Skip to main content
SpringerLink
Log in

Drug-Metabolizing Cytochrome P450 Enzymes Have Multifarious Influences on Treatment Outcomes

  • Review Article
  • Published:
Clinical Pharmacokinetics Aims and scope Submit manuscript

Abstract

Drug metabolism is a critical process for the removal of unwanted substances from the body. In humans, approximately 80% of oxidative metabolism and almost 50% of the overall elimination of commonly used drugs can be attributed to one or more of various cytochrome P450 (CYP) enzymes from CYP families 1–3. In addition to the basic metabolic effects for elimination, CYP enzymes in vivo are capable of affecting the treatment outcomes in many cases. Drug-metabolizing CYP enzymes are mainly expressed in the liver and intestine, the two principal drug oxidation and elimination organs, where they can significantly influence the drug action, safety, and bioavailability by mediating phase I metabolism and first-pass metabolism. Furthermore, CYP-mediated local drug metabolism in the sites of action may also have the potential to impact drug response, according to the literature in recent years. This article underlines the ability of CYP enzymes to influence treatment outcomes by discussing CYP-mediated diversified drug metabolism in primary metabolic sites (liver and intestine) and typical action sites (brain and tumors) according to their expression levels and metabolic activity. Moreover, intrinsic and extrinsic factors of personal differential CYP phenotypes that contribute to interindividual variation of treatment outcomes are also reviewed to introduce the multifarious pivotal role of CYP-mediated metabolism and clearance in drug therapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Rendic S, Guengerich FP. Survey of human oxidoreductases and cytochrome P450 enzymes involved in the metabolism of xenobiotic and natural chemicals. Chem Res Toxicol. 2015;28(1):38–42.

    Article  CAS  PubMed  Google Scholar 

  2. Guengerich FP, Waterman MR, Egli M. Recent structural insights into cytochrome P450 function. Trends Pharmacol Sci. 2016;37(8):625–40.

    Article  CAS  PubMed  Google Scholar 

  3. Almazroo OA, Miah MK, Venkataramanan R. Drug metabolism in the liver. Clin Liv Dis. 2017;21(1):1–20.

    Article  Google Scholar 

  4. Ingelman-Sundberg M. Human drug metabolising cytochrome P450 enzymes: properties and polymorphisms. Naunyn Schmiedeberg Arch Pharmacol. 2004;369(1):89–104.

    Article  CAS  Google Scholar 

  5. Albertolle ME, Phan TTN, Pozzi A, Guengerich FP. Sulfenylation of human liver and kidney microsomal cytochromes P450 and other drug-metabolizing enzymes as a response to redox alteration. Mol Cell Proteom. 2018;17(5):889–900.

    Article  CAS  Google Scholar 

  6. Xiao Y, Ge M, Xue X, Wang C, Wang H, Wu X, et al. Hepatic cytochrome P450s metabolize aristolochic acid and reduce its kidney toxicity. Kidney Int. 2008;73(11):1231–9.

    Article  CAS  PubMed  Google Scholar 

  7. Goldstein I, Rivlin N, Shoshana OY, Ezra O, Madar S, Goldfinger N, et al. Chemotherapeutic agents induce the expression and activity of their clearing enzyme CYP3A4 by activating p53. Carcinogenesis. 2013;34(1):190–8.

    Article  CAS  PubMed  Google Scholar 

  8. van Herwaarden AE, van Waterschoot RA, Schinkel AH. How important is intestinal cytochrome P450 3A metabolism? Trends Pharmacol Sci. 2009;30(5):223–7.

    Article  PubMed  CAS  Google Scholar 

  9. Miksys S, Tyndale RF. Brain drug-metabolizing cytochrome P450 enzymes are active in vivo, demonstrated by mechanism-based enzyme inhibition. Neuropsychopharmacology. 2009;34(3):634–40.

    Article  CAS  PubMed  Google Scholar 

  10. McMillan DM, Tyndale RF. CYP-mediated drug metabolism in the brain impacts drug response. Pharmacol Ther. 2018;184:189–200.

    Article  CAS  PubMed  Google Scholar 

  11. Gerets HH, Tilmant K, Gerin B, Chanteux H, Depelchin BO, Dhalluin S, et al. Characterization of primary human hepatocytes, HepG2 cells, and HepaRG cells at the mRNA level and CYP activity in response to inducers and their predictivity for the detection of human hepatotoxins. Cell Biol Toxicol. 2012;28(2):69–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Martínez C, García-Martín E, Pizarro RM, García-Gamito FJ, Agúndez JA. Expression of paclitaxel-inactivating CYP3A activity in human colorectal cancer: implications for drug therapy. Br J Cancer. 2002;87(6):681–6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Fahy BN, Guo T, Ghose R. Impact of hepatic malignancy on CYP3A4 gene expression. J Surg Res. 2012;178(2):768–72.

    Article  CAS  PubMed  Google Scholar 

  14. Gharavi N, El-Kadi AO. Expression of cytochrome P450 in lung tumor. Curr Drug Metab. 2004;5(2):203–10.

    Article  CAS  PubMed  Google Scholar 

  15. Eichelbaum M, Ingelman-Sundberg M, Evans WE. Pharmacogenomics and individualized drug therapy. Ann Rev Med. 2006;57:119–37.

    Article  CAS  PubMed  Google Scholar 

  16. Lin JH, Lu AY. Interindividual variability in inhibition and induction of cytochrome P450 enzymes. Annu Rev Pharmacol Toxicol. 2001;41:535–67.

    Article  CAS  PubMed  Google Scholar 

  17. Lin JH, Lu AY. Inhibition and induction of cytochrome P450 and the clinical implications. Clin Pharmacokinet. 1998;35(5):361–90.

    Article  CAS  PubMed  Google Scholar 

  18. Danielson PB. The cytochrome P450 superfamily: biochemistry, evolution and drug metabolism in humans. Curr Drug Metab. 2002;3(6):561–97.

