Inhibitory and Stimulatory Effects of Selective Serotonin Reuptake Inhibitors on Cytochrome P450 2D6-mediated Dopamine Formation from p-Tyramine
DOI:
https://doi.org/10.18433/jpps30622Abstract
PURPOSE: The effects of selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine and paroxetine on dopamine formation from p-tyramine, mediated by cytochrome P450 (CYP) 2D6.2 (Arg296Cys, Ser486Thr) and CYP2D6.10 (Pro34Ser, Ser486Thr), were compared with their effects on CYP2D6.1 (wild type)-mediated dopamine formation, to investigate the influence of a CYP2D6 polymorphism on neuroactive amine metabolism in the brain. METHODS: The Michaelis constants (Km) and maximal velocity (Vmax) values of dopamine formation mediated by CYP2D6.1, CYP2D6.2, and CYP2D6.10 (expressed in recombinant Escherichia coli), and inhibition constants (Ki) of the SSRIs toward dopamine formation catalyzed by the CYP2D6 variants were estimated. RESULTS: The Km values for CYP2D6.2 and CYP2D6.10 decreased at lower fluoxetine concentrations, while the Vmax values for all CYP2D6 variants increased, indicating that fluoxetine stimulated dopamine formation. Conversely, paroxetine competitively inhibited dopamine formation mediated by CYP2D6.1, CYP2D6.2, and CYP2D6.10 with Ki values of 0.47, 1.33, and 31.3 µM, respectively. CONCLUSIONS: These results suggest that the inhibition/stimulation of CYP2D6
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References
Rendic S. Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev, 2002;34:83–448.
Niwa T, Murayama N, Imagawa Y, Yamazaki H. Regioselective hydroxylation of steroid hormones by human cytochromes P450. Drug Metab Rev, 2015;47:89–110. DOI: 10.3109/03602532.2015.1011658.
Shimada T, Yamazaki H, Mimura M, Inui Y, Guengerich FP. Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians. J Pharmacol Exp Ther, 1994;270:414–423.
Imaoka S, Yamada T, Hiroi T, Hayashi K, Sakaki T, Yabusaki Y, Funae Y. Multiple forms of human P450 expressed in Saccharomyces cerevisiae. Systematic characterization and comparison with those of the rat. Biochem Pharmacol, 1996;51:1041–1050.
Funae Y, Kishimoto W, Cho T, Niwa T, Hiroi T. CYP2D in the brain. Drug Metab Pharmacokinet, 2003;18:337–349.
Williams JA, Hyland R, Jones BC, Smith DA, Hurst S, Goosen TC, Peterkin V, Koup JR, Ball SE. Drug-drug interactions for UDP-glucuronosyltransferase substrates: a pharmacokinetic explanation for typically observed low exposure (AUCi/AUC) ratios. Drug Metab Dispos, 2004;32:1201–1208.
McFayden MC, Melvin WT, Murray GI. Regional distribution of individual forms of cytochrome P450 mRNA in normal adult human brain. Biochem Pharmacol, 1998;55:825–830.
The Human Cytochrome P450 (CYP) Allele Nomenclature Committee. The Human Cytochrome P450 (CYP) Allele Nomenclature Database. 2017. Available at: https://www.pharmvar.org/gene/CYP2D6. Accessed July 7, 2019.
Niwa T, Murayama N, Yamazaki H. Comparison of cytochrome P450 2D6 and variants in terms of drug oxidation rates and substrate inhibition. Curr Drug Metab, 2011;12:412–435.
Bertilsson L, Alm C, De Las Carreras C, Widen J, Edman G, Schalling D. Debrisoquine hydroxylation polymorphism and personality. Lancet, 1989;1(8637):555.
Llerena A, Edman G, Cobaleda J, Benítez J, Schalling D, Bertilsson L. Relationship between personality and debrisoquine hydroxylation capacity. Suggestion of an endogenous neuroactive substrate or product of the cytochrome P4502D6. Acta Psychiatr Scand, 1993;87:23–28.
Yu A, Kneller BM, Rettie AE, Haining RL. Expression, purification, biochemical characterization, and comparative function of human cytochrome P450 2D6.1, 2D6.2, 2D6.10, and 2D6.17 allelic isoforms. J Pharmacol Exp Ther, 2002;303:1291–1300.
Kubota T, Yamaura Y, Ohkawa N, Hara H, Chiba K. Frequencies of CYP2D6 mutant alleles in a normal Japanese population and metabolic activity of dextromethorphan O-demethylation in different CYP2D6 genotypes. Br J Clin Pharmacol, 2000;50:31–34.
Nishida Y, Fukuda T, Yamamoto I, Azuma J. CYP2D6 genotypes in a Japanese population: low frequencies of CYP2D6 gene duplication but high frequency of CYP2D6*10. Pharmacogenetics, 2000;10:567–570.
Johansson I, Oscarson M, Yue QY, Bertilsson L, Sjöqvist F, Ingelman-Sundberg M. Genetic analysis of the Chinese cytochrome P4502D locus: characterization of variant CYP2D6 genes present in subjects with diminished capacity for debrisoquine hydroxylation. Mol Pharmacol, 1994;46:452–459.
