Pharmacoepigenetics and Pharmacoepigenomics: An Overview

Author(s): Jacob Peedicayil*

Journal Name: Current Drug Discovery Technologies

Volume 16 , Issue 4 , 2019

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Abstract:

Background: The rapid and major advances being made in epigenetics are impacting pharmacology, giving rise to new sub-disciplines in pharmacology, pharmacoepigenetics, the study of the epigenetic basis of variation in response to drugs; and pharmacoepigenomics, the application of pharmacoepigenetics on a genome-wide scale.

Methods: This article highlights the following aspects of pharmacoepigenetics and pharmacoepigenomics: epigenetic therapy, the role of epigenetics in pharmacokinetics, the relevance of epigenetics to adverse drug reactions, personalized medicine, drug addiction, and drug resistance, and the use of epigenetic biomarkers in drug therapy.

Results: Epigenetics is having an increasing impact on several areas of pharmacology.

Conclusion: Pharmacoepigenetics and pharmacoepigenomics are new sub-disciplines in pharmacology and are likely to have an increasing impact on the use of drugs in clinical practice.

Keywords: Epigenetics, pharmacoepigenetics, pharmacoepigenomics, gene expression, pharmacoepigenetics, pharmacoepigenomics.

[1]
Peedicayil J. Pharmacoepigenetics and pharmacoepigenomics. Pharmacogenomics 2008; 9: 1785-6.
[2]
Gomez A, Ingelman-Sundberg M. Pharmacoepigenetics: Its role in interindividual differences in drug response. Clin Pharmacol Ther 2009; 85: 426-30.
[3]
Ingelman-Sundberg M, Gomez A. The past, present, and future of pharmacoepigenomics. Pharmacogenomics 2010; 11: 625-7.
[4]
Baer-Dubowska W, Majchrzak-Celińska A, Chichocki M. Pharmacoepigenetics: A new approach to predicting individual drug responses and targeting new drugs. Pharmacol Rep 2011; 63: 293-304.
[5]
Cressman AM, Piquette-Miller M. Epigenetics: A new link toward understanding human disease and drug response. Clin Pharmacol Ther 2012; 92: 669-73.
[6]
Szyf M. Toward a discipline of pharmacoepigenomics. Curr Pharmacogenom 2004; 2: 357-77.
[7]
Allis CD, Caparros M-L, Jenuwein T, Lachner M, Reinberg D. Overview and Concepts. In: Allis CD, Caparros M-L, Jenuwein T, Reinberg D, Lachner M. (Eds.). Epigenetics. Cold Spring Harbor Laboratory Press, New York, In: 2015; pp. pp. 47-115.
[8]
Peedicayil J. Epigenetic therapy – A new development in pharmacology. Indian J Med Res 2006; 123: 17-24.
[9]
Peedicayil J. Role of epigenetics in pharmacotherapy, psychotherapy and nutritional management of mental disorders. J Clin Pharm Ther 2012; 37: 499-501.
[10]
Peedicayil J, Kumar A. Epigenetic drugs for mood disorders. Prog Mol Biol Transl Sci 2018; 158 (In Press).
[11]
Sharma A, Gerbarg P, Bottiglieri T, et al. S-adenosylmethionine (SAMe) for neuropsychiatric disorders: A clinician-oriented review of research. J Clin Psychiatry 2017; 78: e656-67.
[12]
Peedicayil J. Epigenetic drugs in cognitive disorders. Curr Pharm Des 2014; 20: 1840-6.
[13]
Lu SC, Mato JM. S-adenosylmethionine in liver health, injury, and cancer. Physiol Rev 2012; 92: 1515-42.
[14]
Mato JM, Martinez-Chantar ML, Lu SC. S-adenosylmethionine metabolism and liver disease. Ann Hepatol 2013; 12: 183-9.