    Article  CAS  PubMed  Google Scholar 

  19. van Schaik RH. CYP450 pharmacogenetics for personalizing cancer therapy. Drug Resist Updates. 2008;11(3):77–98.

    Article  CAS  Google Scholar 

  20. Guengerich FP. Human cytochrome P450 enzymes. In: Ortiz de Montellano PR, editor. Cytochrome P450: structure, mechanism, and biochemistry. Cham: Springer International Publishing; 2015. p. 523–785.

    Chapter  Google Scholar 

  21. Zhang HF, Wang HH, Gao N, Wei JY, Tian X, Zhao Y, et al. Physiological content and intrinsic activities of 10 cytochrome P450 isoforms in human normal liver microsomes. J Pharmacol Exp Ther. 2016;358(1):83–93.

    Article  PubMed  Google Scholar 

  22. Xie F, Ding X, Zhang QY. An update on the role of intestinal cytochrome P450 enzymes in drug disposition. Acta Pharm Sin B. 2016;6(5):374–83.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Paine MF, Hart HL, Ludington SS, Haining RL, Rettie AE, Zeldin DC. The human intestinal cytochrome P450 “pie.” Drug Metab Dispos. 2006;34(5):880–6.

    Article  CAS  PubMed  Google Scholar 

  24. Thelen K, Dressman JB. Cytochrome P450-mediated metabolism in the human gut wall. J Pharm Pharmacol. 2009;61(5):541–58.

    Article  CAS  PubMed  Google Scholar 

  25. Cizkova K, Konieczna A, Erdosova B, Ehrmann J. Time-dependent expression of cytochrome p450 epoxygenases during human prenatal development. Organogenesis. 2014;10(1):53–61.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Williams JA, Ring BJ, Cantrell VE, Jones DR, Eckstein J, Ruterbories K, et al. Comparative metabolic capabilities of CYP3A4, CYP3A5, and CYP3A7. Drug Metab Dispos. 2002;30(8):883–91.

    Article  CAS  PubMed  Google Scholar 

  27. Guengerich FP. New trends in cytochrome p450 research at the half-century mark. J Biol Chem. 2013;288(24):17063–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Guengerich FP. Mechanisms of cytochrome P450-catalyzed oxidations. ACS Catal. 2018;8(12):10964–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Guengerich FP, Yoshimoto FK. Formation and cleavage of C–C bonds by enzymatic oxidation–reduction reactions. Chem Rev. 2018;118(14):6573–655.

    Article  CAS  PubMed  Google Scholar 

  30. Lewis DF, Pratt JM. The P450 catalytic cycle and oxygenation mechanism. Drug Metab Rev. 1998;30(4):739–86.

    Article  CAS  PubMed  Google Scholar 

  31. Benet LZ, Cummins CL, Wu CY. Unmasking the dynamic interplay between efflux transporters and metabolic enzymes. Int J Pharm. 2004;277:3–9.

    Article  CAS  PubMed  Google Scholar 

  32. Alqahtani S, Bukhari I, Albassam A, Alenazi M. An update on the potential role of intestinal first-pass metabolism for the prediction of drug–drug interactions: the role of PBPK modeling. Expert Opin Drug Metab Toxicol. 2018;14(6):625–34.

    Article  CAS  PubMed  Google Scholar 

  33. Dufek MB, Knight BM, Bridges AS, Thakker DR. P-glycoprotein increases portal bioavailability of loperamide in mouse by reducing first-pass intestinal metabolism. Drug Metab Dispos. 2013;41(3):642–50.

    Article  CAS  PubMed  Google Scholar 

  34. Schinkel AH, Jonker JW. Mammalian drug efflux transporters of the ATP binding cassette (ABC) family: an overview. Adv Drug Deliv Rev. 2003;55(1):3–29.

    Article  CAS  PubMed  Google Scholar 

  35. Manikandan P, Nagini S. Cytochrome P450 structure, function and clinical significance: a review. Curr Drug Targets. 2018;19(1):38–54.

    Article  CAS  PubMed  Google Scholar 

  36. Desta Z, Ward BA, Soukhova NV, Flockhart DA. Comprehensive evaluation of tamoxifen sequential biotransformation by the human cytochrome P450 system in vitro: prominent roles for CYP3A and CYP2D6. J Pharmacol Exp Ther. 2004;310(3):1062–75.

    Article  CAS  PubMed  Google Scholar 

  37. Jin Y, Desta Z, Stearns V, Ward B, Ho H, Lee KH, et al. CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment. J Natl Cancer Inst. 2005;97(1):30–9.

    Article  CAS  PubMed  Google Scholar 

  38. White IN. Tamoxifen: is it safe? Comparison of activation and detoxication mechanisms in rodents and in humans. Curr Drug Metab. 2003;4(3):223–39.

    Article  CAS  PubMed  Google Scholar 

  39. Dehal SS, Kupfer D. CYP2D6 catalyzes tamoxifen 4-hydroxylation in human liver. Cancer Res. 1997;57(16):3402–6.

    CAS  PubMed  Google Scholar 

  40. Purnapatre K, Khattar SK, Saini KS. Cytochrome P450s in the development of target-based anticancer drugs. Cancer Lett. 2008;259(1):1–15.

    Article  CAS  PubMed  Google Scholar 

  41. Kato M. Intestinal first-pass metabolism of CYP3A4 substrates. Drug Metab Pharmacokinet. 2008;23(2):87–94.

    Article  CAS  PubMed  Google Scholar 

  42. Doherty MM, Charman WN. The mucosa of the small intestine: how clinically relevant as an organ of drug metabolism? Clin Pharmacokinet. 2002;41(4):235–53.

    Article  CAS  PubMed  Google Scholar 

  43. Miyoshi Y, Ando A, Takamura Y, Taguchi T, Tamaki Y, Noguchi S. Prediction of response to docetaxel by CYP3A4 mRNA expression in breast cancer tissues. Int J Cancer. 2002;97(1):129–32.

