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Theoretical study on the metabolic mechanisms of levmepromazine by cytochrome P450

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Abstract

Levomepromazine, an “older” typical neuroleptic, is widely applied in psychiatry for the treatment of schizophrenia. The biotransformation of Levomepromazine remains elusive up to now, but found to result in the formation of different derivatives that may contribute to the therapeutic and/or side-effects of the parent drug. The present work aims to resolve the metabolic details of Levomepromazine catalyzed by cytochrome P450, an important heme-containing enzyme superfamily, based on DFT calculation. Two main metabolic pathways have been addressed, S-oxidation and N-demethylation. The mechanistic conclusions have revealed a stepwise transfer of two electrons mechanism in S-oxidation reaction. N-demethylation is a two-step reaction, including the rate-determining N-methyl hydroxylation which proceeds via the single electron transfer (SET) mechanism and the subsequent C-N bond fission through a water-assisted enzymatic proton-transfer process. N-demethylation is more feasible than S-oxidation due to its lower activation energy and N-desmethyllevomepromazine therefore is the most plausible metabolite of Levomepromazine. Each metabolic pathway proceeds in a spin-selective manner (SSM) mechanism, predominately via the LS state of Cpd I. Our observations are in good accordance with the experimental results, which can provide some general implications for the metabolic mechanism of Levomepromazine-like drugs.

The metabolic mechanisms of levmepromazine by cytochrome P450

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References

  1. Sivaraman P, Mitra A, Jayaram MB (2012) Levomepromazine for schizophrenia. Cochrane Database Syst Rev 38:219–220

    Google Scholar 

  2. Gjerden P, Slørdal L, Bramness JG (2010) Prescription persistence and safety of antipsychotic medication: a national registry-based 3-year follow-up. Eur J Pharmacol 66:911–917

    Article  Google Scholar 

  3. Green B, Pettit T, Faith L, Seaton K (2004) Focus on levomepromazine. Curr Med Res Opin 20:1877–1881

    Article  CAS  Google Scholar 

  4. Dietz I, Schmitz A, Lampey I, Schulz C (2013) Evidence for the use of Levomepromazine for symptom control in the palliative care setting: a systematic review. BMC Palliat Care 1:1

    Google Scholar 

  5. Bylund DB (1981) Interactions of neuroleptic metabolites with dopaminergic, alpha adrenergic and muscarinic cholinergic receptors. J Pharmacol Exp Ther 217:81–86

    CAS  Google Scholar 

  6. Hals PA, Hall H, Dahl SG (1986) Phenothiazine drug metabolites: dopamine D2 receptor, α 1-and α 2-adrenoceptor binding. Eur J Pharmacol 125:373–381

    Article  CAS  Google Scholar 

  7. Lal S, Thavundayil JX, Nair NV, Annable L (2006) Levomepromazine versus chlorpromazine in treatment-resistant schizophrenia: a double-blind randomized trial. J Psychiatry Neurosci 31:271–279

    Google Scholar 

  8. Johnsen HELGE, Dahl SG (1982) Identification of O-demethylated and ring-hydroxylated metabolites of methotrimeprazine (levomepromazine) in man. Drug Metab Dispos 10:63–67

    CAS  Google Scholar 

  9. Hals PA, Dadl SG (1995) Metabolism of LM in man. Eur J Drug Metab Pharmacokinet 20:61–71

    Article  CAS  Google Scholar 

  10. Jorgensen A (1986) Metabolism and pharmacokinetics of antipsychotic drugs. Prog Drug Metab 9:111–174

    Google Scholar 

  11. Dahl SG, Hjorth M, Hough E (1982) Chlorpromazine, methotrimeprazine, and metabolites. Structural changes accompanying the loss of neuroleptic potency by ring sulfoxidation. Mol Pharmacol 21:409–414

    CAS  Google Scholar 

  12. Dahl SG, Hall H (1981) Binding affinity of levomepromazine and two of its major metabolites to central dopamine and α-adrenergic receptors in the rat. Psychopharmacology 74:101–104

    Article  CAS  Google Scholar 

  13. Wójcikowski J, Basińska A, Daniel WA (2014) The cytochrome P450-catalyzed metabolism of levomepromazine: a phenothiazine neuroleptic with a wide spectrum of clinical application. Biochem Pharmacol 90:188–195

    Article  CAS  Google Scholar 

  14. Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA et al. (2013) Gaussian 09, revision D. 01. Gaussian, Inc, Wallingford

    Google Scholar 

  15. Blomberg MRA, Borowski T, Himo F, Liao RZ, Siegbahn PE (2014) Quantum chemical studies of mechanisms for metalloenzymes. Chem Rev 114:3601–3658

    Article  CAS  Google Scholar 

  16. Shaik S, Cohen S, Wang Y, Chen H, Kumar D, Thiel W (2009) P450 enzymes: their structure, reactivity, and selectivity modeled by QM/MM calculations. Chem Rev 110:949–1017

    Article  CAS  Google Scholar 

  17. Yano JK, Wester MR, Schoch GA, Griffin KJ, Stout CD, Johnson EF (2004) The structure of human microsomal cytochrome P450 3A4 determined by X-ray crystallography to 2.05-A resolution. J Biol Chem 279:38091–38094

    Article  CAS  Google Scholar 

  18. Chen Z, Kang Y, Zhang C, Tao J, Xue Y (2015) Metabolic mechanisms of caffeine catalyzed by cytochrome P450 isoenzyme 1A2: a theoretical study. Theor Chem Accounts 134:1–14

