Modulation of rabbit and human hepatic cytochrome P-450-catalyzed steroid hydroxylations by alpha-naphthoflavone.
Rifampicin induces cytochrome P-450 3c, progesterone 16 alpha- and 6 beta-hydroxylation, 17 beta-estradiol 2-hydroxylation, benzo[a] pyrene hydroxylation, and erythromycin N-demethylation in rabbit liver microsomes. Kinetic analysis of the 6 beta-hydroxylation of progesterone as catalyzed by liver microsomes prepared from rifampicin-treated B/J rabbits exhibits a curvilinear double-reciprocal plot, suggestive of substrate activation. Further experimentation demonstrated that alpha-naphthoflavone could augment the catalytic efficiency [Vmax/Km] observed for the 16 alpha- and 6 beta-hydroxylation of progesterone and the 2-hydroxylation of 17 beta-estradiol, whereas erythromycin N-demethylase activity was partially inhibited. Allosteric activation of these steroid hydroxylases by alpha-naphthoflavone is also found for human liver microsomes, indicating that the activation of these enzymes is conserved in man and rabbit.
Schwab
G E
GE
Department of Basic and Clinical Research, Research Institute of Scripps Clinic, La Jolla, California 92037.
Raucy
J L
JL
Johnson
E F
EF
D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D001571:Benzoflavones / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D004958:Estradiol / Q000378:metabolism*; D005419:Flavonoids / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D008862:Microsomes, Liver / Q000201:enzymology*; D011374:Progesterone / Q000378:metabolism*; D011817:Rabbits; D012293:Rifampin / Q000494:pharmacology
D001571:Benzoflavones; D005419:Flavonoids; D011374:Progesterone; D004958:Estradiol; C011512:alpha-naphthoflavone; D003577:Cytochrome P-450 Enzyme System; D012293:Rifampin