    Article  CAS  PubMed  Google Scholar 

  44. Varma MV, Obach RS, Rotter C, Miller HR, Chang G, Steyn SJ, et al. Physicochemical space for optimum oral bioavailability: contribution of human intestinal absorption and first-pass elimination. J Med Chem. 2010;53(3):1098–108.

    Article  CAS  PubMed  Google Scholar 

  45. Yang J, Tucker GT, Rostami-Hodjegan A. Cytochrome P450 3A expression and activity in the human small intestine. Clin Pharmacol Ther. 2004;76(4):391.

    Article  CAS  PubMed  Google Scholar 

  46. Galetin A, Gertz M, Houston JB. Contribution of intestinal cytochrome p450-mediated metabolism to drug–drug inhibition and induction interactions. Drug Metab Pharmacokinet. 2010;25(1):28–47.

    Article  CAS  PubMed  Google Scholar 

  47. van Waterschoot RA, Schinkel AH. A critical analysis of the interplay between cytochrome P450 3A and P-glycoprotein: recent insights from knockout and transgenic mice. Pharmacol Rev. 2011;63(2):390–410.

    Article  PubMed  CAS  Google Scholar 

  48. Holtbecker N, Fromm MF, Kroemer HK, Ohnhaus EE, Heidemann H. The nifedipine–rifampin interaction: evidence for induction of gut wall metabolism. Drug Metab Dispos. 1996;24(10):1121–3.

    CAS  PubMed  Google Scholar 

  49. Lampen A, Zhang Y, Hackbarth I, Benet LZ, Sewing KF, Christians U. Metabolism and transport of the macrolide immunosuppressant sirolimus in the small intestine. J Pharmacol Exp Ther. 1998;285(3):1104–12.

    CAS  PubMed  Google Scholar 

  50. Thummel KE, O’Shea D, Paine MF, Shen DD, Kunze KL, Perkins JD, et al. Oral first-pass elimination of midazolam involves both gastrointestinal and hepatic CYP3A-mediated metabolism. Clin Pharmacol Ther. 1996;59(5):491–502.

    Article  CAS  PubMed  Google Scholar 

  51. Wu CY, Benet LZ, Hebert MF, Gupta SK, Rowland M, Gomez DY, et al. Differentiation of absorption and first-pass gut and hepatic metabolism in humans: studies with cyclosporine. Clin Pharmacol Ther. 1995;58(5):492–7.

    Article  CAS  PubMed  Google Scholar 

  52. Khokhar JY, Tyndale RF. Drug metabolism within the brain changes drug response: selective manipulation of brain CYP2B alters propofol effects. Neuropsychopharmacology. 2011;36(3):692–700.

    Article  CAS  PubMed  Google Scholar 

  53. Meyer RP, Gehlhaus M, Knoth R, Volk B. Expression and function of cytochrome p450 in brain drug metabolism. Curr Drug Metab. 2007;8(4):297–306.

    Article  CAS  PubMed  Google Scholar 

  54. Yu LJ, Matias J, Scudiero DA, Hite KM, Monks A, Sausville EA, et al. P450 enzyme expression patterns in the NCI human tumor cell line panel. Drug Metab Dispos. 2001;29(3):304–12.

    CAS  PubMed  Google Scholar 

  55. Navarro-Mabarak C, Camacho-Carranza R, Espinosa-Aguirre JJ. Cytochrome P450 in the central nervous system as a therapeutic target in neurodegenerative diseases. Drug Metab Rev. 2018;50(2):95–108.

    Article  CAS  PubMed  Google Scholar 

  56. Miksys S, Tyndale RF. Cytochrome P450-mediated drug metabolism in the brain. J Psychiatry Neurosci. 2013;38(3):152–63.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Miksys S, Hoffmann E, Tyndale RF. Regional and cellular induction of nicotine-metabolizing CYP2B1 in rat brain by chronic nicotine treatment. Biochem Pharmacol. 2000;59(12):1501–11.

    Article  CAS  PubMed  Google Scholar 

  58. Dauchy S, Dutheil F, Weaver RJ, Chassoux F, Daumas-Duport C, Couraud PO, et al. ABC transporters, cytochromes P450 and their main transcription factors: expression at the human blood–brain barrier. J Neurochem. 2008;107(6):1518–28.

    Article  CAS  PubMed  Google Scholar 

  59. Walther B, Ghersi-Egea JF, Minn A, Siest G. Subcellular distribution of cytochrome P-450 in the brain. Brain Res. 1986;375(2):338–44.

    Article  CAS  PubMed  Google Scholar 

  60. Miksys S, Rao Y, Sellers EM, Kwan M, Mendis D, Tyndale RF. Regional and cellular distribution of CYP2D subfamily members in rat brain. Xenobiotica. 2000;30(6):547–64.

    Article  CAS  PubMed  Google Scholar 

  61. Miksys S, Rao Y, Hoffmann E, Mash DC, Tyndale RF. Regional and cellular expression of CYP2D6 in human brain: higher levels in alcoholics. J Neurochem. 2002;82(6):1376–87.

    Article  CAS  PubMed  Google Scholar 

  62. Upadhya SC, Tirumalai PS, Boyd MR, Mori T, Ravindranath V. Cytochrome P4502E (CYP2E) in brain: constitutive expression, induction by ethanol and localization by fluorescence in situ hybridization. Arch Biochem Biophys. 2000;373(1):23–34.

    Article  CAS  PubMed  Google Scholar 

  63. Booth Depaz IM, Toselli F, Wilce PA, Gillam EM. Differential expression of human cytochrome P450 enzymes from the CYP3A subfamily in the brains of alcoholic subjects and drug-free controls. Drug Metab Dispos. 2013;41(6):1187–94.

    Article  PubMed  CAS  Google Scholar 

  64. Hedlund E, Gustafsson JA, Warner M. Cytochrome P450 in the brain; a review. Curr Drug Metab. 2001;2(3):245–63.

    Article  CAS  PubMed  Google Scholar 

  65. Meyer RP, Lindberg RL, Hoffmann F, Meyer UA. Cytosolic persistence of mouse brain CYP1A1 in chronic heme deficiency. Biol Chem. 2005;386(11):1157–64.

