COMPARISON OF PYRAZOLE AND 4-BROMPYRAZOLE AS INHIBITORS OF ALCOHOL DEHYDROGENASES: THEIR POTENCY, TOXICITY AND DURATION OF ACTION IN MICE

¹ Department of Pharmacology, Stanford University School of Medicine, Stanford, California

Alcohol dehydrogenases of yeast and mouse liver differ in their relative sensitivity to inhibition by pyrazole and 4-brompyrazole. Yeast alcohol dehydrogenase is relatively insensitive to 4-brompyrazole. The K₁ for pyrazole is 1.1 x 10^-5 M; for 4-brompyrazole, 1.1 x 10^-3 M. Both inhibit competitively with ethanol. Yeast alcohol dehydrogenase can be used for assay of blood alcohol in pyrazole-treated mice. Mouse liver alcohol dehydrogenase is strongly inhibited by both compounds. The K₁ for pyrazole is 8 x 10^-7 M, competitive with ethanol, and for 4-brompyrazole, 3 x 10^-7 M, competitive or mixed type inhibition. Pyrazole has a half-life of about 10 hours and 4-brompyrazole about three hours in mice, as estimated from alcohol elimination rates. The LD50 after single i.p. injections of pyrazole in mice is 7.9 mmol/kg; for 4-brompyrazole, 2.5 mmol/kg. Thus the ratio of efficacy to toxicity is about the same for the two compounds, but 4-brompyrazole has a shorter duration of action.