[15]
Remely M, Lovrecic L, de la Garza AL, et al. Therapeutic perspectives of epigenetically active nutrients. Br J Pharmacol 2015; 172: 2756-68.
[16]
Szyf M. DNA demethylation agents in clinical medicine. In: Tollefsbol TO, Ed. Handbook of Epigenetics. Elsevier, Waltham, MA 2017; pp. 595-603.
[17]
Kundakovic M. DNA methyltransferase inhibitors and psychiatric disorders. In: Peedicayil J, Grayson DR, Avramopoulos D, Eds. Epigenetics in Psychiatry. Elsevier, Waltham, MA 2014; pp. 497-514.
[18]
Peedicayil J. The role of DNA methylation in the pathogenesis and treatment of cancer. Curr Clin Pharmacol 2012; 7: 333-40.
[19]
Estey EH. Epigenetics in clinical practice: The examples of azacytidine and decitabine in myelodysplasia and acute myeloid leukemia. Leukemia 2013; 27: 1803-12.
[20]
Park J, Terranova-Barberio M, Zhong AY, et al. Clinical applications of histone deacetylase inhibitors. In: Tollefsbol TO (Ed) Handbook of Epigenetics Elsevier. Waltham, MA 2017; pp. 605-21.
[21]
Seto E, Yoshida M. Erasers of histone acetylation: The histone deacetylase enzymes. In: Allis CD, Caparros M-L, Jenuwein T, Reinberg D (Eds) Epigenetics Cold Spring Harbor Laboratory Press, New York. 2015; pp. 143-68.
[22]
Ptak C, Petronis A. Epigenetics and complex disease: From etiology to new therapeutics. Annu Rev Pharmacol Toxicol 2008; 48: 257-76.
[23]
Szyf M. Epigenetics, DNA methylation, and chromatin modifying drugs. Annu Rev Pharmacol Toxicol 2009; 49: 243-63.
[24]
Eckschlager T, Plch J, Stiborova M, et al. Histone deacetylase inhibitors as anticancer drugs. Int J Mol Sci 2017; 18E1414
[25]
Zheng Y, Liu L, Shukla GC. A comprehensive review of web-based non-coding RNA resources for cancer research. Cancer Lett 2017; 407: 1-8.
[26]
Alural B, Genc S, Haggarty SJ. Diagnostic and therapeutic potential of miRNAs in neuropsychiatric disorders: Past, present, and future. Prog Neuropsychopharmacol Biol Psychiatry 2017; 73: 87-103.
[27]
Dong Y, Liu C, Zhou Y, et al. Role of noncoding RNAs in regulation of cardiac cell death and cardiovascular diseases. Cell Mol Life Sci 2018; 75: 291-300.
[28]
Wang Z, Lu Q, Wang Z. Epigenetic alterations in cellular immunity: New insights into autoimmune diseases. Cell Physiol Biochem 2017; 41: 645-60.
[29]
Hammond SM. An overview of microRNAs. Adv Drug Deliv Rev 2015; 87: 3-14.
[30]
Müller S, Brown PJ. Epigenetic chemical probes. Clin Pharmacol Ther 2012; 92: 689-93.
[31]
Wapenaar H, Dekker FJ. Histone acetyltransferases: Challenges in targeting bi-substrate enzymes. Clin Epigenetics 2016; 8: 59.
[32]
Højfeldt JW, Agger K, Helin K. Histone lysine demethylases as targets for anticancer therapy. Nat Rev Drug Discov 2013; 12: 917-30.
[33]
Padmanabhan B, Mathur S, Manjula R, Tripathi S. Bromodomain and extra-terminal (BET) family proteins: New therapeutic targets in major diseases. J Biosci 2016; 41: 295-311.
[34]
Pérez-Salvia M, Esteller M. Bromodomain inhibitors and cancer therapy: From structures to applications. Epigenetics 2017; 12: 323-39.
[35]
Xu Y, Vakoc CR. Targeting cancer cells with BET bromodomain inhibitors. Cold Spring Harb Perspect Med 2017; 7(7)a026674
[36]
