The steroid antagonist RU38486 is metabolized by the liver microsomal P450 mono-oxygenases.
Microsomal preparations from adult male rat liver actively oxidized RU38486 into the 11 beta-monodemethylated, 11 beta-didemethylated and 17 alpha-hydroxylated derivatives, metabolites which are known to be formed in vivo. These oxidative reactions were inhibited at different degrees by P450 chemical inhibitors. Pretreatment of the animals by P450 mono-oxygenase prototype inducers led to drastic changes in RU38486 metabolization. Methylcholanthrene treatment carried out a significant decrease while phenobarbital markedly increased the metabolic activity of the liver microsomes. Moreover, antibodies to methylcholantrene-inducible P450 forms did not affect the metabolic activity while a complete blockade-of RU38486 oxidation was observed in the presence of antibodies to phenobarbital- inducible forms. The present results demonstrate that liver P450 mono-oxygenases are engaged in different oxidative steps of RU38486 metabolism and that phenobarbital-inducible but not methylcholanthrene-inducible P450 forms are active in RU38486 degradation.
Chasserot-Golaz
S
S
Institut de Biologie Moleculaire et Cellulaire, Strasbourg, France.
Ribeiro
V
V
Genot
G
G
Lechner
M C
MC
Beck
G
G
D000375:Aging; D000818:Animals; D000906:Antibodies; D001711:Biotransformation; D003577:Cytochrome P-450 Enzyme System / Q000276:immunology / Q000378:metabolism*; D007700:Kinetics; D008099:Liver / Q000254:growth & development*; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D015735:Mifepristone / Q000378:metabolism*; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D012016:Reference Values
D000906:Antibodies; D015735:Mifepristone; D008748:Methylcholanthrene; D003577:Cytochrome P-450 Enzyme System; D010634:Phenobarbital