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PubMed1997

Roles of efficient substrates in enhancement of peroxidase-catalyzed oxidations.

Efficient peroxidase substrates may have a critical role in the oxidation of secondary compounds by peroxidases. Hydrazines are often oxidized slowly by peroxidases due, in part, to hydrazine-dependent inactivation of these enzymes. Peroxidase-catalyzed oxidation of hydrazines may be dramatically affected by an efficient peroxidase substrate. We investigated this hypothesis in a model system using the well-known peroxidase substrate chlorpromazine (CPZ) and the hydrazine derivative isoniazid. CPZ stimulated isoniazid oxidation as measured by nitroblue tetrazolium (NBT) reduction and O2 consumption. The kinetics of isoniazid and CPZ oxidation by horseradish peroxidase (HRP) in the presence of both compounds suggested CPZ was acting as an electron transfer mediator between HRP and isoniazid. Indeed, CPZ.+, the product of CPZ oxidation by HRP, was able to oxidize isoniazid. The rate constant for this pH-dependent reaction was (2.6 +/- 0.1) x 10(4) M-1 s-1 at pH 4.5. In the absence of CPZ, isoniazid-dependent irreversible inactivation of HRP was observed. The inactivation process involved the formation of compound III followed by accumulation of irreversibly inactivated HRP. CPZ completely inhibited inactivation. Thus, by acting as a redox mediator and preventing HRP inactivation, CPZ stimulated isoniazid oxidation by several orders of magnitude. Similarly, other efficient peroxidase substrates, such as phenol and tyrosine, were also able to dramatically stimulate isoniazid oxidation by HRP. We suggest that the presence of efficient peroxidase substrates may potentiate the activation of isoniazid and other hydrazines. As such, these substrates may have a vital role in the pharmacological and toxicological properties of hydrazines and other compounds.

Carbon Monoxide↗
PubMed1964

PHARMACOGENETICS.

Explore the source record for details and available documents.

Abnormalities, Drug-Induced↗
PubMed1984

Acetylation pharmacogenetics: experimental models for human toxicity.

Hereditary acetylation polymorphisms well-suited to experimental pharmacogenetic investigation are now known in three laboratory animal species (rabbit, mouse, and hamster). These animal models provide new evidence for the profound influence of this trait on the metabolic fate of arylamines and hydrazines, and on their pharmacological and toxicological profiles. The rabbit polymorphism most closely resembles that in humans. For the rabbit model, studies have shown that 1) monoacetylhydrazine is a polymorphic substrate for liver N-acetyltransferase in rapid and slow acetylators. This observation, in conjunction with human epidemiological data of others, opposes the commonly held view that rapid acetylators are predisposed to isoniazid (INH)-induced hepatotoxicity. 2) Slow acetylators are much more sensitive than rapid acetylators to the lethal central nervous system toxicity of INH. 3) In hepatocytes in short-term culture and exposed to arylamines and hydrazines, DNA damage is produced by hydralazine in slow acetylator hepatocytes but not in rapid acetylator hepatocytes, whereas hepatocytes from rapid acetylators are more sensitive to toxicity and DNA damage from 2-aminofluorene and benzidine. These investigations in animal models of the acetylation polymorphism provide new insights into human toxicity resulting from environmental arylamines and hydrazines.

Acetylation↗
PubMed1979

[Effect of proximate environment on drug susceptibility of mice (author's transl)].

The present study was performed in order to elucidate the effect of proximate environment on drug susceptibility of mice. Three experiments were carried out independently. In the first experiment, mongrel and ddS mice produced under an unsatisfactory control of proximate environment were purchased, and acute toxicity tests of thiamine hydrochloride (B1HCl) and isonicotinic acid hydrazide (INAH) were practiced at two different conditioned rooms. In the second experiment, ddY mice produced under the conventional environment controlled to a certain extent were purchased, and the toxic effect of B1HCl was examined under the similar environment. In the third experiment, the sensitivity to B1HCl of RFVL mice produced under the strict barrier system was tested at the severe air-conditioned room. LD50 and their fLD50 values were calculated by Litchfield-Wilcoxon's method, and the variance analyses were carried out. The severer the environmental control after the purchase of mice turned to the higher the drug sensitivity. This respect was more remarkable in INAH of which the toxic response is appeared slowly compared with B1HCl. Furthermore, seasonal variation was found in LD50 values. However, seasonal effect differed from rearing and experimental conditions. In the third experiment which these proximate environments were controlled severely, seasonal variation was very small. From the results of these experiments, it was defined that the use of animals produced under the satisfactory rearing condition and severe environmental control are necessary for animal experiments.

Air Conditioning↗
PubMed1985

Plasma hydrazine concentrations in man after isoniazid and hydralazine administration.

