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Theoretical study on the mechanism of N- and α-carbon oxidation of lapatinib catalyzed by cytochrome P450 monooxygenase

  • Hong Huang
  • Xue Bai
  • Lijun YangEmail author
Original Paper
  • 53 Downloads

Abstract

Lapatinib, an orally active dual tyrosine kinase inhibitor, is efficacious in combination therapy with capecitabine for advanced metastatic breast cancer. Despite its importance, it has been associated with hepatotoxicity observed in clinical trials and postmarketing surveillance. The mechanisms of hepatotoxicity at the chemical and cellular levels may link to drug metabolism. In this study, the N- and α-carbon oxidation processes of lapatinib catalyzed by CYP3A4 were explored by density functional theory method. The calculation results show that oxidation of C6 is the primary metabolic process and carboxylic acid is the main metabolic product. Both hydroxylation of C8 and subsequent formation of primary amines are feasible. However, it is not easy for the primary amines to form active metabolites nitroso, which indicates that there are other paths for the production of nitroso. Carboxylic acid is not the main metabolite of N7 oxidation because of higher hydrolysis energy barrier of intermediate nitrone. It is worthy to study subsequent N-hydroxylation and its downstream reaction, which may be the main pathway for the formation of nitroso. These results lay the foundation for drug design and optimization.

Keywords

Density functional theory Lapatinib N- and α-carbon oxidation Active metabolite 

Notes

Acknowledgments

The authors also acknowledge the State Key Laboratory of Biotherapy and Cancer Center (Sichuan University) for the use of computing facilities.

Funding information

This work is based on research supported by the Meritocracy Research Funds of China West Normal University (17YC037).

Supplementary material

894_2019_4125_MOESM1_ESM.pdf (1.4 mb)
ESM 1 (PDF 1409 kb)

