Induction of rat hepatic microsomal drug metabolizing enzymes by pyrazole and 4-substituted pyrazoles.

Abstract

Pyrazole and 4-methylpyrazole are potent inhibitors of liver alcohol dehydrogenase and as such have been proposed as potential antidotes to alcohol poisoning. These drugs are also inducers of hepatic cytochrome P-450. We tested pyrazole and four 4-substituted pyrazoles for their potential as inducers of cytochrome P-450 and drug metabolism in mature male rats. Total cytochrome P-450 was significantly increased (p < 0.05) 1.3 fold by treatment with 4-methylpyrazole. P-nitrophenol hydroxylase (PNPH) activity (nmol/min/mg protein) was increased 1.9 fold following treatment with pyrazole and with 4-methylpyrazole. Treatment with 4-methyl-pyrazole also resulted in a 2.9 fold increase in ethoxyresorufin deethylase (EROD) activity. In addition, pyrazole treatment led to a significant decrease in the activity of benzphetamine demethylase. 4-lodopyrazole increased the turnover (nmol/min/nmol P-450) of EROD and PNPH by 1.5 fold each. 4-Nitropyrazole had no significant effect on any of the activities or turnover rat...