Inducibility of P450Coh by pyrazole and its derivatives.
Pyrazole and several of its derivatives increase the hepatic microsomal coumarin 7-hydroxylase to a variable extent. The strongest inducers are pyrazole itself and those derivatives which have a hydroxy group or a halogen at the 4-position of the molecule. The increase in coumarin 7-hydroxylase is due to an increase in the microsomal P450Coh and the corresponding mRNA. The increase of P450Coh by pyrazole and 4-hydroxypyrazole is selective because several other mono-oxygenase enzymes and the total P450 content are either not affected or even decreased. These include the testosterone 15 alpha-hydroxylase (P45015 alpha), a close structural analogue of P450Coh, which is induced only marginally by pyrazole and even decreased by 4-iodopyrazole, and P450ac which is decreased by pyrazole and 4-hydroxypyrazole. Introducing a methyl residue at the 4-position will alter the induction properties of the compound essentially bymaking it less selective for P450Coh. These results demonstrate the special selective action of pyrazole and some of its derivatives on the hepatic microsomal mono-oxygenase complex and the unique mode of regulation of the cytochrome P450Coh even within the same subfamily of cytochromes P450.
Kojo
A
A
Department of Pharmacology and Toxicology, University of Kuopio, Finland.
Heiskanen
R
R
Rytkönen
A L
AL
Honkakoski
P
P
Juvonen
R
R
Lang
M
M
D000818:Animals; D000937:Antigen-Antibody Reactions; D001189:Aryl Hydrocarbon Hydroxylases; D065637:Cytochrome P-450 CYP2A6; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000302:isolation & purification / Q000378:metabolism; D015342:DNA Probes / Q000138:chemical synthesis; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction; D000077604:Fomepizole; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000302:isolation & purification; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000302:isolation & purification; D011720:Pyrazoles / Q000494:pharmacology*; D013250:Steroid Hydroxylases / Q000378:metabolism
D065607:Cytochrome P-450 Enzyme Inhibitors; D015342:DNA Probes; D007527:Isoenzymes; D011720:Pyrazoles; C010201:4-iodopyrazole; C014606:4-hydroxypyrazole; D000077604:Fomepizole; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; D065637:Cytochrome P-450 CYP2A6; C050356:steroid 15-alpha-hydroxylase