Stimulatory and Inhibitory Effect of Antipsychotic Agents Including Dopaminergic Neuro-depressants on Dopamine Formation from p-tyramine Mediated by Cytochrome P450 2D6

Toshiro      Niwa; Yuka      Yamamoto

doi:10.2174/2949681016666230914115021

Abstract

Background and Objectives: The effects of antipsychotic agents, including dopamine D2 receptor blocking agents such as haloperidol, chlorpromazine, and sulpiride, and related compounds such as mirtazapine and sertraline, on dopamine formation from p-tyramine catalyzed by cytochrome P450 (CYP) 2D6.2 (Arg296Cys;Ser486Thr), CYP2D6.10 (Pro34Ser;Ser486Thr), and CYP2D6.39 (Ser486Thr) were compared with those of CYP2D6.1.

Methods: Dopamine was determined by high-performance liquid chromatography, and Michaelis constants (K_m), maximal velocity (k_cat) values for dopamine formation, and inhibition constants (Ki) of psychotropic agents were estimated.

Results: K_m values for all CYP2D6 variants decreased at lower concentrations, and kcat values for CYP2D6 variants except for CYP2D6.10 gradually increased with increasing haloperidol concentrations up to 5 or 10 μM. The k_cat/K_m values for all CYP2D6 variants increased at under 2.5 μM concentrations. Lower sertraline concentrations decreased K_m values for CYP2D6.10. Chlorpromazine at concentrations under 10 μM competitively inhibited the activities catalyzed by all variants; however, the activities for only CYP2D6.10 were increased by chlorpromazine at concentrations over 250 μM. Mirtazapine and sertraline similarly decreased dopamine formation among all variants except for CYP2D6.10. However, CYP2D6.10 inhibition by mirtazapine was weaker than that of the other variants, and sertraline decreased K_m values for CYP2D6.10.

Conclusion: Haloperidol and sertraline, but not sulpiride, decreased the Km and/or increased kcat values for CYP2D6. The present findings suggest that Dopamine D₂ receptor-blocking agents and related compounds may polymorphically affect dopamine formation catalyzed by CYP2D6 in the brain.

Keywords: CYP2D6, dopamine formation, genetic polymorphism, dopaminergic neuro-depressant, haloperidol, sertraline, sulpiride.

[1]
Rendic, S. Summary of information on human CYP enzymes: Human P450 metabolism data. Drug Metab. Rev.,  2002, 34(1-2), 83-448.
 [http://dx.doi.org/10.1081/DMR-120001392] [PMID: 11996015]

[2]
McFadyen, M.C.E.; Melvin, W.T.; Murray, G.I. Regional distribution of individual forms of cytochrome P450 mRNA in normal adult human brain. Biochem. Pharmacol.,  1998, 55(6), 825-830.
 [http://dx.doi.org/10.1016/S0006-2952(97)00516-9] [PMID: 9586955]

[3]
The Pharmacogene Variation (PharmVar) Consortium. The Human Cytochrome P450 (CYP) Allele Nomenclature Database. 2023. Available from: https://www.pharmvar.org/gene/CYP2D6

[4]
Bertilsson, L.; Alm, C.; Carreras, C.L.; Widen, J.; Edman, G.; Schalling, D. Debrisoquine hydroxylation polymorphism and personality. Lancet,  1989, 333(8637), 555.
 [http://dx.doi.org/10.1016/S0140-6736(89)90094-9] [PMID: 2564084]

[5]
Dorado, P. Pe as-LLed, E.M.; LLerena, A. CYP2D6 polymorphism: Implications for antipsychotic drug response, schizophrenia and personality traits. Pharmacogenomics,  2007, 8(11), 1597-1608.
 [http://dx.doi.org/10.2217/14622416.8.11.1597] [PMID: 18034624]

[6]
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. Pharmacogenomics,  2009, 10, 1111-1120.
 [http://dx.doi.org/10.2217/pgs.09.75]

[7]
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(6), 567-570.
 [http://dx.doi.org/10.1097/00008571-200008000-00010] [PMID: 10975611]

[8]
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(1), 31-34.
 [http://dx.doi.org/10.1046/j.1365-2125.2000.00209.x] [PMID: 10886115]

[9]
Yu, A.; Kneller, B.M.; Rettie, A.E.; Haining, R.L. 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(3), 1291-1300.
 [http://dx.doi.org/10.1124/jpet.102.039891] [PMID: 12438554]

[10]
Marez, D.; Legrand, M.; Sabbagh, N.; Lo Guidice, J.M.; Spire, C.; Lafitte, J.J.; Meyer, U.A.; 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(3), 193-202.
 [http://dx.doi.org/10.1097/00008571-199706000-00004]

[11]
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(5), 412-435.
 [http://dx.doi.org/10.2174/138920011795495286] [PMID: 21453270]

[12]
Philips, S.R.; Rozdilsky, B.; Boulton, A.A. 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(1), 51-57.
 [PMID: 623853]

[13]
Belujon, P.; Grace, A.A. Dopamine system dysregulation in major depressive disorders. Int. J. Neuropsychopharmacol.,  2017, 20(12), 1036-1046.
 [http://dx.doi.org/10.1093/ijnp/pyx056] [PMID: 29106542]