References

  1. 1.
    Xia W, Mullin RJ, Keith BR, Liu L, Ma H, Rusnak DW, Owens G, Alligood KJ, Spector NL (2002) Anti-tumor activity of GW572016: a dual tyrosine kinase inhibitor blocks EGF activation of EGFR/ErbB2 and downstream Erk1/2 and AKT pathways. Oncogene 21(41):6255–6263.  https://doi.org/10.1038/sj.onc.1205794 CrossRefPubMedGoogle Scholar
  2. 2.
    Gomez HL, Doval DC, Chavez MA, Ang PC-S, Aziz Z, Nag S, Ng C, Franco SX, Chow LWC, Arbushites MC, Casey MA, Berger MS, Stein SH, Sledge GW (2008) Efficacy and safety of lapatinib as first-line therapy for ErbB2-amplified locally advanced or metastatic breast cancer. J. Clin. Oncol. 26(18):2999–3005.  https://doi.org/10.1200/JCO.2007.14.0590 CrossRefPubMedGoogle Scholar
  3. 3.
    Cristofanilli M, Johnston SRD, Manikhas A, Gomez HL, Gladkov O, Shao Z, Safina S, Blackwell KL, Alvarez RH, Rubin SD, Ranganathan S, Redhu S, Trudeau ME (2013) A randomized phase II study of lapatinib+pazopanib versus lapatinib in patients with HER2+inflammatory breast cancer. Breast Cancer Res. Treat. 137(2):471–482.  https://doi.org/10.1007/s10549-012-2369-x CrossRefPubMedGoogle Scholar
  4. 4.
    Zhang J, Salminen A, Yang X, Luo Y, Wu Q, White M, Greenhaw J, Ren L, Bryant M, Salminen W, Papoian T, Mattes W, Shi Q (2017) Effects of 31 FDA approved small-molecule kinase inhibitors on isolated rat liver mitochondria. Arch. Toxicol. 91(8):2921–2938.  https://doi.org/10.1007/s00204-016-1918-1 CrossRefPubMedGoogle Scholar
  5. 5.
    Uetrecht J, Naisbitt DJ (2013) Idiosyncratic adverse drug reactions: current concepts. Pharmacol. Rev. 65(2):779–808.  https://doi.org/10.1124/pr.113.007450 CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Eno MR, El-Gendy BE-DM, Cameron MD (2016) P450 3A-catalyzed O-dealkylation of lapatinib induces mitochondrial stress and activates Nrf2. Chem. Res. Toxicol. 29(5):784–796.  https://doi.org/10.1021/acs.chemrestox.5b00524 CrossRefPubMedGoogle Scholar
  7. 7.
    Barbara JE, Kazmi F, Parkinson A, Buckley DB (2013) Metabolism-dependent inhibition of CYP3A4 by lapatinib: evidence for formation of a metabolic intermediate complex with a ntroso/oxime metabolite formed via a nitrone intermediate. Drug Metab. Dispos. 41(5):1012–1022.  https://doi.org/10.1124/dmd.113.051151 CrossRefPubMedGoogle Scholar
  8. 8.
    Castellino S, Michael OM, Kevin K, BD J, BG D, Christopher M (2012) Human metabolism of lapatinib, a dual kinase inhibitor: implications for hepatotoxicity. Drug Metab. Dispos. 40(1):139–150.  https://doi.org/10.1124/dmd.111.040949 CrossRefPubMedGoogle Scholar
  9. 9.
    Teng WC, Jing WO, New LS, Wahlin MD, Nelson SD, Ho HK, Chan ECY (2010) Mechanism-based inactivation of cytochrome P450 3A4 by lapatinib. Mol. Pharmacol. 78(4):693–703.  https://doi.org/10.1124/mol.110.065839 CrossRefPubMedGoogle Scholar
  10. 10.
    Takakusa H, Wahlin MD, Zhao C, Hanson KL, New LS, Chan ECY, Nelson SD (2011) Metabolic-intermediate complex formation of human cytochrome P450 3A4 by lapatinib. Drug Metab. Dispos. 39(6):1022–1030.  https://doi.org/10.1124/dmd.110.037531 CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Polli JW, Humphreys JE, Harmon KA, Castellino S, O’Mara MJ, Olson KL, John-Williams LS, Koch KM, Serabjit-Singh CJ (2008) The role of efflux and uptake transporters in N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methylsulfonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine (GW572016, lapatinib) disposition and drug interactions. Drug Metab. Dispos. 36(4):695–701.  https://doi.org/10.1124/dmd.107.018374 CrossRefPubMedGoogle Scholar
  12. 12.
    Ling TY, Kiat HH, Alexandre C (2015) Metabolism-related pharmacokinetic drug−drug interactions with tyrosine kinase inhibitors: current understanding, challenges and recommendations. Br. J. Clin. Pharmacol. 79(2):241–253.  https://doi.org/10.1111/bcp.12496 CrossRefGoogle Scholar
  13. 13.
    Chan ECY, New LS, Chua TB, Yap CW, Ho HK, Nelson SD (2012) Interaction of lapatinib with cytochrome P450 3A5. Drug Metab. Dispos. 40(7):1414–1422.  https://doi.org/10.1124/dmd.112.044958 CrossRefPubMedGoogle Scholar
  14. 14.
    Hardy KD, Wahlin MD, Papageorgiou I, Unadkat J, Rettie AE, Nelson SD (2013) Studies on the role of metabolic activation in tyrosine kinase inhibitor (TKI)-dependent hepatotoxicity: induction of CYP3A4 enhances the cytotoxicity of lapatinib in hepaRG cells. Drug Metab. Dispos. 42(1):162–171.  https://doi.org/10.1124/dmd.113.054817 CrossRefPubMedGoogle Scholar
  15. 15.
