title: Effect of genetic polymorphism on the inhibition of dopamine formation from p-tyramine catalyzed by brain cytochrome P450 2D6.
abstract: The inhibitory effects of steroid hormones, including glucocorticoids such as cortisol, and related compounds on dopamine formation from p-tyramine, catalyzed by cytochrome P450 (CYP) 2D6.2 (Arg296Cys, Ser486Thr) and CYP2D6.10 (Pro34Ser, Ser486Thr) were compared with the effects of those catalyzed by CYP2D6.1 (wild type), to investigate the effect of a CYP2D6 polymorphism on neuroactive amine metabolism in the brain. Inhibition constants (Ki) or 50% inhibitory concentrations of six steroid hormones (cortisol, cortisone, corticosterone, dehydroepiandrosterone, progesterone, and pregnenolone) and quinidine and quinine-typical potent inhibitors of the human CYP2D6 and rat CYP2D subfamily, respectively-toward dopamine formation catalyzed by CYP2D6.1, CYP2D6.2, and CYP2D6.10 expressed in recombinant Escherichia coli were compared. Although most steroid hormones had no or minor inhibitory effects on the dopamine formation by all CYP2D6 variants, progesterone inhibited the metabolism and Kivalue against CYP2D6.10 was approximately twice that for CYP2D6.1 and CYP2D6.2. Quinidine exhibited stronger inhibition than quinine; however, these two compounds inhibited the CYP2D6.10-mediated reaction more weakly than the CYP2D6.1 and CYP2D6.2 reactions. These results suggest that CYP2D6 polymorphism would affect drug interaction through dopamine formation in the brain.
authors.affiliation: School of Pharmacy, Shujitsu University, 1-6-1 Nishigawara, Naka-ku, Okayama 703-8516, Japan. Electronic address: tniwa@shujitsu.ac.jp.
authors.forename: Toshiro
authors.initials: T
authors.lastname: Niwa
authors.affiliation: School of Pharmacy, Shujitsu University, 1-6-1 Nishigawara, Naka-ku, Okayama 703-8516, Japan.
authors.forename: Marina
authors.initials: M
authors.lastname: Shizuku
authors.affiliation: School of Pharmacy, Shujitsu University, 1-6-1 Nishigawara, Naka-ku, Okayama 703-8516, Japan.
authors.forename: Kaori
authors.initials: K
authors.lastname: Yamano
mesh_terms: D000818:Animals; D019389:Cytochrome P-450 CYP2D6 / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D065690:Cytochrome P-450 CYP2D6 Inhibitors / Q000737:chemistry; D004298:Dopamine / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D011110:Polymorphism, Genetic; D011802:Quinidine / Q000737:chemistry; D011803:Quinine / Q000737:chemistry; D051381:Rats; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014439:Tyramine / Q000737:chemistry* / Q000378:metabolism
chemical_list: D065690:Cytochrome P-450 CYP2D6 Inhibitors; D011994:Recombinant Proteins; D011803:Quinine; D019389:Cytochrome P-450 CYP2D6; D011802:Quinidine; D004298:Dopamine; D014439:Tyramine
keywords: CYP2D6; Dopamine formation; Drug interaction; Genetic polymorphism