Selective induction of coumarin 7‐hydroxylase by pyrazole in D2mice

Abstract

Pyrazole, was given to DBA/2N (D2) C57BL/6N (B6) and AKR/N mice to study its effects on hepatic drug metabolism. A decrease in the total amount of microsomal cytochrome P‐450 as well as in the activities of ethylmorphine demethylase and benzo[a]pyrene hydroxylase was found. On the other hand ethoxycourmarin de‐ethylase was increased 1.5–2.5‐fold (depending on the strain of mouse) and coumarin 7‐hydroxylase as much as sevenfold (but only in D2 mice) after pyrazole treatment. This increase was much higher than that caused by phenobarbital, the only well known inducer of coumarin 7‐hydroxylase. By reconstituting the mono‐oxygenase complex after purification of cytochrome P‐450 we found a 40‐fold increase in coumarin 7‐hydroxylase and eightfold increase in ethoxycoumarin de‐ethylase after pyrazole treatment. This was found only in D2 mice. An antibody previously developed against a cytochrome P‐450 fraction from the D2 strain with a high coumarin 7‐hydroxylase activity inhibited the microsomal coumarin 7‐hydroxylase almost 100% after pyrazole pretreatment of the animals. In the case of control or phenobarbital‐treated mice the inhibition was somewhat weaker. With the reconstituted mono‐oxygenase complex the inhibition of coumarin 7‐hydroxylase was almost 100% both for control and pyrazole‐treated D2 mice. The data indicate that pyrazole causes an induction of the microsomal monooxygenase complex different from that caused by phenobarbital or 3‐methylcholanthrene and selective for coumarin 7‐hydroxylation or 7‐ethoxycoumarin de‐ethylation. This induction was strong in D2, weak in B6 and absent in AKR/N mice. Copyright © 1985, Wiley Blackwell. All rights reserved