[14]
Funae, Y.; Kishimoto, W.; Cho, T.; Niwa, T.; Hiroi, T. CYP2D in the brain. Drug Metab. Pharmacokinet.,  2003, 18(6), 337-349.
 [http://dx.doi.org/10.2133/dmpk.18.337] [PMID: 15618754]

[15]
Hiroi, T.; Imaoka, S.; Funae, Y. Dopamine formation from tyramine by CYP2D6. Biochem. Biophys. Res. Commun.,  1998, 249(3), 838-843.
 [http://dx.doi.org/10.1006/bbrc.1998.9232] [PMID: 9731223]

[16]
Haduch, A.; Bromek, E.; Daniel, W.A. Role of brain cytochrome P450 (CYP2D) in the metabolism of monoaminergic neurotransmitters. Pharmacol. Rep.,  2013, 65(6), 1519-1528.
 [http://dx.doi.org/10.1016/S1734-1140(13)71513-5] [PMID: 24553000]

[17]
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.
 [http://dx.doi.org/10.1016/j.abb.2017.03.009] [PMID: 28347660]

[18]
Niwa, T.; Sugimoto, S. Inhibitory and stimulatory effects of selective serotonin reuptake inhibitors on cytochrome P450 2D6-mediated dopamine formation from p-tyramine. J. Pharm. Pharm. Sci.,  2019, 22(1), 585-592.
 [http://dx.doi.org/10.18433/jpps30622] [PMID: 31804922]

[19]
Niwa, T.; Arima, J.; Michihiro, Y. Role of amino acids at positions 34, 296, and 486 of cytochrome P450 2D6 in the stimulatory and inhibitory effects of psychotropic agents on dopamine formation from p -tyramine. Xenobiotica,  2021, 51(11), 1229-1235.
 [http://dx.doi.org/10.1080/00498254.2021.1989520] [PMID: 34605737]

[20]
Seeman, P. Atypical antipsychotics: Mechanism of action. Can. J. Psychiatry,  2002, 47(1), 27-38.
 [http://dx.doi.org/10.1177/070674370204700106] [PMID: 11873706]

[21]
Yamaoka, K.; Tanigawara, Y.; Nakagawa, T.; Uno, T. A pharmacokinetic analysis program (multi) for microcomputer. J. Pharmacobiodyn.,  1981, 4(11), 879-885.
 [http://dx.doi.org/10.1248/bpb1978.4.879] [PMID: 7328489]

[22]
Contomin sugar-coated tablets, Interview form, Mitsubishi Tanabe Pharma. 2021. Available from: https://www.pmda.go.jp/files/000223548.pdf

[23]
Bressolle, F.; Brès, J.; Fauré-Jeantis, A. Absolute bioavailability, rate of absorption, and dose proportionality of sulpiride in humans. J. Pharm. Sci.,  1992, 81(1), 26-32.
 [http://dx.doi.org/10.1002/jps.2600810106] [PMID: 1619566]

[24]
Niwa, T.; Inoue, S.; Shiraga, T.; Takagi, A. No inhibition of cytochrome P450 activities in human liver microsomes by sulpiride, an antipsychotic drug. Biol. Pharm. Bull.,  2005, 28(1), 188-191.
 [http://dx.doi.org/10.1248/bpb.28.188] [PMID: 15635191]

[25]
Niwa, T.; Murayama, N.; Yamazaki, H. Heterotropic cooperativity in oxidation mediated by cytochrome p450. Curr. Drug Metab.,  2008, 9(5), 453-462.
 [http://dx.doi.org/10.2174/138920008784746364] [PMID: 18537580]

[26]
Hackett, J.C. Membrane-embedded substrate recognition by cytochrome P450 3A4. J. Biol. Chem.,  2018, 293(11), 4037-4046.
 [http://dx.doi.org/10.1074/jbc.RA117.000961] [PMID: 29382727]

[27]
Niwa, T.; Sasaki, S.; Yamamoto, Y.; Tanaka, M. Effect of human cytochrome P450 2D6 polymorphism on progesterone hydroxylation. Eur. J. Drug Metab. Pharmacokinet.,  2022, 47(5), 741-747.
 [http://dx.doi.org/10.1007/s13318-022-00784-7] [PMID: 35838883]

[28]
Niwa, T.; Narita, K.; Okamoto, A.; Murayama, N.; Yamazaki, H. Comparison of steroid hormone hydroxylations by and docking to human cytochromes P450 3A4 and 3A5. J. Pharm. Pharm. Sci.,  2019, 22(1), 332-339.
 [http://dx.doi.org/10.18433/jpps30558] [PMID: 31339834]

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DOI https://dx.doi.org/10.2174/2949681016666230914115021	Print ISSN 2949-6810
Publisher Name Bentham Science Publisher	Online ISSN 2949-6829

Drug Metabolism and Bioanalysis Letters

Stimulatory and Inhibitory Effect of Antipsychotic Agents Including Dopaminergic Neuro-depressants on Dopamine Formation from p-tyramine Mediated by Cytochrome P450 2D6

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