Abstract
Aging is associated with reduced liver function that may increase the risk for adverse drug reactions in older adults. We hypothesized that age-related changes to epigenetic regulation of genes involved in drug metabolism may contribute to this effect. We reviewed published epigenome-wide studies of human blood and identified the cytochrome P450 2E1 (CYP2E1) gene as a top locus exhibiting epigenetic changes with age. To investigate potential functional changes with age in the liver, the primary organ of drug metabolism, we obtained liver tissue from mice aged 4–32 months from the National Institute on Aging. We assayed global DNA methylation (5-methylcytosine, 5mC), hydroxymethylation (5-hydroxymethylcytosine, 5hmC), and locus-specific 5mC and histone acetylation changes around mouse Cyp2e1. The mouse livers exhibit significant global decreases in 5mC and 5hmC with age. Furthermore, 5mC significantly increased with age at two regulatory regions of Cyp2e1 in tandem with decreases in its gene and protein expressions. H3K9ac levels also changed with age at both regulatory regions of Cyp2e1 investigated, while H3K27ac did not. To test if these epigenetic changes are associated with varying rates of drug metabolism, we assayed clearance of the CYP2E1-specific probe drug chlorzoxazone in microsome extracts from the same livers. CYP2E1 intrinsic clearance is associated with DNA methylation and H3K9ac levels at the Cyp2e1 locus but not with chronological age. This suggests that age-related epigenetic changes may influence rates of hepatic drug metabolism. In the future, epigenetic biomarkers could prove useful to guide dosing regimens in older adults.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
American Geriatrics Society. American Geriatrics Society 2019 updated AGS Beers Criteria® for potentially inappropriate medication use in older adults: 2019 AGS BEERS CRITERIA® UPDATE EXPERT PANEL. J Am Geriatr Soc. 2019;67:674–94. https://doi.org/10.1111/jgs.15767.
Barrera LO, Li Z, Smith AD, Arden KC, Cavenee WK, Zhang MQ, et al. Genome-wide mapping and analysis of active promoters in mouse embryonic stem cells and adult organs. Genome Res. 2008;18:46–59. https://doi.org/10.1101/gr.6654808.
Barzilai N, Huffman DM, Muzumdar RH, Bartke A. The critical role of metabolic pathways in aging. Diabetes. 2012;61:1315–22. https://doi.org/10.2337/db11-1300.
Benayoun BA, Pollina EA, Brunet A. Epigenetic regulation of ageing: linking environmental inputs to genomic stability. Nat Rev Mol Cell Biol. 2015;16:593–610. https://doi.org/10.1038/nrm4048.
Bonder MJ, Kasela S, Kals M, Tamm R, Lokk K, Barragan I, et al. Genetic and epigenetic regulation of gene expression in fetal and adult human livers. BMC Genomics. 2014;15:860. https://doi.org/10.1186/1471-2164-15-860.
Booth LN, Brunet A. The aging epigenome. Mol Cell. 2016;62:728–44. https://doi.org/10.1016/j.molcel.2016.05.013.
Budnitz DS, Pollock DA, Weidenbach KN, Mendelsohn AB, Schroeder TJ, Annest JL. National surveillance of emergency department visits for outpatient adverse drug events. JAMA. 2006;296:1858–66. https://doi.org/10.1001/jama.296.15.1858.
Budnitz DS, Lovegrove MC, Shehab N, Richards CL. Emergency hospitalizations for adverse drug events in older Americans. N Engl J Med. 2011;365:2002–12. https://doi.org/10.1056/NEJMsa1103053.
Cardelli M. The epigenetic alterations of endogenous retroelements in aging. Mech Ageing Dev. 2018;174:30–46. https://doi.org/10.1016/j.mad.2018.02.002.
Caro AA, Cederbaum AI. Oxidative stress, toxicology, and pharmacology of CYP2E1. Annu Rev Pharmacol Toxicol. 2004;44:27–42. https://doi.org/10.1146/annurev.pharmtox.44.101802.121704.
Dozmorov MG. Polycomb repressive complex 2 epigenomic signature defines age-associated hypermethylation and gene expression changes. Epigenetics. 2015;10:484–95. https://doi.org/10.1080/15592294.2015.1040619.
Duron E, Hanon O. Hypertension, cognitive decline and dementia. Arch Cardiovasc Dis. 2008;101:181–9. https://doi.org/10.1016/s1875-2136(08)71801-1.
ElDesoky ES. Pharmacokinetic-pharmacodynamic crisis in the elderly. Am J Ther. 2007;14:488–98. https://doi.org/10.1097/01.mjt.0000183719.84390.4d.
