Metabolic Fate of Hydrazines and Hydrazides

Colvin, L. B.

doi:10.1002/jps.2600581202

Cited by 35 publications

(25 citation statements)

References 39 publications

(20 reference statements)

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“…We will review the role played in this process by cytochrome P450 (CYP450) and its relation to recently documented adverse interactions between INH and other commonly used drugs. For information on the hydrazines and hydrazides, the reader is referred to the extensive review published by Colvin in 1969 [1].…”

Section: Introductionmentioning

confidence: 99%

Isoniazid: Metabolic Aspects and Toxicological Correlates

Preziosi

2007

CDM

132

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For over half a century, pyridine-4-carboxy hydrazide (isonicotinyl hydrazide; isoniazid - INH) has been a front-line weapon in the battle against tuberculosis. Its metabolism has been the subject of important research, much of which has focused on the pharmacodynamic and toxicological aspects of certain INH metabolites. Since 1952, when the drug was first introduced, multiple INH metabolites have been identified, including hydrazine (HZ), isonicotinic acid (INA), ammonia, the acetylated derivative N(1)-acetyl-N(2)-isonicotinylhydrazide (AcINH), hydrazones with pyruvic and ketoglutaric acids (INH-PA and INH-KA, respectively), monoacetylhydrazine (AcHZ), diacetylhydrazine (DiAcHZ), and oxidizing free radicals. Their formation is the result of hydrolysis (INA, HZ), cytochrome P450 (CYP)-dependent oxidation (HZ, NH(3), oxidizing free radicals), and N-acetyltransferase (NAT) activity (AcINH, AcHZ, DiAcHZ). Doubts remain about isonicotinamide (INAAM) as an INH metabolite in mammals. Quantitatively speaking, one of the major metabolites is AcINH, which is produced by the enzyme NAT. It has virtually no antitubercular activity and is far less toxic than INH. Its formation and elimination are genetically controlled, and its elimination profile is trimodal (rapid, intermediate, and slow acetylation). Slow acetylation, which is transmitted as an autosomal recessive trait, increases the risk for peripheral neurotoxicity and hepatotoxicity in INH users. Thus far, there is no conclusive pharmacogenetic evidence that the formation of HZ and oxidizing radicals are linked to CYP polymorphisms. This article examines INH, HZ and its mono- and diacetylated metabolites, and ammonia (which in vitro and in vivo studies indicate as another derivative of HZ) in terms of their potential to cause neurotoxic and hepatotoxic effects (the two major forms of INH toxicity observed in animals and humans). INH hepatotoxicity seems to be related mainly to HZ, AcHZ, and other HZ metabolites that are capable of generating free radicals. The pathological aspects of slow INH acetylation will be discussed in relation to the drug's hepato- and neurotoxic effects. The mechanism underlying INH neurotoxicity has yet to be fully defined. The metabolite(s) involved in this phenomenon remain obscure although a major role is clearly played by HZ (and possibly also by the ammonia it releases). There is some evidence of the involvement of gamma-glutamyl HZ and of a chemical analogue of a Schiff base formed by INH and pyridoxal-phosphate. Recent findings have also revealed important interactions between INH and the various isoforms of CYP, and these may play a role in clinically relevant interactions between INH and several other drugs. All of these aspects of INH will be covered in the review.

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Section: Introductionmentioning

confidence: 99%

Isoniazid: Metabolic Aspects and Toxicological Correlates

Preziosi

2007

CDM

132

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“…Hydrazine can also form ammonia; it has been reported (Colvin, 1969) that the blood ammonia level of dogs increases upon hydrazine administration. Diacetylhydrazine has no effect on blood ammonia levels.…”

Section: List Of Tablesmentioning

confidence: 99%

“…In biological fluids, the most common method of determining metabolized and unchanged hydrazine compounds containing free hydrazine nitrogen is by the analysis of hydrazones after reaction with p-dimethylaminobenzaldehyde (Dambrauskas, 1962(Dambrauskas, , 1964Reynolds, 1965;Prough, 1977), p-chlorobenzaldehyde (Colvin, 1969), salicylaldehyde (Abdou, 1977), or 2-furaldehyde (Wood, 1976). …”

Section: List Of Tablesmentioning

confidence: 99%

Development of Analytical Techniques for Toxicokinetic Research

Hershey¹,

Sherman²,

Pustinger³

1979

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“…These studies began with a demonstration of the carcinogenicity of the antituberculosis drugisonicotinic acid hydrazide (Juhasz et al, 1957). This finding was followed by numerous other investigations into synthetic hydrazines widely found in the environment and to which the human population is exposed to a considerable degree (Biancifiori & Ribacchi, 1962;Druckrey et al, 1967;Colvin, 1969;Juchau & Horita, 1972; IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man, 1974;LaRue, 1977). The field recently received additional attention when the various naturally occurring hydrazine ingredients of the edible mushrooms Aqaricus bisporus (Levenberg, 1960) and Gyromitra esculenta (List and Luft, 1968) and tobacco (Liu et al, 1974) were also shown to cause cancer in laboratory animals (Toth, 1973;.…”

mentioning

confidence: 91%

1-Acetyl-2-phenylhydrazine carcinogenesis in mice

Tóth¹

1979

Br J Cancer

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Metabolic Fate of Hydrazines and Hydrazides

Cited by 35 publications

References 39 publications

Isoniazid: Metabolic Aspects and Toxicological Correlates

Isoniazid: Metabolic Aspects and Toxicological Correlates

Development of Analytical Techniques for Toxicokinetic Research

1-Acetyl-2-phenylhydrazine carcinogenesis in mice

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