    Article  CAS  PubMed  Google Scholar 

  66. Meyer RP, Podvinec M, Meyer UA. Cytochrome P450 CYP1A1 accumulates in the cytosol of kidney and brain and is activated by heme. Mol Pharmacol. 2002;62(5):1061–7.

    Article  CAS  PubMed  Google Scholar 

  67. Zanger UM, Raimundo S, Eichelbaum M. Cytochrome P450 2D6: overview and update on pharmacology, genetics, biochemistry. Naunyn Schmiedebergs Arch Pharmacol. 2004;369(1):23–37.

    Article  CAS  PubMed  Google Scholar 

  68. Chen ZR, Somogyi AA, Reynolds G, Bochner F. Disposition and metabolism of codeine after single and chronic doses in one poor and seven extensive metabolisers. Br J Clin Pharmacol. 1991;31(4):381–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Sindrup SH, Arendt-Nielsen L, Brøsen K, Bjerring P, Angelo HR, Eriksen B, et al. The effect of quinidine on the analgesic effect of codeine. Eur J Clin Pharmacol. 1992;42(6):587–91.

    Article  CAS  PubMed  Google Scholar 

  70. Chen ZR, Irvine RJ, Bochner F, Somogyi AA. Morphine formation from codeine in rat brain: a possible mechanism of codeine analgesia. Life Sci. 1990;46(15):1067–74.

    Article  CAS  PubMed  Google Scholar 

  71. Court MH, Duan SX, Hesse LM, Venkatakrishnan K, Greenblatt DJ. Cytochrome P-450 2B6 is responsible for interindividual variability of propofol hydroxylation by human liver microsomes. Anesthesiology. 2001;94(1):110–9.

    Article  CAS  PubMed  Google Scholar 

  72. Miksys S, Wadji FB, Tolledo EC, Remington G, Nobrega JN, Tyndale RF. Rat brain CYP2D enzymatic metabolism alters acute and chronic haloperidol side-effects by different mechanisms. Prog Neuropsychopharmacol Biol Psychiatry. 2017;78:140–8.

    Article  CAS  PubMed  Google Scholar 

  73. Ding X, Kaminsky LS. Human extrahepatic cytochromes P450: function in xenobiotic metabolism and tissue-selective chemical toxicity in the respiratory and gastrointestinal tracts. Annu Rev Pharmacol Toxicol. 2003;43:149–73.

    Article  CAS  PubMed  Google Scholar 

  74. Rodriguez-Antona C, Ingelman-Sundberg M. Cytochrome P450 pharmacogenetics and cancer. Oncogene. 2006;25(11):1679–91.

    Article  CAS  PubMed  Google Scholar 

  75. Toussaint C, Albin N, Massaad L, Grunenwald D, Parise O, Morizet J, et al. Main drug- and carcinogen-metabolizing enzyme systems in human non-small cell lung cancer and peritumoral tissues. Cancer Res. 1993;53(19):4608–12.

    CAS  PubMed  Google Scholar 

  76. Guo Z, Johnson V, Barrera J, Porras M, Hinojosa D, Hernández I, et al. Targeting cytochrome P450-dependent cancer cell mitochondria: cancer associated CYPs and where to find them. Cancer Metastasis Rev. 2018;37:409–23.

    Article  CAS  PubMed  Google Scholar 

  77. Verma H, Singh Bahia M, Choudhary S, Kumar Singh P, Silakari O. Drug metabolizing enzymes-associated chemo resistance and strategies to overcome it. Drug Metab Rev. 2019;51(2):196–223.

    Article  CAS  PubMed  Google Scholar 

  78. Fleming I. The factor in EDHF: cytochrome P450 derived lipid mediators and vascular signaling. Vasc Pharmacol. 2016;86:31–40.

    Article  CAS  Google Scholar 

  79. Fleming I. Vascular cytochrome p450 enzymes: physiology and pathophysiology. Trends Cardiovasc Med. 2008;18(1):20–5.

    Article  CAS  PubMed  Google Scholar 

  80. Fleming I. The cytochrome P450 pathway in angiogenesis and endothelial cell biology. Cancer Metastasis Rev. 2011;30:541–55.

    Article  CAS  PubMed  Google Scholar 

  81. Imig JD. Epoxide hydrolase and epoxygenase metabolites as therapeutic targets for renal diseases. Am J Physiol Ren Physiol. 2005;289(3):F496-503.

    Article  CAS  Google Scholar 

  82. Capdevila JH, Wang W, Falck JR. Arachidonic acid monooxygenase: genetic and biochemical approaches to physiological/pathophysiological relevance. Prostaglandins Other Lipid Mediat. 2015;120:40–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Capdevila J, Wang W. Role of cytochrome P450 epoxygenase in regulating renal membrane transport and hypertension. Curr Opin Nephrol Hypertens. 2013;22(2):163–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Panigrahy D, Greene ER, Pozzi A, Wang DW, Zeldin DC. EET signaling in cancer. Cancer Metastasis Rev. 2011;30:525–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Cheranov SY, Karpurapu M, Wang D, Zhang B, Venema RC, Rao GN. An essential role for SRC-activated STAT-3 in 14,15-EET-induced VEGF expression and angiogenesis. Blood. 2008;111(12):5581–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Mitra R, Guo Z, Milani M, Mesaros C, Rodriguez M, Nguyen J, et al. CYP3A4 mediates growth of estrogen receptor-positive breast cancer cells in part by inducing nuclear translocation of phospho-Stat3 through biosynthesis of (±)-14,15-epoxyeicosatrienoic acid (EET). J Biol Chem. 2011;286(20):17543–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Jiang JG, Chen CL, Card JW, Yang S, Chen JX, Fu XN, et al. Cytochrome P450 2J2 promotes the neoplastic phenotype of carcinoma cells and is up-regulated in human tumors. Cancer Res. 2005;65(11):4707–15.

