Allosteric regulation of the 16 alpha-hydroxylation of progesterone as catalyzed by rabbit microsomal cytochrome P-450 3b.
A variety of compounds that can arise from the metabolism of progesterone in vivo stimulate the 16 alpha-hydroxylation of progesterone as catalyzed by highly purified, reconstituted preparations of cytochrome P-450 3b obtained from rabbit strain IIIVO/J. In general, reduction of the 20-keto moiety of progesterone or related compounds increases the extent of stimulation. Reduction of the 3-keto group also results in increased stimulatory activity in most cases. The resulting 3 beta-hydroxy derivatives are more active than the corresponding 3 alpha-isomers. In a similar fashion, 5 beta-pregnanes exhibit greater activity than the corresponding 5 alpha-pregnanes. The effect of these allosteric effectors is saturable at relatively low concentrations when compared to other positive effectors of P-450-mediated metabolism. These compounds increase the apparent ratio of Vmax/Km without altering the amount of reductase required for half-maximal activity when reconstituted with the cytochrome. In contrast, many of these compounds do not affect or inhibit the 6 beta-hydroxylation of progesterone catalyzed by a subform of P-450 3b that is expressed in New Zealand White rabbits but not in strain IIIVO/J. Many of the compounds investigated here are metabolites of progesterone and, therefore, may modulate P-450 3b-mediated metabolism during pregnancy.
D000494:Allosteric Regulation; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D000072467:Cytochrome P450 Family 2; D006900:Hydroxylation; D007700:Kinetics; D008862:Microsomes, Liver / Q000201:enzymology*; D011374:Progesterone / Q000378:metabolism*; D011817:Rabbits; D039181:Steroid 16-alpha-Hydroxylase
D011374:Progesterone; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C450239:CYP2C3 protein, Oryctolagus cuniculus; D000072467:Cytochrome P450 Family 2; D039181:Steroid 16-alpha-Hydroxylase