Magistri M, Velmesher D, Makhmutova M, et al. The BET-bromodomain inhibitor JQ1 reduces inflammation and tau phosphorylation at Ser396 in the brain of the 3xTg model of Alzheimer’s disease. Curr Alzheimer Res 2016; 13: 985-95.
[37]
Gomez A, Ingelman-Sundberg M. Pharmacoepigenetic aspects of gene polymorphism on drug therapies: Effects of DNA methylation on drug response. Expert Rev Clin Pharmacol 2009; 2: 55-65.
[38]
Kacevska M, Ivanov M, Ingelman-Sundberg M. Epigenetic-dependent regulation of drug transport and metabolism: An update. Pharmacogenomics 2012; 13: 1373-85.
[39]
Kacevska M, Ivanov M, Ingelman-Sundberg M. Perspectives on epigenetics and its relevance to adverse drug reactions. Clin Pharmacol Ther 2011; 89: 902-7.
[40]
Fisel P, Schaeffler E, Schwab M. DNA methylation of ADME genes. Clin Pharmacol Ther 2016; 99: 512-27.
[41]
He Y, Chevillet JR, Liu G, et al. The effects of microRNA on the absorption, distribution, metabolism, and excretion of drugs. Br J Pharmacol 2015; 172: 2733-47.
[42]
Giacomini KM, Sugiyama Y. Membrane transporters and drug response. In: Brunton LL, Chabner BA, Knollmann BC, (Eds) The Pharmacological Basis of Therapeutics, McGraw-Hill, New York. 2011; pp. 89-121.
[43]
Masereeuw R, Russell FG. Regulatory pathways for ATP-binding cassette transport proteins in kidney proximal tubules. AAPS J 2012; 14: 883-94.
[44]
Wu L-X, Wen C-J, Li Y, et al. Interindividual epigenetic variation in ABCB1 promoter and its relationship with ABCB1 expression and function in healthy Chinese subjects. Br J Clin Pharmacol 2015; 80: 1109-21.
[45]
Arrigoni E, Galimberti S, Petrini M, et al. ATP-binding cassette transmembrane transporters and their epigenetic control in cancer: An overview. Expert Opin Drug Metab Toxicol 2016; 12: 1419-32.
[46]
Li W, Zhang H, Assaraf YG, et al. Overcoming ABC transporter-mediated multidrug resistance: Molecular mechanisms and novel therapeutic drug strategies. Drug Resist Updat 2016; 27: 14-29.
[47]
Wu W, Dnyanmote AV, Nigam SK. Remote communication through solute carriers and ATP binding cassette drug transporter pathways: An update on the remote sensing and signaling hypothesis. Mol Pharmacol 2011; 79: 795-805.
[48]
Hirota T, Tanaka T, Takesue H, et al. Epigenetic regulation of drug transporter expression in human tissues. Expert Opin Drug Metab Toxicol 2017; 13: 19-30.
[49]
Majchrzak-Celińska A, Baer-Dubowska W. Pharmacoepigenetics: An element of personalized therapy? Expert Opin Drug Metab Toxicol 2017; 13: 387-98.
[50]
Zhang N, Lei J, Lei H, et al. MicroRNA-101 overexpression by IL-6 and TNF-α inhibits cholesterol efflux by suppressing ATP-binding cassette transporter A1 expression. Exp Cell Res 2015; 336: 33-42.
[51]
Kim I-W, Han N, Burckart GJ, Oh JM. Epigenetic changes in gene expression for drug-metabolizing enzymes and transporters. Pharmacotherapy 2014; 34: 140-50.
[52]
Oberstadt MC, Bien-Moller S, Weitmann K, et al. Epigenetic modulation of the drug resistance genes MGMT, ABCB1 and ABCG2 in glioblastoma multiforme. BMC Cancer 2013; 13: 617.
[53]
Gonzalez FJ, Coughtrie M, Tukey RH. Drug metabolism. In: Brunton LL, Chabner BA, Knollman BC (Eds) The Pharmalogical Basis of Therapeutics McGraw-Hill, New York. 2011; pp. 123-43.