Fisel P, Schaeffeler E, Schwab M. DNA methylation of ADME genes. Clin Pharmacol Ther. 2016;99:512–27. https://doi.org/10.1002/cpt.343.
Fishilevich S, Nudel R, Rappaport N, et al. GeneHancer: genome-wide integration of enhancers and target genes in GeneCards. Database (Oxford). 2017. https://doi.org/10.1093/database/bax028.
French SW. The importance of CYP2E1 in the pathogenesis of alcoholic liver disease and drug toxicity and the role of the proteasome. Subcell Biochem. 2013;67:145–64. https://doi.org/10.1007/978-94-007-5881-0_4.
Gravina S, Dong X, Yu B, Vijg J. Single-cell genome-wide bisulfite sequencing uncovers extensive heterogeneity in the mouse liver methylome. Genome Biol. 2016;17:150. https://doi.org/10.1186/s13059-016-1011-3.
Hahn O, Grönke S, Stubbs TM, Ficz G, Hendrich O, Krueger F, et al. Dietary restriction protects from age-associated DNA methylation and induces epigenetic reprogramming of lipid metabolism. Genome Biol. 2017;18:56. https://doi.org/10.1186/s13059-017-1187-1.
Hannum G, Guinney J, Zhao L, Zhang L, Hughes G, Sadda S, et al. Genome-wide methylation profiles reveal quantitative views of human aging rates. Mol Cell. 2013;49:359–67. https://doi.org/10.1016/j.molcel.2012.10.016.
Heyn H, Li N, Ferreira HJ, Moran S, Pisano DG, Gomez A, et al. Distinct DNA methylomes of newborns and centenarians. Proc Natl Acad Sci U S A. 2012;109:10522–7. https://doi.org/10.1073/pnas.1120658109.
Horvath S. DNA methylation age of human tissues and cell types. Genome Biol. 2013;14:3156. https://doi.org/10.1186/gb-2013-14-10-r115.
Horvath S, Raj K. DNA methylation-based biomarkers and the epigenetic clock theory of ageing. Nat Rev Genet. 2018;19:371–84. https://doi.org/10.1038/s41576-018-0004-3.
Houston JB (1994) Utility of in vitro drug metabolism data in predicting in vivo metabolic clearance. Biochemical Pharmacology 47(9):1469–1479. https://doi.org/10.1016/0006-2952(94)90520-7
Hunt CM, Strater S, Stave GM. Effect of normal aging on the activity of human hepatic cytochrome P450IIE1. Biochem Pharmacol. 1990;40:1666–9. https://doi.org/10.1016/0006-2952(90)90470-6.
Ingelman-Sundberg M. Human drug metabolising cytochrome P450 enzymes: properties and polymorphisms. Naunyn Schmiedeberg's Arch Pharmacol. 2004;369:89–104. https://doi.org/10.1007/s00210-003-0819-z.
Issa J-P. Epigenetic variation and human disease. J Nutr. 2002;132:2388S–92S. https://doi.org/10.1093/jn/132.8.2388S.
Jia L, Chang X, Qian S, Liu C, Lord CC, Ahmed N, et al. Hepatocyte toll-like receptor 4 deficiency protects against alcohol-induced fatty liver disease. Mol Metab. 2018;14:121–9. https://doi.org/10.1016/j.molmet.2018.05.015.
Kent WJ, Sugnet CW, Furey TS, Roskin KM, Pringle TH, Zahler AM, et al. The human genome browser at UCSC. Genome Res. 2002;12:996–1006. https://doi.org/10.1101/gr.229102.
Knights KM, Stresser DM, Miners JO, Crespi CL. In vitro drug metabolism using liver microsomes. Curr Protoc Pharmacol. 2016;74:7.8.1–7.8.24. https://doi.org/10.1002/cpph.9.
Koh KH, Xie H, Yu A-M, Jeong H. Altered cytochrome P450 expression in mice during pregnancy. Drug Metab Dispos. 2011;39:165–9. https://doi.org/10.1124/dmd.110.035790.
Kronfol MM, Dozmorov MG, Huang R, Slattum PW, McClay J. The role of epigenomics in personalized medicine. Expert Rev Precis Med Drug Dev. 2017;2:33–45. https://doi.org/10.1080/23808993.2017.1284557.
Lazarou J, Pomeranz BH, Corey PN. Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies. JAMA. 1998;279:1200–5. https://doi.org/10.1001/jama.279.15.1200.
Lee WM. Public health: acetaminophen (APAP) hepatotoxicity—isn’t it time for APAP to go away? J Hepatol. 2017;67:1324–31. https://doi.org/10.1016/j.jhep.2017.07.005.