    Guengerich FP, Yun C-H, 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(44):27321–27329.  https://doi.org/10.1074/jbc.271.44.27321 CrossRefPubMedGoogle Scholar
  16. 16.
    Macdonald TL, Zirvi K, Burka LT, Peyman P, Guengerich FP (1982) Mechanism of cytochrome P-450 inhibition by cyclopropylamines. J. Am. Chem. Soc. 104(7):2050–2052.  https://doi.org/10.1021/ja00371a056 CrossRefGoogle Scholar
  17. 17.
    Guengerich FP, Willard RJ, Shea JP, Richards LE, Macdonald TL (1984) Mechanism-based inactivation of cytochrome P-450 by heteroatom-substituted cyclopropanes and formation of ring-opened products. J. Am. Chem. Soc. 106(21):6446–6447.  https://doi.org/10.1021/ja00333a071 CrossRefGoogle Scholar
  18. 18.
    Dinnocenzo JP, Karki SB, Jones JP (1993) On isotope effects for the cytochrome P-450 oxidation of substituted N,N-dimethylanilines. J. Am. Chem. Soc. 115(16):7111–7116.  https://doi.org/10.1021/ja00069a007 CrossRefGoogle Scholar
  19. 19.
    Okazaki O, Guengerich FP (1993) Evidence for specific base catalysis in N-dealkylation reactions catalyzed by cytochrome P450 and chloroperoxidase. J. Biol. Chem. 268(3):1546–1552PubMedGoogle Scholar
  20. 20.
    de Montellano PRO (1995) Oxygen activation and reactivity. In. Boston, MA.  https://doi.org/10.1007/978-1-4757-2391-5_8 CrossRefGoogle Scholar
  21. 21.
    Guengerich FP, Okazaki O, Seto Y, Macdonald TL (1995) Radical cation intermediates in N-dealkylation reactions. Xenobiotica 25(7):689–709.  https://doi.org/10.3109/00498259509061886 CrossRefPubMedGoogle Scholar
  22. 22.
    Meunier B, de Visser SP, Shaik S (2004) Mechanism of oxidation reactions catalyzed by cytochrome P450 enzymes. Chem. Rev. 104(9):3947–3980.  https://doi.org/10.1021/cr020443g CrossRefPubMedGoogle Scholar
  23. 23.
    Guengerich FP (2001) Common and uncommon cytochrome P450 reactions related to metabolism and chemical toxicity. Chem. Res. Toxicol. 14(6):611–650.  https://doi.org/10.1021/tx0002583 CrossRefPubMedGoogle Scholar
  24. 24.
    Wang Y, Kumar D, Yang C, Han K, Shaik S (2007) Theoretical study of N-demethylation of substituted N,N-dimethylanilines by cytochrome P450: the mechanistic significance of kinetic isotope effect profiles. J. Phys. Chem. B 111(26):7700–7710.  https://doi.org/10.1021/jp072347v CrossRefPubMedGoogle Scholar
  25. 25.
    Karki SB, Dinnocenzo JP, Jones JP, Korzekwa KR (1995) Mechanism of oxidative amine dealkylation of substituted N,N-dimethylanilines by cytochrome P-450: application of isotope effect profiles. J. Am. Chem. Soc. 117(13):3657–3664.  https://doi.org/10.1021/ja00118a001 CrossRefGoogle Scholar
  26. 26.
    Seger ST, Rydberg P, Olsen L (2015) Mechanism of the N-hydroxylation of primary and secondary amines by cytochrome P450. Chem. Res. Toxicol. 28(4):597–603.  https://doi.org/10.1021/tx500371a CrossRefPubMedGoogle Scholar
  27. 27.
    Li C, Wu W, Cho KB, Shaik S (2009) Oxidation of tertiary amines by cytochrome P450—kinetic isotope effect as a spin-state reactivity probe. Chemistry – A European Journal 15(34):8492–8503.  https://doi.org/10.1002/chem.200802215 CrossRefGoogle Scholar
  28. 28.
    Shaik S, de Visser SP, Ogliaro F, Schwarz H, Schröder D (2002) Two-state reactivity mechanisms of hydroxylation and epoxidation by cytochrome P-450 revealed by theory. Curr. Opin. Chem. Biol. 6(5):556–567.  https://doi.org/10.1016/S1367-5931(02)00363-0 CrossRefPubMedGoogle Scholar
  29. 29.
    Shaik S, Cohen S, de Visser SP, Sharma PK, Kumar D, Kozuch S, Ogliaro F, Danovich D (2004) The “rebound controversy”: an overview and theoretical modeling of the rebound step in C−H hydroxylation by cytochrome P450. Eur. J. Inorg. Chem. 2004(2):207–226.  https://doi.org/10.1002/ejic.200300448 CrossRefGoogle Scholar
  30. 30.
    Shaik S, Kumar D, de Visser SP, Altun A, Thiel W (2005) Theoretical perspective on the structure and mechanism of cytochrome P450 enzymes. Chem. Rev. 105(6):2279–2328.  https://doi.org/10.1021/cr030722j CrossRefPubMedGoogle Scholar
  31. 31.
    de Visser SP, Ogliaro F, Sharma PK, Shaik S (2002) What factors affect the regioselectivity of oxidation by cytochrome P450? A DFT study of allylic hydroxylation and double bond epoxidation in a model reaction. J. Am. Chem. Soc. 124(39):11809–11826.  https://doi.org/10.1021/ja026872d CrossRefPubMedGoogle Scholar
  32. 32.
    Li C, Wu W, Kumar D, Shaik S (2006) Kinetic isotope effect is a sensitive probe of spin state reactivity in C−H hydroxylation of N,N-dimethylaniline by cytochrome P450. J. Am. Chem. Soc. 128(2):394–395.  https://doi.org/10.1021/ja055987p CrossRefPubMedGoogle Scholar