    Article  CAS  PubMed  Google Scholar 

  88. Webler AC, Michaelis UR, Popp R, Barbosa-Sicard E, Murugan A, Falck JR, et al. Epoxyeicosatrienoic acids are part of the VEGF-activated signaling cascade leading to angiogenesis. Am J Physiol Cell Physiol. 2008;295(5):C1292–301.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Guo Z, Sevrioukova IF, Denisov IG, Zhang X, Chiu TL, Thomas DG, et al. Heme binding biguanides target cytochrome P450-dependent cancer cell mitochondria. Cell Chem Biol. 2017;24(10):1259-75.e6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. McFadyen MC, McLeod HL, Jackson FC, Melvin WT, Doehmer J, Murray GI. Cytochrome P450 CYP1B1 protein expression: a novel mechanism of anticancer drug resistance. Biochem Pharmacol. 2001;62(2):207–12.

    Article  CAS  PubMed  Google Scholar 

  91. Lin H, Hu B, He X, Mao J, Wang Y, Wang J, et al. Overcoming taxol-resistance in A549 cells: a comprehensive strategy of targeting P-gp transporter, AKT/ERK pathways, and cytochrome P450 enzyme CYP1B1 by 4-hydroxyemodin. Biochem Pharmacol. 2020;171:113733.

    Article  CAS  PubMed  Google Scholar 

  92. Martinez VG, O’Connor R, Liang Y, Clynes M. CYP1B1 expression is induced by docetaxel: effect on cell viability and drug resistance. Br J Cancer. 2008;98(3):564–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Dutour R, Roy J, Cortés-Benítez F, Maltais R, Poirier D. Targeting cytochrome P450 (CYP) 1B1 enzyme with four series of A-ring substituted estrane derivatives: design, synthesis, inhibitory activity, and selectivity. J Med Chem. 2018;61(20):9229–45.

    Article  CAS  PubMed  Google Scholar 

  94. Swanson HI, Njar VC, Yu Z, Castro DJ, Gonzalez FJ, Williams DE, et al. Targeting drug-metabolizing enzymes for effective chemoprevention and chemotherapy. Drug Metab Dispos. 2010;38(4):539–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Raccor BS, Kaspera R. Extra-hepatic isozymes from the CYP1 and CYP2 families as potential chemotherapeutic targets. Curr Top Med Chem. 2013;13(12):1441–53.

    Article  CAS  PubMed  Google Scholar 

  96. Francis S, Delgoda R. A patent review on the development of human cytochrome P450 inhibitors. Expert Opin Ther Pat. 2014;24(6):699–717.

    Article  CAS  PubMed  Google Scholar 

  97. Alzahrani AM, Rajendran P. The multifarious link between cytochrome P450s and cancer. Oxid Med Cell Longev. 2020;2020:3028387.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  98. Travica S, Pors K, Loadman PM, Shnyder SD, Johansson I, Alandas MN, et al. Colon cancer-specific cytochrome P450 2W1 converts duocarmycin analogues into potent tumor cytotoxins. Clin Cancer Res. 2013;19(11):2952–61.

    Article  CAS  PubMed  Google Scholar 

  99. Peter Guengerich F, Chun YJ, Kim D, Gillam EM, Shimada T. Cytochrome P450 1B1: a target for inhibition in anticarcinogenesis strategies. Mutat Res. 2003;523:173–82.

    Article  PubMed  CAS  Google Scholar 

  100. Karlgren M, Ingelman-Sundberg M. Tumour-specific expression of CYP2W1: its potential as a drug target in cancer therapy. Expert Opin Ther Targets. 2007;11(1):61–7.

    Article  CAS  PubMed  Google Scholar 

  101. Michaelis UR, Fisslthaler B, Barbosa-Sicard E, Falck JR, Fleming I, Busse R. Cytochrome P450 epoxygenases 2C8 and 2C9 are implicated in hypoxia-induced endothelial cell migration and angiogenesis. J Cell Sci. 2005;118:5489–98.

    Article  CAS  PubMed  Google Scholar 

  102. Karkhanis A, Hong Y, Chan ECY. Inhibition and inactivation of human CYP2J2: implications in cardiac pathophysiology and opportunities in cancer therapy. Biochem Pharmacol. 2017;135:12–21.

    Article  CAS  PubMed  Google Scholar 

  103. Dutour R, Poirier D. Inhibitors of cytochrome P450 (CYP) 1B1. Eur J Med Chem. 2017;135:296–306.

    Article  CAS  PubMed  Google Scholar 

  104. Dhaini HR, Thomas DG, Giordano TJ, Johnson TD, Biermann JS, Leu K, et al. Cytochrome P450 CYP3A4/5 expression as a biomarker of outcome in osteosarcoma. J Clin Oncol. 2003;21(13):2481–5.

    Article  CAS  PubMed  Google Scholar 

  105. Zhou SF, Liu JP, Chowbay B. Polymorphism of human cytochrome P450 enzymes and its clinical impact. Drug Metab Rev. 2009;41(2):89–295.

    Article  CAS  PubMed  Google Scholar 

  106. Zanger UM, Schwab M. Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol Ther. 2013;138(1):103–41.

    Article  CAS  PubMed  Google Scholar 

  107. Nebert DW, Russell DW. Clinical importance of the cytochromes P450. Lancet. 2002;360(9340):1155–62.

    Article  CAS  PubMed  Google Scholar 

  108. Ingelman-Sundberg M, Sim SC, Gomez A, Rodriguez-Antona C. Influence of cytochrome P450 polymorphisms on drug therapies: pharmacogenetic, pharmacoepigenetic and clinical aspects. Pharmacol Ther. 2007;116(3):496–526.

    Article  CAS  PubMed  Google Scholar 

  109. Ingelman-Sundberg M. Pharmacogenetics of cytochrome P450 and its applications in drug therapy: the past, present and future. Trends Pharmacol Sci. 2004;25(4):193–200.

    Article  CAS  PubMed  Google Scholar 

  110. Ingelman-Sundberg M. Genetic polymorphisms of cytochrome P450 2D6 (CYP2D6): clinical consequences, evolutionary aspects and functional diversity. Pharmacogenom J. 2005;5(1):6–13.

