Effect of genetic polymorphism on the inhibition of CYP2D6-mediated dopamine formation from p-tyramine by steroid hormones and related compounds including typical CYP2D inhibitors and antidepressants

[Speaker] Toshiro Niwa:1
[Co-author] Marina Shizuku:1, Kaori Yamano:1, Mayumi Yanai:1
1:School of Pharmacy, Shujitsu University, Japan

[Background] Dopamine is formed from p- and m-tyramine through ring-hydroxylation by polymorphic human CYP2D6 and rat CYP2D4 in the brain. The inhibitory effects of steroid hormones, and related compounds including typical CYP2D inhibitors and antidepressants on dopamine formation from p-tyramine, catalyzed by CYP2D6.2 (Arg296Cys, Ser486Thr) and CYP2D6.10 (Pro34Ser, Ser486Thr) as well as rat CYP2D4 were compared with the effects of those catalyzed by CYP2D6.1 (wild type), to investigate the effect of a CYP2D6 polymorphism on the neuroactive amine metabolism in the brain.

[Methods] CYP2D6.1, CYP2D6.2, CYP2D6.10, and CYP2D4 expressed in recombinant Escherichia coli (Bactosomes) were obtained from Cypex Ltd. Dopamine formation from p-tyramine in the absence or presence of six steroid hormones (cortisol, cortisone, corticosterone, dehydroepiandrosterone, and pregnenolone), typical CYP2D inhibitors (quinidine and quinine), and antidepressants (imipramine, desipramine, and fluvoxamine) was determined by HPLC.

[Results] CYP2D6.10 had a higher Michaelis constant (Km) than CYP2D6.1 and CYP2D6.2, Progesterone inhibited dopamine formation and inhibitory constant (Ki) against CYP2D6.10 was approximately twice that for CYP2D6.1 and CYP2D6.2, whereas no or minor inhibition was observed for other steroid hormones. 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. Against CYP2D4-mediated dopamine formation, quinine inhibited stronger than quinidine. Ki values of imipramine and desipramine against CYP2D6.10 were higher than that against CYP2D6.1, whereas the maximal velocity (Vmax) values for dopamine formation by all CYP2D6 variants gradually increased with increasing fluvoxamine concentrations, indicating that fluvoxamine stimulated dopamine formation.

[Conclusions] CYP2D6 polymorphism would affect drug interaction through dopamine formation in the brain.

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