Pharmacological and Toxicological Properties of 4‐Hydroxypyrazole, a Metabolite of Pyrazole

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Abstract
The effects of 4‐hydroxypyrazole (4‐HP), a principal metabolite of pyrazole, were studied in mice. The compound was toxic, much more so than pyrazole with an LD50 of 1.1 mmol/kg (92 mg/kg) and doses greater than 1.5 mmol/kg (126 mg/kg) were almost invariably fatal. Toxicity seemed to be centred on the liver with microscopic evidence of centrolobular necrosis apparent. Mouse liver catalase was almost totally inhibited 1 hour after administration of 1 mmol/kg of 4‐HP. Tryptophan pyrrolase was also inhibited. 4‐HP seemed to penetrate into the brain as judged by inhibition of brain catalase activity. A slight increase in brain serotonin concentration was found but 4‐HP hadno effect in the doses used(l.5 mmol/kgor4× 1.0 mmol/kg)on brain or heart noradrenaline. We conclude that the pyrazole‐induced decrease in brain noradrenaline is not mediated via 4‐HP. Furthermore, simultaneous treatment with methanol and pyrazole, which prevents the formation of 4‐HP, did not prevent the decrease in brain noradrenaline levels. Since methanol prevented the pyrazole‐induced decrease in brain catalase activity, we can also rule out the possibility that the decrease in brain noradrenaline is secondary to pyrazole‐induced inhibition of brain catalase. It is concluded that though 4‐HP is an active metabolite of pyrazole, causing, in particular, the hepatotoxicity of the parent molecule, it is not responsible for all the varied biological effects of pyrazole.