    Article  CAS  Google Scholar 

  111. Seripa D, Pilotto A, Panza F, Matera MG, Pilotto A. Pharmacogenetics of cytochrome P450 (CYP) in the elderly. Ageing Res Rev. 2010;9(4):457–74.

    Article  CAS  PubMed  Google Scholar 

  112. Higashi MK, Veenstra DL, Kondo LM, Wittkowsky AK, Srinouanprachanh SL, Farin FM, et al. Association between CYP2C9 genetic variants and anticoagulation-related outcomes during warfarin therapy. JAMA. 2002;287(13):1690–8.

    Article  CAS  PubMed  Google Scholar 

  113. Zineh I, Pacanowski M, Woodcock J. Pharmacogenetics and coumarin dosing–recalibrating expectations. N Engl J Med. 2013;369(24):2273–5.

    Article  CAS  PubMed  Google Scholar 

  114. Pirmohamed M, Burnside G, Eriksson N, Jorgensen AL, Toh CH, Nicholson T, et al. A randomized trial of genotype-guided dosing of warfarin. N Engl J Med. 2013;369(24):2294–303.

    Article  CAS  PubMed  Google Scholar 

  115. Türk D, Hanke N, Wolf S, Frechen S, Eissing T, Wendl T, et al. Physiologically based pharmacokinetic models for prediction of complex CYP2C8 and OATP1B1 (SLCO1B1) drug–drug–gene interactions: a modeling network of gemfibrozil, repaglinide, pioglitazone, rifampicin, clarithromycin and itraconazole. Clin Pharmacokinet. 2019;58(12):1595–607.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  116. Samer CF, Lorenzini KI, Rollason V, Daali Y, Desmeules JA. Applications of CYP450 testing in the clinical setting. Mol Diagn Ther. 2013;17(3):165–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Mann A, Miksys SL, Gaedigk A, Kish SJ, Mash DC, Tyndale RF. The neuroprotective enzyme CYP2D6 increases in the brain with age and is lower in Parkinson’s disease patients. Neurobiol Aging. 2012;33(9):2160–71.

    Article  CAS  PubMed  Google Scholar 

  118. Parkinson A, Mudra DR, Johnson C, Dwyer A, Carroll KM. The effects of gender, age, ethnicity, and liver cirrhosis on cytochrome P450 enzyme activity in human liver microsomes and inducibility in cultured human hepatocytes. Toxicol Appl Pharmacol. 2004;199(3):193–209.

    Article  CAS  PubMed  Google Scholar 

  119. Ferguson CS, Tyndale RF. Cytochrome P450 enzymes in the brain: emerging evidence of biological significance. Trends Pharmacol Sci. 2011;32(12):708–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Guo Y, Hu B, Xie Y, Billiar TR, Sperry JL, Huang M, et al. Regulation of drug-metabolizing enzymes by local and systemic liver injuries. Expert Opin Drug Metab Toxicol. 2016;12(3):245–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Raunio H, Juvonen R, Pasanen M, Pelkonen O, Pääkkö P, Soini Y. Cytochrome P4502A6 (CYP2A6) expression in human hepatocellular carcinoma. Hepatology. 1998;27(2):427–32.

    Article  CAS  PubMed  Google Scholar 

  122. Matsuda Y, Yamakawa K, Saoo K, Hosokawa K, Yokohira M, Kuno T, et al. CYP2A6 overexpression in human lung cancers correlates with a high malignant status. Oncol Rep. 2007;18(1):53–7.

    CAS  PubMed  Google Scholar 

  123. Renton KW. Regulation of drug metabolism and disposition during inflammation and infection. Expert Opin Drug Metab Toxicol. 2005;1(4):629–40.

    Article  CAS  PubMed  Google Scholar 

  124. Stavropoulou E, Pircalabioru GG, Bezirtzoglou E. The role of cytochromes P450 in infection. Front Immunol. 2018;9:89.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  125. Lee JI, Zhang L, Men AY, Kenna LA, Huang SM. CYP-mediated therapeutic protein–drug interactions: clinical findings, proposed mechanisms and regulatory implications. Clin Pharmacokinet. 2010;49(5):295–310.

    Article  CAS  PubMed  Google Scholar 

  126. Hayden MS, West AP, Ghosh S. NF-kappaB and the immune response. Oncogene. 2006;25(51):6758–80.

    Article  CAS  PubMed  Google Scholar 

  127. Morgan ET. Impact of infectious and inflammatory disease on cytochrome P450-mediated drug metabolism and pharmacokinetics. Clin Pharmacol Ther. 2009;85(4):434–8.

    Article  CAS  PubMed  Google Scholar 

  128. Morgan ET, Goralski KB, Piquette-Miller M, Renton KW, Robertson GR, Chaluvadi MR, et al. Regulation of drug-metabolizing enzymes and transporters in infection, inflammation, and cancer. Drug Metab Dispos. 2008;36(2):205–16.

    Article  CAS  PubMed  Google Scholar 

  129. Aitken AE, Morgan ET. Gene-specific effects of inflammatory cytokines on cytochrome P450 2C, 2B6 and 3A4 mRNA levels in human hepatocytes. Drug Metab Dispos. 2007;35(9):1687–93.

    Article  CAS  PubMed  Google Scholar 

  130. Williams SJ, Farrell GC. Inhibition of antipyrine metabolism by interferon. Br J Clin Pharmacol. 1986;22(5):610–2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Aitken AE, Richardson TA, Morgan ET. Regulation of drug-metabolizing enzymes and transporters in inflammation. Annu Rev Pharmacol Toxicol. 2006;46:123–49.

    Article  CAS  PubMed  Google Scholar 

  132. El-Kadi AO, Bleau AM, Dumont I, Maurice H, du Souich P. Role of reactive oxygen intermediates in the decrease of hepatic cytochrome P450 activity by serum of humans and rabbits with an acute inflammatory reaction. Drug Metab Dispos. 2000;28(9):1112–20.