[54]
Ingelman-Sundberg M, Zhong X-B, Hankinson O, et al. Potential role of epigenetic mechanisms in the regulation of drug metabolism and transport. Drug Metab Dispos 2013; 41: 1725-31.
[55]
Cascorbi I. Overlapping effects of genetic variation and epigenetics on drug response: Challenges of pharmacoepigenomics. Pharmacogenomics 2013; 14: 1807-9.
[56]
Habano W, Kawamura K, Lizuka N, et al. Analysis of DNA methylation landscape reveals the roles of DNA methylation in the regulation of drug metabolizing enzymes. Clin Epigenetics 2015; 7: 105.
[57]
Vyhlidal CA, Bi C, Ye SQ, et al. Dynamics of cytosine methylation in the proximal promoters of CYP3A4 and CYP3A7 in pediatric and prenatal livers. Drug Metab Dispos 2016; 44: 1020-6.
[58]
Gomez A, Ingelman-Sundberg M. Epigenetic and microRNA-dependent control of cytochrome P450 expression: A gap between DNA and protein. Pharmacogenomics 2009; 10: 1067-76.
[59]
Yu A-M, Ingelman-Sundberg M, Cherrington NJ, et al. Regulation of drug metabolism and toxicity by multiple factors of genetics, epigenetics, lncRNAs, gut microbiota and diseases: A meeting report of the 21st International Symposium on Microsomes and Drug Oxidations (MDO). Acta Pharm Sin B 2017; 7: 241-8.
[60]
Jones SM, Boobis AR, Moore GE, et al. Expression of CYP2E1 during human fetal development: Methylation of the CYP2E1 gene in human fetal and adult liver samples. Biochem Pharmacol 1992; 43: 1876-9.
[61]
Gomez A, Karlgren M, Edler D, et al. Expression of CYP2W1 in colon tumours: Regulation by gene methylation. Pharmacogenomics 2007; 8: 1315-25.
[62]
Ivanov M, Kals M, Kacevska M, et al. Ontogeny, distribution and potential roles of 5-hydroxymethylcytosine in human liver function. Genome Biol 2013; 14: R83.
[63]
Ivanov M, Kals M, Lauschke V, et al. Single base resolution analysis of 5-hydroxymethylcytosine in 188 human genes: Implications for hepatic gene expression. Nucleic Acids Res 2016; 44: 6756-69.
[64]
Thomson JP, Hunter JM, Lempiäinen H, et al. Dynamic changes in 5-hydroxymethylation signatures underpin early and late events in drug exposed liver. Nucleic Acids Res 2013; 41: 5639-54.
[65]
Csoka AB, Szyf M. Epigenetic side-effects of common pharmaceuticals: A potential new field in medicine and pharmacology. Med Hypotheses 2009; 73: 770-80.
[66]
Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale’s Pharmacology. Elsevier, London 2016.
[67]
Fouse SD, Nagarajan RO, Costello JF. Genome-scale methylation analysis. Epigenomics 2010; 2: 105-17.
[68]
Bettscheider M, Kuczynska A, Almeida O, et al. Optimized analysis of DNA methylation and gene expression from small, anatomically-defined areas of the brain. J Vis Exp 2012; 65e3938
[69]
Fraga MF, Ballestar E, Paz MF, et al. Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci USA 2005; 102: 10604-9.
[70]
Ingelman-Sundberg M. Personalized medicine into the next generation. J Intern Med 2015; 277: 152-4.
[71]
Peedicayil J. Personalized pharmacoepigenomics. In: Tollefsbol TO (Ed) Personalized Epigenetics, Elsevier, Waltham, MA. 2015; pp. 351-67.
[72]
O’Brien CP. Drug addiction. In: Brunton LL, Chabner BA, Knollmann BC, (Eds) The Pharmacalogical Basis of Therapeutics, McGraw-Hill, New York. 2011; pp. 649-68.