  33. 33.
    Rydberg P, Ryde U, Olsen L (2008) Sulfoxide, sulfur, and nitrogen oxidation and dealkylation by cytochrome P450. J. Chem. Theory Comput. 4(8):1369–1377.  https://doi.org/10.1021/ct800101v CrossRefPubMedGoogle Scholar
  34. 34.
    Cho K-B, Moreau Y, Kumar D, Rock DA, Jones JP, Shaik S (2007) Formation of the active species of cytochrome P450 by using iodosylbenzene: a case for spin-selective reactivity. Chem. Eur. J. 13(14):4103–4115.  https://doi.org/10.1002/chem.200601704 CrossRefPubMedGoogle Scholar
  35. 35.
    Taxak N, Desai PV, Patel B, Mohutsky M, Klimkowski VJ, Gombar V, Bharatam PV (2012) Metabolic-intermediate complex formation with cytochrome P450: theoretical studies in elucidating the reaction pathway for the generation of reactive nitroso intermediate. J. Comput. Chem. 33(21):1740–1747.  https://doi.org/10.1002/jcc.23008 CrossRefPubMedGoogle Scholar
  36. 36.
    Hirao H, Chuanprasit P, Cheong YY, Wang X (2013) How is a metabolic intermediate formed in the mechanism-based inactivation of cytochrome P450 by using 1,1-dimethylhydrazine: hydrogen abstraction or nitrogen oxidation? Chem. Eur. J. 19(23):7361–7369.  https://doi.org/10.1002/chem.201300689 CrossRefPubMedGoogle Scholar
  37. 37.
    Taxak N, Bharatam PV (2014) Drug metabolism. Resonance 19(3):259–282.  https://doi.org/10.1007/s12045-014-0031-0 CrossRefGoogle Scholar
  38. 38.
    Olsen L, Rydberg P, Rod TH, Ryde U (2006) Prediction of activation energies for hydrogen abstraction by cytochrome P450. J. Med. Chem. 49(22):6489–6499.  https://doi.org/10.1021/jm060551l CrossRefPubMedGoogle Scholar
  39. 39.
    Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Scalmani G, Barone V, Petersson GA, Nakatsuji H, Li X, Caricato M, Marenich AV, Bloino J, Janesko BG, Gomperts R, Mennucci B, Hratchian HP, Ortiz JV, Izmaylov AF, Sonnenberg JL, Williams, Ding F, Lipparini F, Egidi F, Goings J, Peng B, Petrone A, Henderson T, Ranasinghe D, Zakrzewski VG, Gao J, Rega N, Zheng G, Liang W, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai H, Vreven T, Throssell K, Montgomery Jr. JA, Peralta JE, Ogliaro F, Bearpark MJ, Heyd JJ, Brothers EN, Kudin KN, Staroverov VN, Keith TA, Kobayashi R, Normand J, Raghavachari K, Rendell AP, Burant JC, Iyengar SS, Tomasi J, Cossi M, Millam JM, Klene M, Adamo C, Cammi R, Ochterski JW, Martin RL, Morokuma K, Farkas O, Foresman JB, Fox DJ (2013) Gaussian 09 rev. D.01. Wallingford, CTGoogle Scholar
  40. 40.
    Shaik S, Kumar D, de Visser SP (2008) A valence bond modeling of trends in hydrogen abstraction barriers and transition states of hydroxylation reactions catalyzed by cytochrome P450 enzymes. J. Am. Chem. Soc. 130(31):10128–10140.  https://doi.org/10.1021/ja8019615 CrossRefPubMedGoogle Scholar
  41. 41.
    Shaik S, Hirao H, Kumar D (2007) Reactivity patterns of cytochrome P450 enzymes: multifunctionality of the active species, and the two states-two oxidants conundrum. Nat. Prod. Rep. 24(3):533–552.  https://doi.org/10.1039/B604192M CrossRefPubMedGoogle Scholar
  42. 42.
    Alberro N, Torrent S, Miquel AA, Rubiales G, Cossío FP (2018) Density functional theory study on the demethylation reaction between methylamine, dimethylamine, trimethylamine, and tamoxifen catalyzed by a Fe(IV)–oxo porphyrin complex. J. Phys. Chem. A 122(6):1658–1671.  https://doi.org/10.1021/acs.jpca.7b10654 CrossRefPubMedGoogle Scholar
  43. 43.
    Li XX, Wang Y, Zheng QC, Zhang HX (2016) Detoxification of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) by cytochrome P450 enzymes: a theoretical investigation. J. Inorg. Biochem. 154(154):21–28.  https://doi.org/10.1016/j.jinorgbio.2015.10.009 CrossRefPubMedGoogle Scholar
  44. 44.
    Fu Z, Wang Y, Wang Z, Xie H, Chen J (2015) Transformation pathways of isomeric perfluorooctanesulfonate precursors catalyzed by the active species of P450 enzymes: in silico investigation. Chem. Res. Toxicol. 28(3):482–489.  https://doi.org/10.1021/tx500470f CrossRefPubMedGoogle Scholar
  45. 45.
    Hirao H, Thellamurege N, Chuanprasit P, Xu K (2013) Importance of H-abstraction in the final step of nitrosoalkane formation in the mechanism-based inactivation of cytochrome P450 by amine-containing drugs. Int. J. Mol. Sci. 14(12):24692–24705.  https://doi.org/10.3390/ijms141224692 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Chemical Synthesis and Pollution Control Key Laboratory of Sichuan ProvinceChina West Normal UniversityNanchongPeople’s Republic of China

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