    CAS  PubMed  Google Scholar 

  133. Neyrinck AM, Cani PD, Dewulf EM, De Backer F, Bindels LB, Delzenne NM. Critical role of Kupffer cells in the management of diet-induced diabetes and obesity. Biochem Biophys Res Commun. 2009;385(3):351–6.

    Article  CAS  PubMed  Google Scholar 

  134. Tindberg N, Bengtsson I, Hu Y. A novel lipopolysaccharide-modulated Jun binding repressor in intron 2 of CYP2E1. J Neurochem. 2004;89(6):1336–46.

    Article  CAS  PubMed  Google Scholar 

  135. Bibi Z. Role of cytochrome P450 in drug interactions. Nutr Metab (Lond). 2008;5:27.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  136. Go RE, Hwang KA, Choi KC. Cytochrome P450 1 family and cancers. J Steroid Biochem Mol Biol. 2015;147:24–30.

    Article  CAS  PubMed  Google Scholar 

  137. Shimada T, Hayes CL, Yamazaki H, Amin S, Hecht SS, Guengerich FP, et al. Activation of chemically diverse procarcinogens by human cytochrome P-450 1B1. Cancer Res. 1996;56(13):2979–84.

    CAS  PubMed  Google Scholar 

  138. Nebert DW, Dalton TP. The role of cytochrome P450 enzymes in endogenous signalling pathways and environmental carcinogenesis. Nat Rev Cancer. 2006;6(12):947–60.

    Article  CAS  PubMed  Google Scholar 

  139. Jiang JG, Ning YG, Chen C, Ma D, Liu ZJ, Yang S, et al. Cytochrome p450 epoxygenase promotes human cancer metastasis. Cancer Res. 2007;67(14):6665–74.

    Article  CAS  PubMed  Google Scholar 

  140. Shu Y, He D, Li W, Wang M, Zhao S, Liu L, et al. Hepatoprotective effect of Citrus aurantium L. against APAP-induced liver injury by regulating liver lipid metabolism and apoptosis. Int J Biol Sci. 2020;16(5):752–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Horley NJ, Beresford KJ, Chawla T, McCann GJ, Ruparelia KC, Gatchie L, et al. Discovery and characterization of novel CYP1B1 inhibitors based on heterocyclic chalcones: overcoming cisplatin resistance in CYP1B1-overexpressing lines. Eur J Med Chem. 2017;129:159–74.

    Article  CAS  PubMed  Google Scholar 

  142. Cui J, Meng Q, Zhang X, Cui Q, Zhou W, Li S. Design and synthesis of new α-naphthoflavones as cytochrome P450 (CYP) 1B1 inhibitors to overcome docetaxel-resistance associated with CYP1B1 overexpression. J Med Chem. 2015;58(8):3534–47.

    Article  CAS  PubMed  Google Scholar 

  143. Wang YM, Lin W, Chai SC, Wu J, Ong SS, Schuetz EG, et al. Piperine activates human pregnane X receptor to induce the expression of cytochrome P450 3A4 and multidrug resistance protein 1. Toxicol Appl Pharmacol. 2013;272(1):96–107.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Hisaka A, Nakamura M, Tsukihashi A, Koh S, Suzuki H. Assessment of intestinal availability (FG) of substrate drugs of cytochrome p450s by analyzing changes in pharmacokinetic properties caused by drug–drug interactions. Drug Metab Dispos. 2014;42(10):1640–5.

    Article  PubMed  CAS  Google Scholar 

  145. Ioannides C. Effect of diet and nutrition on the expression of cytochromes P450. Xenobiotica. 1999;29(2):109–54.

    Article  CAS  PubMed  Google Scholar 

  146. Yue J, Khokhar J, Miksys S, Tyndale RF. Differential induction of ethanol-metabolizing CYP2E1 and nicotine-metabolizing CYP2B1/2 in rat liver by chronic nicotine treatment and voluntary ethanol intake. Eur J Pharmacol. 2009;609:88–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Zhong Y, Dong G, Luo H, Cao J, Wang C, Wu J, et al. Induction of brain CYP2E1 by chronic ethanol treatment and related oxidative stress in hippocampus, cerebellum, and brainstem. Toxicology. 2012;302:275–84.

    Article  CAS  PubMed  Google Scholar 

  148. Miksys S, Lerman C, Shields PG, Mash DC, Tyndale RF. Smoking, alcoholism and genetic polymorphisms alter CYP2B6 levels in human brain. Neuropharmacology. 2003;45(1):122–32.

    Article  CAS  PubMed  Google Scholar 

  149. Wienkers LC, Heath TG. Predicting in vivo drug interactions from in vitro drug discovery data. Nat Rev Drug Discov. 2005;4(10):825–33.

    Article  CAS  PubMed  Google Scholar 

  150. Verbeurgt P, Mamiya T, Oesterheld J. How common are drug and gene interactions? Prevalence in a sample of 1143 patients with CYP2C9, CYP2C19 and CYP2D6 genotyping. Pharmacogenomics. 2014;15(5):655–65.

    Article  CAS  PubMed  Google Scholar 

  151. Zhou S, Yung Chan S, Cher Goh B, Chan E, Duan W, Huang M, et al. Mechanism-based inhibition of cytochrome P450 3A4 by therapeutic drugs. Clin Pharmacokinet. 2005;44(3):279–304.

    Article  CAS  PubMed  Google Scholar 

  152. Ogilvie BW, Zhang D, Li W, Rodrigues AD, Gipson AE, Holsapple J, et al. Glucuronidation converts gemfibrozil to a potent, metabolism-dependent inhibitor of CYP2C8: implications for drug–drug interactions. Drug Metabol Dispos. 2006;34(1):191–7.

    Article  CAS  Google Scholar 

  153. Karonen T, Filppula A, Laitila J, Niemi M, Neuvonen PJ, Backman JT. Gemfibrozil markedly increases the plasma concentrations of montelukast: a previously unrecognized role for CYP2C8 in the metabolism of montelukast. Clin Pharmacol Ther. 2010;88(2):223–30.

