Mechanistic studies on the activation of biphenyl 2-hydroxylation by glucocorticoids.
In order to establish the mechanism by which the selective activation of biphenyl 2-hydroxylation by betamethasone occurs the effect of modifying possible critical factors in the hydroxylation process has been examined. Activation of biphenyl 2-hydroxylation by betamethasone was found in detergent-solubilized rat liver microsomes indicating that intact microsomal membranes are probably not necessary for the activation. Betamethasone had no effect on the spectrally apparent binding of biphenyl or of other type I, type II or reverse type I model substrates. The activation process did not appear to be greatly influenced by changing the ratio of cytochrome P-450 reductase to cytochrome P-450 nor by changing the amount of NADPH. Addition of NADH increased the extent of activation suggesting that betamethasone facilitates transference of the second electron to cytochrome P-450. However, betamethasone also stimulated cumene hydroperoxide supported biphenyl 2-hydroxylation; therefore a step subsequent to cytochrome P-450 reduction is also involved in the activation. Activation did not correlate with increased uncoupling of an active oxygen-cytochrome P-450 complex to form hydrogen peroxide.
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism*; D001555:Benzene Derivatives / Q000494:pharmacology; D001623:Betamethasone / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003579:Cytochrome Reductases / Q000378:metabolism; D003902:Detergents; D004789:Enzyme Activation / Q000187:drug effects; D006900:Hydroxylation; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D009243:NAD / Q000494:pharmacology; D009249:NADP / Q000378:metabolism; D010084:Oxidation-Reduction; D051381:Rats; D011919:Rats, Inbred Strains
D001555:Benzene Derivatives; D001713:Biphenyl Compounds; D003902:Detergents; D009243:NAD; D009249:NADP; D003577:Cytochrome P-450 Enzyme System; D001623:Betamethasone; D001189:Aryl Hydrocarbon Hydroxylases; D003579:Cytochrome Reductases; C007164:cumene hydroperoxide