Lesurf R, Cotto KC, Wang G, Griffith M, Kasaian K, Jones SJ, et al. ORegAnno 3.0: a community-driven resource for curated regulatory annotation. Nucleic Acids Res. 2016;44:D126–32. https://doi.org/10.1093/nar/gkv1203.
Lieber CS. Cytochrome P-4502E1: its physiological and pathological role. Physiol Rev. 1997;77:517–44. https://doi.org/10.1152/physrev.1997.77.2.517.
Lucas D, Ferrara R, Gonzalez E, Bodenez P, Albores A, Manno M, et al. Chlorzoxazone, a selective probe for phenotyping CYP2E1 in humans. Pharmacogenetics. 1999;9:377–88. https://doi.org/10.1097/00008571-199906000-00013.
Mach J, Huizer-Pajkos A, Mitchell SJ, McKenzie C, Phillips L, Kane A, et al. The effect of ageing on isoniazid pharmacokinetics and hepatotoxicity in Fischer 344 rats. Fundam Clin Pharmacol. 2016;30:23–34. https://doi.org/10.1111/fcp.12157.
Martinez SM, Bradford BU, Soldatow VY, Kosyk O, Sandot A, Witek R, et al. Evaluation of an in vitro toxicogenetic mouse model for hepatotoxicity. Toxicol Appl Pharmacol. 2010;249:208–16. https://doi.org/10.1016/j.taap.2010.09.012.
Marttila S, Kananen L, Häyrynen S, Jylhävä J, Nevalainen T, Hervonen A, et al. Ageing-associated changes in the human DNA methylome: genomic locations and effects on gene expression. BMC Genomics. 2015;16:179. https://doi.org/10.1186/s12864-015-1381-z.
McCarroll SA, Murphy CT, Zou S, Pletcher SD, Chin CS, Jan YN, et al. Comparing genomic expression patterns across species identifies shared transcriptional profile in aging. Nat Genet. 2004;36:197–204. https://doi.org/10.1038/ng1291.
McClay JL, Aberg KA, Clark SL, Nerella S, Kumar G, Xie LY, et al. A methylome-wide study of aging using massively parallel sequencing of the methyl-CpG-enriched genomic fraction from blood in over 700 subjects. Hum Mol Genet. 2014;23:1175–85. https://doi.org/10.1093/hmg/ddt511.
McLachlan AJ, Pont LG. Drug metabolism in older people—a key consideration in achieving optimal outcomes with medicines. J Gerontol A Biol Sci Med Sci. 2012;67A:175–80. https://doi.org/10.1093/gerona/glr118.
McLachlan A, Hilmer S, Le Couteur D. Variability in response to medicines in older people: phenotypic and genotypic factors. Clin Pharmacol Ther. 2009;85:431–3. https://doi.org/10.1038/clpt.2009.1.
McLean AJ, Le Couteur DG. Aging biology and geriatric clinical pharmacology. Pharmacol Rev. 2004;56:163–84. https://doi.org/10.1124/pr.56.2.4.
Mouse Genome Sequencing Consortium, Waterston RH, Lindblad-Toh K, et al. Initial sequencing and comparative analysis of the mouse genome. Nature. 2002;420:520–62. https://doi.org/10.1038/nature01262.
Newman M, Blyth BJ, Hussey DJ, Jardine D, Sykes PJ, Ormsby RJ. Sensitive quantitative analysis of murine LINE1 DNA methylation using high resolution melt analysis. Epigenetics. 2012;7:92–105. https://doi.org/10.4161/epi.7.1.18815.
Pal S, Tyler JK. Epigenetics and aging. Sci Adv. 2016;2:e1600584. https://doi.org/10.1126/sciadv.1600584.
Park H-J, Choi Y-J, Kim JW, Chun HS, Im I, Yoon S, et al. Differences in the epigenetic regulation of cytochrome P450 genes between human embryonic stem cell-derived hepatocytes and primary hepatocytes. PLoS One. 2015;10:e0132992. https://doi.org/10.1371/journal.pone.0132992.
Peters MJ, Joehanes R, Pilling LC, et al. The transcriptional landscape of age in human peripheral blood. Nat Commun. 2015;6. https://doi.org/10.1038/ncomms9570.
Porubsky PR, Meneely KM, Scott EE. Structures of human cytochrome P-450 2E1. J Biol Chem. 2008;283:33698–707. https://doi.org/10.1074/jbc.M805999200.
Reynolds LM, Taylor JR, Ding J, Lohman K, Johnson C, Siscovick D, et al. Age-related variations in the methylome associated with gene expression in human monocytes and T cells. Nat Commun. 2014;5:5366. https://doi.org/10.1038/ncomms6366.