    Article  CAS  PubMed  Google Scholar 

  154. Backman JT, Filppula AM, Niemi M, Neuvonen PJ. Role of cytochrome P450 2C8 in drug metabolism and interactions. Pharmacol Rev. 2016;68(1):168–241.

    Article  PubMed  Google Scholar 

  155. Riess H, Prandoni P, Harder S, Kreher S, Bauersachs R. Direct oral anticoagulants for the treatment of venous thromboembolism in cancer patients: potential for drug–drug interactions. Crit Rev Oncol Hematol. 2018;132:169–79.

    Article  PubMed  Google Scholar 

  156. Larson KB, Wang K, Delille C, Otofokun I, Acosta EP. Pharmacokinetic enhancers in HIV therapeutics. Clin Pharmacokinet. 2014;53(10):865–72.

    Article  CAS  PubMed  Google Scholar 

  157. Moore LB, Goodwin B, Jones SA, Wisely GB, Serabjit-Singh CJ, Willson TM, et al. St John’s wort induces hepatic drug metabolism through activation of the pregnane X receptor. Proc Natl Acad Sci USA. 2000;97(13):7500–2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Williamson B, Dooley KE, Zhang Y, Back DJ, Owen A. Induction of influx and efflux transporters and cytochrome P450 3A4 in primary human hepatocytes by rifampin, rifabutin, and rifapentine. Antimicrob Agents Chemother. 2013;57(12):6366–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Jana S, Paliwal J. Molecular mechanisms of cytochrome p450 induction: potential for drug–drug interactions. Curr Protein Pept Sci. 2007;8(6):619–28.

    Article  CAS  PubMed  Google Scholar 

  160. Handschin C, Meyer UA. Induction of drug metabolism: the role of nuclear receptors. Pharmacol Rev. 2003;55(4):649–73.

    Article  CAS  PubMed  Google Scholar 

  161. Mutoh S, Sobhany M, Moore R, Perera L, Pedersen L, Sueyoshi T, et al. Phenobarbital indirectly activates the constitutive active androstane receptor (CAR) by inhibition of epidermal growth factor receptor signaling. Sci Signal. 2013;6(274):ra31.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  162. Kocarek TA, Zangar RC, Novak RF. Post-transcriptional regulation of rat CYP2E1 expression: role of CYP2E1 mRNA untranslated regions in control of translational efficiency and message stability. Arch Biochem Biophys. 2000;376(1):180–90.

    Article  CAS  PubMed  Google Scholar 

  163. Tannenbaum C, Sheehan NL. Understanding and preventing drug–drug and drug–gene interactions. Expert Rev Clin Pharmacol. 2014;7(4):533–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Malki MA, Pearson ER. Drug–drug–gene interactions and adverse drug reactions. Pharmacogenom J. 2020;20(3):355–66.

    Article  CAS  Google Scholar 

  165. Storelli F, Samer C, Reny JL, Desmeules J, Daali Y. Complex drug–drug–gene-disease interactions involving cytochromes P450: systematic review of published case reports and clinical perspectives. Clin Pharmacokinet. 2018;57(10):1267–93.

    Article  CAS  PubMed  Google Scholar 

  166. Laine K, Tybring G, Härtter S, Andersson K, Svensson JO, Widén J, et al. Inhibition of cytochrome P4502D6 activity with paroxetine normalizes the ultrarapid metabolizer phenotype as measured by nortriptyline pharmacokinetics and the debrisoquin test. Clin Pharmacol Ther. 2001;70(4):327–35.

    Article  CAS  PubMed  Google Scholar 

  167. Bahar MA, Setiawan D, Hak E, Wilffert B. Pharmacogenetics of drug–drug interaction and drug–drug–gene interaction: a systematic review on CYP2C9, CYP2C19 and CYP2D6. Pharmacogenomics. 2017;18(7):701–39.

    Article  CAS  PubMed  Google Scholar 

  168. Manyike PT, Kharasch ED, Kalhorn TF, Slattery JT. Contribution of CYP2E1 and CYP3A to acetaminophen reactive metabolite formation. Clin Pharmacol Ther. 2000;67(3):275–82.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

A special thanks for the long-term subsidy mechanism from the Ministry of Finance and the Ministry of Education of PRC (People’s Republic of China) for BUCM (Beijing University of Chinese Medicine).

Author information

Authors and Affiliations

  1. School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 100029, China

    Yurong Song, Chenxi Li, Guangzhi Liu, Rui Liu, Youwen Chen, Wen Li, Zhiwen Cao, Baosheng Zhao & Yuanyan Liu

  2. Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, 100700, China

    Cheng Lu

Authors
  1. Yurong Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chenxi Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Guangzhi Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rui Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Youwen Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Wen Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Zhiwen Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Baosheng Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Cheng Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yuanyan Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Baosheng Zhao, Cheng Lu or Yuanyan Liu.

Ethics declarations

Funding

This work was supported by the Beijing Natural Science Foundation (7202111) and the National Science and Technology Major Project (2018ZX10101001-005-003).

Conflict of interest

Yurong Song, Chenxi Li, Guangzhi Liu, Rui Liu, Youwen Chen, Wen Li, Zhiwen Cao, Baosheng Zhao, Cheng Lu, and Yuanyan Liu have no conflicts of interest that are directly relevant to the content of this article.

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Availability of data and material

Not applicable.

Code availability

Not applicable.

Author contributions

Yuanyan Liu: conceptualization; Youwen Chen, Zhiwen Cao: investigation; Yurong Song: writing the original draf; Chenxi Li, Rui Liu, and Wen Li: figures; Guangzhi Liu: tables; Cheng Lu, Baosheng Zhao, and Yuanyan Liu: reviewing and editing.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Song, Y., Li, C., Liu, G. et al. Drug-Metabolizing Cytochrome P450 Enzymes Have Multifarious Influences on Treatment Outcomes. Clin Pharmacokinet 60, 585–601 (2021). https://doi.org/10.1007/s40262-021-01001-5

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40262-021-01001-5

Search

Navigation