Induction of rat hepatic microsomal drug metabolizing enzymes by pyrazole and 4-substituted pyrazoles.
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 less than 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-methylpyrazole also resulted in a 2.9 fold increase in ethoxyresorufin demethylase (EROD) activity. In addition, pyrazole treatment led to a significant decrease in the activity of benzphetamine demethylase. 4-Iodopyrazole 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 rates tested. In contrast to results with cultured chick hepatocytes, where induction was directly related to the hydrophobicity of the 4-substituent, the present data indicate that the process of induction of in vivo is more complex.
Hayes
A L
AL
Division of Intramural Clinical and Biological Research, National Institute of Alcohol Abuse and Alcoholism, Rockville, MD 20852.
Marden
L J
LJ
McGuire
M V
MV
Cornell
N W
NW
D000818:Animals; D019363:Cytochrome P-450 CYP1A1; D019392:Cytochrome P-450 CYP2E1; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects*; D006899:Mixed Function Oxygenases / Q000378:metabolism; D010088:Oxidoreductases / Q000378:metabolism; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains
D011720:Pyrazoles; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D010088:Oxidoreductases; D019392:Cytochrome P-450 CYP2E1; D019363:Cytochrome P-450 CYP1A1; C019781:benzphetamine N-demethylase; D010089:Oxidoreductases, N-Demethylating