[73]
Sadock BJ, Sadock VA, Ruiz P. Kaplan & Sadock’s Synopsis of Psychiatry. Lippincott Williams & Wilkins, New Delhi 2015.
[74]
Peedicayil J. The role of epigenetics in mental disorders. Indian J Med Res 2007; 126: 105-11.
[75]
Robison AJ, Nestler EJ. Transcriptional and epigenetic mechanisms of addiction. Nat Rev Neurosci 2011; 12: 623-37.
[76]
Nestler EJ. Epigenetic mechanisms of drug addiction. Neuropharmacology 2014; 76(B): 259-68.
[77]
Pandey SC, Ugale R, Zhang H, et al. Brain chromatin remodeling: A novel mechanism of alcoholism. J Neurosci 2008; 28: 3729-37.
[78]
Moonat S, Starkman BG, Sakharkar AJ, et al. Neuroscience of alcoholism: Molecular and cellular mechanisms. Cell Mol Life Sci 2010; 67: 73-88.
[79]
Welberg L. Addiction: From mechanisms to treatment. Nat Rev Neurosci 2011; 12: 621.
[80]
Motta SS, Cluzel P, Aldana M. Adaptive resistance in bacteria requires epigenetic inheritance, genetic noise, and cost of efflux pumps. PLoS One 2015; 10e0118464
[81]
Beaulaurier J, Zhang XS, Zhu S, et al. Single molecule-level detection and long read-based phasing of epigenetic variations in bacterial methylomes. Nat Commun 2015; 6: 7438.
[82]
Sandoval-Motta S, Aldana M. Adaptive resistance to antibiotics in bacteria: A systems biology perspective. Wiley Interdiscip Rev Syst Biol Med 2016; 8: 253-67.
[83]
Cohen NR, Ross CA, Jain S, et al. A role for the bacterial GATC methylome in antibacterial stress survival. Nat Genet 2016; 48: 581-6.
[84]
Glasspool RM, Teodoridis JM, Brown R. Epigenetics as a mechanism driving polygenic clinical drug resistance. Br J Cancer 2006; 94: 1087-92.
[85]
Wilting RH, Dannenberg J-H. Epigenetic mechanisms in tumorigenesis, tumor cell heterogeneity and drug resistance. Drug Resist Updat 2012; 15: 21-38.
[86]
Rodríguez-Paredes M, Esteller M. Cancer epigenetics reaches mainstream oncology. Nat Med 2011; 17: 330-9.
[87]
Easwaran H, Tsai H-C, Baylin SB. Cancer epigenetics: Tumor heterogeneity, plasticity of stem-like states, and drug resistance. Mol Cell 2014; 54: 716-27.
[88]
Lauschke VM, Barragan I, Ingelman-Sundberg M. Pharmacoepigenetics and Toxicoepigenetics: Novel mechanistic insights and therapeutic opportunities. Annu Rev Pharmacol Toxicol 2018; 58: 161-85.
[89]
Mulero-Navarro S, Esteller M. Epigenetic biomarkers in cancer: The time is now. Crit Rev Oncol Hematol 2008; 68: 1-11.
[90]
Costa-Pinheiro P, Montezuma D, Henrique R, et al. Diagnostic and prognostic epigenetic biomarkers in cancer. Epigenomics 2015; 7: 1003-15.
[91]
Lin C-C, Huang T-L. Epigenetic biomarkers in neuropsychiatric disorders. In: Yasui DH, Peedicayil J, Grayson DR (Eds), Neuropsychiatric disorders and epigenetics, Elsevier, Waltham, MA,. 2016; pp. 35-66.
[92]
Hampel H, O’Bryant SE, Castrillo JI, et al. Precision medicine: The golden gate for detection, treatment and prevention of Alzheimer’s disease. J Prev Alzheimers Dis 2016; 3: 243-59.


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Article Details

VOLUME: 16
ISSUE: 4
Year: 2019
Page: [392 - 399]
Pages: 8
DOI: 10.2174/1570163815666180419154633
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