    Article  CAS  Google Scholar 

  19. Tao J, Kang Y, Xue ZY, Wang YT, Zhang Y, Chen Q, Chen ZQ, Xue Y (2015) Theoretical study on the N-demethylation mechanism of theobromine catalyzed by P450 isoenzyme 1A2. J Mol Graph Model 61:123–132

    Article  CAS  Google Scholar 

  20. Kwiecień RA, Molinié R, Paneth P, Silvestre V, Lebreton J, Robins RJ (2011) Elucidation of the mechanism of N-demethylation catalyzed by cytochrome P450 monooxygenase is facilitated by exploiting nitrogen-15 heavy isotope effects. Arch Biochem Biophys 510:35–41

    Article  CAS  Google Scholar 

  21. Li D, Wang Y, Yang C, Han K (2009) Theoretical study of N-dealkylation of N-cyclopropyl-N -methylaniline catalyzed by cytochrome P450: insight into the origin of the regioselectivity. Dalton Trans 2:291–297

    Article  Google Scholar 

  22. Wang Y, Wang HM, Wang YH, Yang CL, Yang L, Han KL (2006) Theoretical study of the mechanism of acetaldehyde hydroxylation by compound I of CYP2E1. J Phys Chem B 110:6154–6159

    Article  CAS  Google Scholar 

  23. Kang Y, Tao J, Xue ZY, Zhang Y, Chen ZQ, Xue Y (2016) Quantum chemical exploration on the metabolic mechanisms of caffeine by flavin-containing monooxygenase. Tetrahedron 72:2858–2867

    Article  CAS  Google Scholar 

  24. Xue ZY, Zhang Y, Tao J, Kang Y, Chen ZQ, Xue Y (2016) Theoretical elucidation of the metabolic mechanisms of phenothiazine neuroleptic chlorpromazine catalyzed by cytochrome P450 isoenzyme 1A2. Theor Chem Accounts 135:218. doi:10.1007/s00214-016-1943-4

    Article  CAS  Google Scholar 

  25. Zhang Q, Bell R, Truong TN (1995) Ab initio and density functional theory studies of proton transfer reactions in multiple hydrogen bond systems. J Phys Chem 99:592–599

    Article  CAS  Google Scholar 

  26. Reed AE, Schleyer PVR (1990) Chemical bonding in hypervalent molecules. The dominance of ionic bonding and negative hyperconjugation over d-orbital participation. J Am Chem Soc 112:1434–1445

    Article  CAS  Google Scholar 

  27. Schröder D, Shaik S, Schwarz H (2000) Two-state reactivity as a new concept in organometallic chemistry. Acc Chem Res 33:139–145

    Article  CAS  Google Scholar 

  28. Baciocchi E, Bietti M, Gerini MF, Lanzalunga O (2005) Electron-transfer mechanism in the N-demethylation of N, N-dimethylanilines by the phthalimide-N-oxyl radical. J Org Chem 70:5144–5149

    Article  CAS  Google Scholar 

  29. Guengerich FP, Yun CH, Macdonald TL (1996) Evidence for a 1-electron oxidation mechanism in N-dealkylation of N, N-dialkylanilines by cytochrome p450 2b1 kinetic hydrogen isotope effects, linear free energy relationships, comparisons with horseradish peroxidase, and studies with oxygen surrogates. J Biol Chem 271:27321–27329

    Article  CAS  Google Scholar 

  30. Jurva U, Bissel P, Isin EM, Igarashi K, Kuttab S, Castagnoli N (2005) Model electrochemical-mass spectrometric studies of the cytochrome P450-catalyzed oxidations of cyclic tertiary allylamines. J Am Chem Soc 127:12368–12377

    Article  CAS  Google Scholar 

  31. Li C, Wu W, Kumar D, Shaik S (2006) Kinetic isotope effect is a sensitive probe of spin state reactivity in CH hydroxylation of N, N-dimethylaniline by cytochrome P450. J Am Chem Soc 128:394–395

    Article  CAS  Google Scholar 

  32. Chen H, de Groot MJ, Vermeulen NP, Hanzlik RP (1997) Oxidative N-dealkylation of p-cyclopropyl-N, N-dimethylaniline. A substituent effect on a radical-clock reaction rationalized by ab initio calculations on radical cation intermediates. J Org Chem Rev 62:8227–8230

    Article  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by grants from National Natural Science Foundation of China (Grant No. 21203153), Science & Technology Department of Sichuan Province (Grant No. 2011JY0136) and Department of Education of Sichuan Province (Grant No. 12ZA174) and China West Normal University (Grant No. 11B002).

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    Authors and Affiliations

    1. College of Chemistry and Chemical Engineering, Chemical Synthesis and Pollution Control Key Laboratory of Sichuan Province, China West Normal University, Nanchong, 637002, People’s Republic of China

      Yongting Wang, Qiu Chen, Zhiyu Xue, Yan Zhang & Zeqin Chen

    2. College of Chemistry, Key Laboratory of Green Chemistry and Technology in Ministry of Education, Sichuan University, Chengdu, 610064, People’s Republic of China

      Ying Xue

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    1. Yongting Wang
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    Correspondence to Zeqin Chen.

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    Yongting Wang and Qiu Chen contributed equally to this work.

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    Wang, Y., Chen, Q., Xue, Z. et al. Theoretical study on the metabolic mechanisms of levmepromazine by cytochrome P450. J Mol Model 22, 237 (2016). https://doi.org/10.1007/s00894-016-3107-9

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