Daly AK, Brockmöller J, Broly F, Eichelbaum M, Evans WE, Gonzalez FJ, Huang JD, Idle JR, Ingelman-Sundberg M, Ishizaki T, Jacqz-Aigrain E, Meyer UA, Nebert DW, Steen VM, Wolf CR, Zanger UM. Nomenclature for human CYP2D6 alleles. Pharmacogenetics, 1996;6:193–201.
Marez D, Legrand M, Sabbagh N, Lo Guidice JM, Spire C, Lafitte JJ, Meyer UA, Broly F. Polymorphism of the cytochrome P450 CYP2D6 gene in a European population: characterization of 48 mutations and 53 alleles, their frequencies and evolution. Pharmacogenetics, 1997;7:193–202.
Philips SR, Rozdilsky B, Boulton AA. Evidence for the presence of m-tyramine, p-tyramine, tryptamine, and phenylethylamine in the rat brain and several areas of the human brain. Biol Psychiatry, 1978;13:51–57.
Hiroi T, Imaoka S, Funae Y. Dopamine formation from tyramine by CYP2D6. Biochem Biophys Res Commun, 1998;249:838–843.
Haduch A, Bromek E, Daniel WA. Role of brain cytochrome P450 (CYP2D) in the metabolism of monoaminergic neurotransmitters. Pharmacol Rep, 2013;65:1519–1528.
Niwa T, Shizuku M, Yamano K. Effect of genetic polymorphism on the inhibition of dopamine formation from p-tyramine catalyzed by brain cytochrome P450 2D6. Arch Biochem Biophys, 2017;620:23–27. DOI: 10.1016/j.abb.2017.03.009.
Pacher P, Kecskemeti V. Cardiovascular side effects of new antidepressants and antipsychotics: new drugs, old concerns? Curr Pharm Des, 2004;10:2463–2475.
Deligiannidis KM, Byatt N, Freeman MP. Pharmacotherapy for mood disorders in pregnancy: a review of pharmacokinetic changes and clinical recommendations for therapeutic drug monitoring. J Clin Psychopharmacol, 2014;34:244–255. DOI: 10.1097/JCP.0000000000000087.
Imidol interview form. Mitsubishi Tanabe Pharma. 2018, Available at: http://www.info.pmda.go.jp/go/pack/1174006F1027_4_19/?view=frame&style=SGML&lang=ja. Accessed July 7. 2019.
Niwa T, Yanai M, Matsumoto M, Shizuku M. Effect of cytochrome P450 (CYP) 2D6 genetic polymorphism on the inhibitory action of antidepressants on CYP2D6-mediated dopamine formation from p-tyramine. J Pharm Pharm Sci, 2018;21:135-142. DOI: 10.18433/jpps29673.
Jakubovski E, Varigonda AL, Freemantle N, Taylor MJ, Bloch MH. Systematic review and meta-analysis: dose-response relationship of selective serotonin reuptake inhibitors in major depressive disorder. Am J Psychiatry, 2016;173:174–183. DOI: 10.1176/appi.ajp.2015.15030331.
Omori IM, Watanabe N, Nakagawa A, Cipriani A, Barbui C, McGuire H, Churchill R, Furukawa TA. Fluvoxamine versus other anti-depressive agents for depression. Cochrane Database Syst Rev, 2010;3 CD006114. DOI: 10.1002/14651858.CD006114.pub2.
Luvox interview form. AbbVie Inc. 2019. Available at: http://www.info.pmda.go.jp/go/pack/1179039F1036_3_10/?view=frame&style=SGML&lang=ja. Accessed July 7, 2019.
Figgitt DP, McClellan KJ. Fluvoxamine. An updated review of its use in the management of adults with anxiety disorders. Drugs, 2000;60:925–954.
Sharma T, Guski LS, Freund N, Gøtzsche PC. Suicidality and aggression during antidepressant treatment: systematic review and meta-analyses based on clinical study reports. BMJ, 2016;352:i65. DOI: 10.1136/bmj.i65.
Niwa T, Hiroi T, Tsuzuki D, Yamamoto S, Narimatsu S, Fukuda T, Azuma J, Funae Y. Effect of genetic polymorphism on the metabolism of endogenous neuroactive substances, progesterone and p-tyramine, catalyzed by CYP2D6. Mol Brain Res, 2004;129:117–123.
Yamaoka K, Tanigawara Y, Nakagawa T, Uno T. A pharmacokinetic analysis program (multi) for microcomputer. J Pharmacobiodyn, 1981;4:879–885.
U.S. Food and Drug Administration, Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. 2017. Available at: http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm#4. Accessed July 7, 2019.
European Medicines Agency, Guideline on the investigation of drug interactions. CPMP/EWP/560/95/Rev. 1 Corr. 2**. 2012. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/07/WC500129606.pdf#search='European+Medicines+Agency%2C+drug+interaction. Accessed July 7, 2019.
