Potent inhibition of human liver aldehyde oxidase by raloxifene.
The selective estrogen receptor modulator, raloxifene, has been demonstrated as a potent uncompetitive inhibitor of human liver aldehyde oxidase-catalyzed oxidation of phthalazine, vanillin, and nicotine-Delta1'(5')-iminium ion, with K(i) values of 0.87 to 1.4 nM. Inhibition was not time-dependent. Raloxifene has also been shown to be a noncompetitive inhibitor of an aldehyde oxidase-catalyzed reduction reaction of a hydroxamic acid-containing compound, with a K(i) of 51 nM. However, raloxifene had only small effects on xanthine oxidase, an enzyme related to aldehyde oxidase. In addition, several other compounds of the same therapeutic class as raloxifene were examined for their potential to inhibit aldehyde oxidase. However, none were as potent as raloxifene, since IC(50) values were orders of magnitude higher and ranged from 0.29 to 57 micro M. In an examination of analogs of raloxifene, it was shown that the bisphenol structure with a hydrophobic group on the 3-position of the benzthiophene ring system was the most important element that imparts inhibitory potency. The relevance of these data to the mechanistic understanding of aldehyde oxidase catalysis, as well as to the potential for raloxifene to cause drug interactions with agents for which aldehyde oxidase-mediated metabolism is important, such as zaleplon or famciclovir, is discussed.
Obach
R Scott
RS
Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Pfizer Global Research and Development, Groton Laboratories, Groton, CT 06340, USA. obachrs@groton.pfizer.com
D042931:Aldehyde Oxidase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D001547:Benzaldehydes / Q000378:metabolism; D004791:Enzyme Inhibitors; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D009538:Nicotine / Q000031:analogs & derivatives* / Q000378:metabolism; D010084:Oxidation-Reduction; D010793:Phthalazines / Q000378:metabolism; D020849:Raloxifene Hydrochloride / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology*; D014969:Xanthine Oxidase / Q000378:metabolism
D001547:Benzaldehydes; D004791:Enzyme Inhibitors; D010793:Phthalazines; D020845:Selective Estrogen Receptor Modulators; D020849:Raloxifene Hydrochloride; D009538:Nicotine; C034629:nicotine imine; C043388:phthalazine; C100058:vanillin; D014969:Xanthine Oxidase; D042931:Aldehyde Oxidase