Selective induction of coumarin 7-hydroxylase by pyrazole in D2 mice

• Published in: European journal of biochemistry Vol. 152; no. 1; pp. 3 - 8
• Main Authors: JUVONEN, R. O, KAIPAINEN, P. K, LANG, M. A
• Format: Journal Article
• Language: English
• Published: Oxford Blackwell 01.10.1985
• Subjects: Analytical, structural and metabolic biochemistry; Animals; Antibodies - immunology; Aryl Hydrocarbon Hydroxylases; Biological and medical sciences; Cytochrome P-450 CYP2A6; Cytochrome P-450 Enzyme System - metabolism; Enzyme Induction - drug effects; Enzymes and enzyme inhibitors; Fundamental and applied biological sciences. Psychology; Male; Mice; Mice, Inbred Strains; Microsomes, Liver - enzymology; Mixed Function Oxygenases - antagonists & inhibitors; Mixed Function Oxygenases - biosynthesis; Mixed Function Oxygenases - immunology; Mixed Function Oxygenases - metabolism; Oxidoreductases; Pyrazoles - pharmacology; Drug; Vertebrata; Specificity; Mammalia; Mouse; Enzyme; Induction; Animal; Liver; Rodentia; Metabolism
• ISSN: 0014-2956; 1432-1033
• DOI: 10.1111/j.1432-1033.1985.tb09156.x

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 ethoxycoumarin 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 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.