Pharmaceuticals and Medical Devices Agency, Methods of drug interaction studies (PMSB/ELD Notification No. 813; June 4, 2001). 2001. Available at: http://www.nihs.go.jp/phar/pdf/DiGlEngFinal011209.pdf. Accessed July 7, 2019.
Hiroi T, Imaoka S, Chow T, Funae Y. Tissue distributions of CYP2D1, 2D2, 2D3 and 2D4 mRNA in rats detected by RT-PCR. Biochim Biophys Acta, 1998;1380:305–312.
Kishimoto W, Hiroi T, Shiraishi M, Osada M, Imaoka S, Kominami S, Igarashi T, Funae Y. Cytochrome P450 2D catalyze steroid 21-hydroxylation in the brain. Endocrinology, 2004;145:699–705.
Komori M. A novel P450 expressed at the high level in rat brain, Biochem Biophys Res Commun, 1993;196:721–728.
Venhorst J, ter Laak AM, Commandeur JN, Funae Y, Hiroi T, Vermeulen NP. Homology modeling of rat and human cytochrome P450 2D (CYP2D) isoforms and computational rationalization of experimental ligand-binding specificities. J Med Chem, 2003;46:74–86.
Niwa T, Okada K, Hiroi T, Imaoka S, Narimatsu S, Funae Y. Effect of psychotropic drugs on the 21-hydroxylation of neurosteroids, progesterone and allopregnanolone, catalyzed by rat CYP2D4 and human CYP2D6 in the brain. Biol Pharm Bull, 2008;31:348–351.
Niwa T, Shiraga T, Yamasaki S, Ishibashi K, Ohno Y, Kagayama A. In vitro activation of 7-benzyloxyresorufin O-debenzylation and nifedipine oxidation in human liver microsomes. Xenobiotica, 2003;33:717–729.
Niwa T, Murayama N, Yamazaki H. Heterotropic cooperativity in oxidation mediated by cytochrome P450. Curr Drug Metab, 2008;9:453–462.
Hiroi T, Kishimoto W, Chow T, Imaoka S, Igarashi T, Funae Y. Progesterone oxidation by cytochrome P450 2D isoforms in the brain. Endocrinology, 2001;142:3901–3908.
Niwa T, Yasumura M, Murayama N, Yamazaki H. Comparison of catalytic properties of cytochromes P450 3A4 and 3A5 by molecular docking simulation. Drug Metab Lett, 2014;8:43–50.
Ito K, Iwatsubo T, Kanamitsu S, Nakajima Y, Sugiyama Y. Quantitative prediction of in vivo drug clearance and drug interactions from in vitro data on metabolism, together with binding and transport. Annu Rev Pharmacol Toxicol, 1998;38:461–499.
Ito K, Iwatsubo T, Kanamitsu S, Ueda K, Suzuki H, Sugiyama Y. Prediction of pharmacokinetic alterations caused by drug-drug interactions: metabolic interaction in the liver. Pharmacol Rev, 1998;50:387–412.
Paxil package insert and interview form. GlaxoSmithKline, 2018. Available at: http://www.info.pmda.go.jp/go/pack/1179041G1020_1_11/?view=frame&style=SGML&lang=ja. Accessed July 7, 2019.
Crewe HK, Lennard MS, Tucker GT, Woods FR, Haddock RE. The effect of selective serotonin re-uptake inhibitors on cytochrome P4502D6 (CYP2D6) activity in human liver microsomes. Br J Clin Pharmacol, 1992;34:262–265.
Liu ZQ, Cheng ZN, Huang SL, Chen XP, Ou-Yang DS, Jiang CH, Zhou HH. Effect of the CYP2C19 oxidation polymorphism on fluoxetine metabolism in Chinese healthy subjects. Br J Clin Pharmacol, 2001;52:96–99.
Ozdemir V, Naranjo CA, Herrmann N, Reed K, Sellers EM, Kalow W. Paroxetine potentiates the central nervous system side effects of perphenazine: contribution of cytochrome P4502D6 inhibition in vivo. Clin Pharmacol Ther, 1997;62:334–347.
Albers LJ, Reist C, Helmeste D, Vu R, Tang SW. Paroxetine shifts imipramine metabolism. Psychiatry Res, 1996;59:189–196.
Hemeryck A, Lefebvre RA, De Vriendt C, Belpaire FM. Paroxetine affects metoprolol pharmacokinetics and pharmacodynamics in healthy volunteers. Clin Pharmacol Ther, 2000;67:283–291.
Ouellet D, Hsu A, Qian J, Lamm JE, Cavanaugh JH, Leonard JM, Granneman GR. Effect of fluoxetine on pharmacokinetics of ritonavir. Antimicrob Agents Chemother, 1998;42:3107–3112.
Cai WM, Chen B, Zhou Y, Zhang YD. Fluoxetine impairs the CYP2D6-mediated metabolism of propafenone enantiomers in healthy Chinese volunteers. Clin Pharmacol Ther, 1999;66:516–521.
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