Involvement of a cytochrome P450 system in microsomal debromination of alpha-(bromisovaleryl)urea.
The reductive debromination of a hypnotic, (alpha-bromisovaleryl)urea to (3-methylbutyryl)urea by rat liver microsomes was studied. Pretreatment of rats with cytochrome P450 inducers such as phenobarbitone, 3-methylcholanthrene, acetone and pregnenolone-16 alpha-carbonitrile enhanced the debromination of (alpha-bromisovaleryl)urea by liver microsomes. Microsomal debromination was inhibited by cytochrome P450 inhibitors such as metyrapone, alpha-naphthoflavone, SKF 525-A and carbon monoxide. Microsomal debromination was enhanced by addition of NADPH-cytochrome P450 reductase and inhibited by addition of an antibody against the flavo enzyme to the liver microsomes. A reconstituted cytochrome P450 system containing NADPH-cytochrome P450 reductase, and cytochrome P450 1AI or P450 2BI exhibited debrominating activity toward the hypnotic. These results indicated that a cytochrome P450 system plays an essential role in the microsomal debromination of (alpha-bromisovaleryl)urea.
Institute of Pharmaceutical Science, Hiroshima University School of Medicine, Japan.
K
K
Oka
S
S
Kitamura
K
K
Tatsumi
D000818:Animals; D001966:Bromine / Q000378:metabolism; D001968:Bromisovalum / Q000378:metabolism*; D019363:Cytochrome P-450 CYP1A1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D019362:Cytochrome P-450 CYP2B1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000378:metabolism*; D004790:Enzyme Induction / Q000187:drug effects; D006993:Hypnotics and Sedatives / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D009251:NADPH-Ferrihemoprotein Reductase / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D010084:Oxidation-Reduction; D051381:Rats; D017208:Rats, Wistar
D065607:Cytochrome P-450 Enzyme Inhibitors; D006993:Hypnotics and Sedatives; D001968:Bromisovalum; D003577:Cytochrome P-450 Enzyme System; D019363:Cytochrome P-450 CYP1A1; D019362:Cytochrome P-450 CYP2B1; D009251:NADPH-Ferrihemoprotein Reductase; D001966:Bromine