo toxicity studies in 1-day-old chicks have shown that the complexes are not toxic up to a concentration of 500 microgram per chick. Infection of the 1-day-old chicks with AMV pretreated with 150 microgram of either of the complexes prevented symptoms of leukemia due to virus inactivation.

Animals↗
PubMed1984

Amino acid content of nerve endings (synaptosomes) in different regions of brain: effects of gabaculine and isonicotinic acid hydrazide.

The amino acid content of synaptosomes was determined in six regions of rat brain, and in all regions the five predominant amino acids were glutamate, glutamine, aspartate, taurine, and GABA (gamma-aminobutyrate). However, the proportions of the individual amino acids varied considerably from one region to another, the GABA content being particularly high and the taurine content low in synaptosomes from the diencephalon and mesencephalon. Administration of isonicotinic acid hydrazide to rats lowered the synaptosomal GABA level by similar amounts in all brain regions, but the administration of gabaculine resulted in a particularly long-acting elevation in GABA levels in the nerve endings of the diencephalon and mesencephalon. The possibility is raised that the high GABA levels in the nerve terminals of the diencephalon may be involved in the gabaculine-induced lowering of the body temperature of the rats. A constancy in the amount of the synaptosomal pool of "aspartate + glutamate + glutamine + GABA" was observed despite large changes in the relative amounts of the four amino acids brought about by gabaculine.

Amino Acids↗
PubMed1978

Effect of hydrazine, isonicotinic acid hydrazide, hydrazine sulfate, and dimethylhydrazine on guanylate cyclase activity.

The chemical carcinogen hydrazine is a potent stimulator of guanylate cyclase. In the present investigation we found that three chemical carcinogens structurally related to hydrazine, isonicotinic acid hydrazide, hydrazine sulfate, and dimethylhydrazine, decreased guanylate cyclase activity. It is of interest that hydrazine has been shown to increase DNA synthesis whereas isonicotinic acid hydrazide, hydrazine sulfate, and dimethylhydrazine decrease DNA synthesis. The relationship, if any, linking the guanylate cyclase-cyclic GMP system to DNA synthesis and carcinogenesis remains to be explored.

Animals↗