By using a specific sensitive stable-isotope dilution gas chromatography-mass spectrometry (GC-MS) assay, hydrazine was detected in the plasma of eight healthy male volunteer subjects taking isoniazid (300 mg daily) for 2 weeks. Accumulation of hydrazine occurred in slow-acetylator phenotypes. Hydrazine was also detected in the plasma of eight out of 14 hypertensive patients treated chronically with hydralazine (200 mg daily). However, the concentrations of hydrazine observed were much lower than in the isoniazid study and were close to the limit of detection. As hydrazine is hepatotoxic, mutagenic and carcinogenic in animals, its presence in human plasma has important toxicological implications.

Acetylation↗
PubMed2002

Clinical toxicology: part II. Diagnosis and management of uncommon poisonings.

OBJECTIVE: To review the diagnosis and management of drug overdose and poisonings in a two-part presentation. DATA SOURCES: A review of articles reported on drug overdose and poisonings. SUMMARY OF REVIEW: In patients who attempt suicide it is usual for the overdose to be a therapeutic agent, although in the severely mentally disturbed patient the agent may be an unusual poison. As with any overdose, the most important aspects in the management is the maintenance of the patient's airway, ventilation and circulation, while the toxin is metabolised and excreted. Adsorbents, gastric lavage and haemodialysis or continuous renal replacement therapy and specific antidotes may be beneficial in individual cases. The diagnosis and management of uncommon poisonings, including pesticides and herbicides (e.g. organophosphates, carbamates, paraquat, chlorophenoxy herbicides), carbon monoxide, cyanide, strychnine, halogenated hydrocarbons, elemental poisons (e.g. iron, arsenic, lead, mercury, selenium, barium, thallium, lithium, sodium, rubidium, cesium), alkaloids (e.g. mushroom, aconite, conium) and cantharidin poisoning along with the miscellaneous poisonings of quinine, chloroquine, isoniazid, thyroxine, cytotoxic agents (e.g. azothioprine, 6-mercaptopurine, colchicine, methotrexate) are discussed in the second part of this presentation on clinical toxicology. CONCLUSIONS: In the critically ill patient who has taken an overdose of a non therapeutic agent, while activated charcoal, continuous renal replacement therapy and specific antidotes may be of benefit, maintenance of the patient's airway, ventilation and circulation still remain the most important aspects of management.

Journal Article↗
PubMed1992

Pharmacodynamic interactions between isoniazid and theophylline in mice and rats, and the influence of pyridoxine.

Convulsions induced by acute administration of isoniazid (1), theophylline (2) as well as combinations of 1 and 2 were evaluated in male albino mice and male Wistar rats. The effect of pyridoxine (3) on these seizures was tested. Serum and brain levels of 1 after coadministration with 2 and caffeine (4) were assessed. The relevance of the observed pharmacokinetic phenomena in serum is questionable for the CNS processes because animals convulsed late (starting 90 min) and no significant changes of brain levels of 1 were observed. In conclusion, interactions of 1 and 2 may not occur through common mechanisms and exist only if the dose of 1 is toxic suggesting toxicological rather than therapeutic relevance.

Animals↗
PubMed2005

Pyridoxine in clinical toxicology: a review.

Pyridoxine (vitamin B6) is a co-factor in many enzymatic pathways involved in amino acid metabolism: the main biologically active form is pyridoxal 5-phosphate. Pyridoxine has been used as an antidote in acute intoxications, including isoniazid overdose, Gyromitra mushroom or false morrel (monomethylhydrazine) poisoning and hydrazine exposure. It is also recommended as a co-factor to improve the conversion of glyoxylic acid into glycine in ethylene glycol poisoning. Other indications are recommended by some sources (for example crimidine poisoning, zipeprol and theophylline-induced seizures, adjunct to d-penicillamine chelation), without significant supporting data. The value of pyridoxine or its congener metadoxine as an agent for hastening ethanol metabolism or improving vigilance in acute alcohol intoxication is controversial. This paper reviews the various indications of pyridoxine in clinical toxicology and the supporting literature. The potential adverse effects of excessive pyridoxine dosage will also be summarized.

Animals↗
PubMed1985

Advances in clinical toxicology.

New data are reviewed in two areas in the management of the acute overdose: gastrointestinal decontamination and systemic antidotes. The mechanism and effectiveness of Ipecac syrup, gastric aspiration and lavage, activated charcoal, gastrointestinal dialysis, and saline cathartics are discussed. Special problems posed by disc batteries and packet ingestion of cocaine (in transporting contraband) are highlighted. The pharmacology and uses of pyridoxine and naloxone as antidotes are detailed.

Antidotes↗