Isoniazid, oxidation

Monoamine Oxidase Inhibitors. MAOIs inactivate the enzyme MAO, which is responsible for the oxidative deamination of a variety of endogenous and exogenous substances. Among the endogenous substances are the neurotransmitters, norepinephrine, dopamine, and serotonin. The prototype MAOI is iproniazid [54-92-2] (25), originally tested as an antitubercular dmg and a close chemical relative of the effective antitubercular, isoniazid [54-85-3] (26). Tubercular patients exhibited mood elevation, although no reHef of their tuberculosis, following chronic administration of iproniazid. In... 

Timmins GS, S Master, F Rusnak, V Deretic (2004) Nitric oxide generated from isoniazid activation by KatG source of nitric oxide and activity against tunerculosis. Antimicrob Agents Chemother 48 3006-3009. 

Chiang and Lin also irradiated alcoholic solutions of isoniazid, but used a high-pressure mercury lamp. From the methanol solution they isolated small yields of isonicotinic acid, isonicotinamide, the hydrazone (263) and the bishydrazide (265). From the ethanolic solution, they obtained isonicotinamide, the hydrazone (262) and the bishydrazide (265). As before, (262) was assumed to arise via photo-oxidation of the solvent. The other products were explained as resulting from either CO-N or N-N bond homolysis [163]. 

FIGURE 4.88 Oxidation of the hydrazine (hydralazine) and the hydrazide (isoniazid) leads to the loss of nitrogen. 

Y. Ono, X. Wu, H. Noda, T. Yoshitani, Participation of P450-Dependent Oxidation of Isoniazid in Isonicotinic Acid Formation in Rat Liver , Biol. Pharm. Bull. 1998, 21, 421 -425. 

Isoniazid possibly exerts its action by inhibiting the synthesis of mycolic acid which is an essential component of mycobacterial cell wall. It is also postulated that the ability of isoniazid to suppress the formation of DNA and RNA and also inhibition of various oxidative mechanisms may be responsible for its action. 

The first generation of antidepressants, MAO (monoamine oxidase) inhibitors, inhibited neurotransmitter degradation by inhibiting monoamine deoxidase, a flavin containing enzyme, found in the mitochondria of neurons and other cell types, that oxidatively deaminates naturally occurring sympathomimetic monoamines, such as norepinephrine, dopamine, and serotonin within the presynapse. In 1952, isoniazid and its isopropyl derivative, iproniazid (1), were developed for the treatment of tuberculosis, where it was subsequently found that these agents had a mood enhancing effect on... 

The heme iron in the peroxidase is oxidized by the peroxide from III+ to V4- in compound I. The compound I is reduced by two sequential one-electron transfer processes giving rise to the original enzyme. A substrate-free radical is in turn generated. This may have toxicological implications. Thus the myeloperoxidase in the bone marrow may catalyze the metabolic activation of phenol or other metabolites of benzene. This may underlie the toxicity of benzene to the bone marrow, which causes aplastic anemia (see below and chap. 6). The myeloperoxidase found in neutrophils and monocytes may be involved in the metabolism and activation of a number of drugs such as isoniazid, clozapine, procainamide, and hydralazine (see below). In in vitro systems, the products of the activation were found to be cytotoxic in vitro. 

For example, it has been suggested that the adverse reactions caused by a number of drugs such as isoniazid, procainamide, hydralazine could be due to metabolic activation by myeloperoxidase in neutrophils. Thus neutrophils will metabolize procainamide (Fig. 4.38) to a hydroxylamine metabolite. In the presence of chloride ion, myeloperoxidase will produce hypochlorous acid, a strong oxidizing agent, which may be responsible for metabolic activation and toxicity. One of the products is N-chloroprocainamide (see also sect. "Hydralazine," chap. 7). 

Zand R, Nelson SD, Slattery JT, et al. Inhibition and induction of cytochrome P4502El-catalyzed oxidation by isoniazid in humans. Clin Pharmacol Ther 1993 54 142-149. 

Human CYP2E1 is one of the most efficient P450s to catalyze the oxidation of acetaminophen to NAPQI (157-159). Ethanol and isoniazid cause a time-dependent inhibition and induction of acetaminophen oxidation to NAPQI in humans (160,161) that can decrease risk for hepatotoxicity over the interval of concurrent administration and increase risk for hepatotoxicity a few hours after removal of ethanol or isoniazid. The latter induction phase of CYP2E1 may, in part, be responsible for cases of acetaminophen hepatotoxicity associated with the use of ethanol (162-165) or isoniazid (166-168). However, the induction is modest (2- to 3-fold) therefore, other susceptibility factors, genetic and others such as decreased glutathione stores and nutritional status, are likely to play an important role in some individuals (169-174). 

Fig. 5.17 Role of chlorpromazine as an electron relay in the oxidation of isoniazid by HRP. Although isoniazid is directly oxidized by HRP, the reaction is much faster when chlorpromazine, a better substrate, is used as a relay in the oxidation of isoniazid...

The antipsychotic chlorpromazine is a prototype heptotoxicant for production of cholestasis. Pleiotropic effects of chlorpromazine on membrane permeability and associated ion gradients and microfilament-mediated canalicular contraction have been attributed to detergent effects. Valproic acid, an anticonvulsant, is associated with microvesicular steatosis. Inhibition of mitochondial fatty acid (S-oxidation is an important component of this toxic effect and is apparently related to carnitine availability as evidenced by the protection afforded by L-carnitine supplements. The hypolipidemic drugs clofibrate, fenofibrate, and gemfibrozil are peroxisome prolif-erators in rodent liver, but not in humans. Isoniazid, an antibiotic used to treat tuberculosis, exhibits an approximately 1 % incidence of hepatotoxicity. Although toxicity is known to be metabolism-dependent and protein adduction has been well-... 

Amiodarone Chloroquine Cisplatin Colchicine Dapsone Disulfiram Glutethimide Gold compounds Hydralazine Isoniazid Misonidazole Nitrous oxide Nitrofuratoin Nucleoside analogs (antiretrovirals) Paclitaxel (taxanes) Phenytoin... 

Methylpyridine 2,6-Dimethylpyridine Isoniazid Cyanoacetate Pyrazine JV-oxide... 

Antibiotics (erythromycin, chloramphenicol, isoniazid) compete for hepatic oxidative pathways that metabolize most benzodiazepines, as well as zolpidem, zopiclone, and buspirone (SEDA-22, 39) (SEDA-22, 41). 

Omeprazole, like cimetidine, can impair benzodiazepine metabolism and lead to adverse effects (SEDA-18, 43). Other drugs, including antibiotics (erythromycin, chloramphenicol, isoniazid), antifungal drugs (ketoconazole, itraconazole, and analogues), some SSRIs (fluoxetine, paroxetine), other antidepressants (nefazodone), protease inhibitors (saquinavir), opioids (fentanyl), calcium channel blockers (diltiazem, verapamil), and disulfiram also compete for hepatic oxidative pathways that metabolize most benzodiazepines, as well as zolpidem, zopiclone, and buspirone (SEDA-22,39) (SEDA-22,41). 

Lauterberg BH, Smith CV, Todd EL, Mitchell JR. Oxidation of hydrazine metabolites formed from isoniazid. Clin Pharmacol Ther 1985 38 566-71. 

---