Pharmacological and toxicological properties of 4-hydroxypyrazole, a metabolite of pyrazole.
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 centered 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 had no effect in the doses used (1.5 mmol/kg or 4 x 1.0 mmol/kg) in 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 of pyrazole.
D000818:Animals; D001679:Biogenic Amines / Q000032:analysis; D001921:Brain / Q000201:enzymology; D001923:Brain Chemistry / Q000187:drug effects; D002374:Catalase / Q000037:antagonists & inhibitors; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D011720:Pyrazoles / Q000494:pharmacology / Q000633:toxicity*; D014366:Tryptophan Oxygenase / Q000037:antagonists & inhibitors
D001679:Biogenic Amines; D011720:Pyrazoles; C014606:4-hydroxypyrazole; D002374:Catalase; D014366:Tryptophan Oxygenase