Routledge PA, O’Mahony MS, Woodhouse KW. Adverse drug reactions in elderly patients. Br J Clin Pharmacol. 2004;57:121–6. https://doi.org/10.1046/j.1365-2125.2003.01875.x.
Ruoß M, Damm G, Vosough M, et al. Epigenetic modifications of the liver tumor cell line HepG2 increase their drug metabolic capacity. Int J Mol Sci. 2019;20:347. https://doi.org/10.3390/ijms20020347.
Scarzello AJ, Jiang Q, Back T, Dang H, Hodge D, Hanson C, et al. LTβR signalling preferentially accelerates oncogenic AKT-initiated liver tumours. Gut. 2016;65:1765–75. https://doi.org/10.1136/gutjnl-2014-308810.
Schmucker DL, Woodhouse KW, Wang RK, Wynne H, James OF, McManus M, et al. Effects of age and gender on in vitro properties of human liver microsomal monooxygenases. Clin Pharmacol Ther. 1990;48:365–74. https://doi.org/10.1038/clpt.1990.164.
Seripa D, Panza F, Daragjati J, Paroni G, Pilotto A. Measuring pharmacogenetics in special groups: geriatrics. Expert Opin Drug Metab Toxicol. 2015;11:1073–88. https://doi.org/10.1517/17425255.2015.1041919.
Slone Epidemiology Center. Patterns of medication use in the United States - a report from the Slone Survey. Boston University; 2006.
Spiers H, Hannon E, Wells S, Williams B, Fernandes C, Mill J. Age-associated changes in DNA methylation across multiple tissues in an inbred mouse model. Mech Ageing Dev. 2016;154:20–3. https://doi.org/10.1016/j.mad.2016.02.001.
Stamatoyannopoulos JA, Snyder M, Hardison R, et al. An encyclopedia of mouse DNA elements (Mouse ENCODE). Genome Biol. 2012;13:418. https://doi.org/10.1186/gb-2012-13-8-418.
Steegenga WT, Boekschoten MV, Lute C, Hooiveld GJ, de Groot PJ, Morris TJ, et al. Genome-wide age-related changes in DNA methylation and gene expression in human PBMCs. AGE. 2014;36:9648. https://doi.org/10.1007/s11357-014-9648-x.
Sultana J, Cutroneo P, Trifirò G. Clinical and economic burden of adverse drug reactions. J Pharmacol Pharmacother. 2013;4:S73–7. https://doi.org/10.4103/0976-500X.120957.
Tammen SA, Dolnikowski GG, Ausman LM, Liu Z, Sauer J, Friso S, et al. Aging and alcohol interact to alter hepatic DNA hydroxymethylation. Alcohol Clin Exp Res. 2014;38:2178–85. https://doi.org/10.1111/acer.12477.
Tost J, Dunker J, Gut IG. Analysis and quantification of multiple methylation variable positions in CpG islands by pyrosequencing. BioTechniques. 2003;35:152–6. https://doi.org/10.2144/03351md02.
White RR, Milholland B, MacRae SL, Lin M, Zheng D, Vijg J. Comprehensive transcriptional landscape of aging mouse liver. BMC Genomics. 2015;16:899. https://doi.org/10.1186/s12864-015-2061-8.
Wilhelm A, Aldridge V, Haldar D, Naylor AJ, Weston CJ, Hedegaard D, et al. CD248/endosialin critically regulates hepatic stellate cell proliferation during chronic liver injury via a PDGF-regulated mechanism. Gut. 2016;65:1175–85. https://doi.org/10.1136/gutjnl-2014-308325.
Wilson VL, Smith RA, Ma S, Cutler RG. Genomic 5-methyldeoxycytidine decreases with age. J Biol Chem. 1987;262:9948–51.
Zanger UM, Schwab M. Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol Ther. 2013;138:103–41. https://doi.org/10.1016/j.pharmthera.2012.12.007.
Zhu T, Zheng SC, Paul DS, et al. Cell and tissue type independent age-associated DNA methylation changes are not rare but common. Aging (Albany NY). 2018;10:3541–57. https://doi.org/10.18632/aging.101666.
Acknowledgments
MMK completed this study in partial fulfillment of the doctoral requirements in Pharmaceutical Sciences at VCU. We are grateful to the staff at the National Institute on Aging Rodent Tissue Bank for providing us with the sample to carry out this study.
Funding
MMK was funded through a graduate studentship from Virginia Commonwealth University (VCU) School of Pharmacy and through R15AG061649 from the US National Institute on Aging. Research reported in this publication was supported by the National Institute on Aging of the National Institutes of Health under Award Number R15AG061649 to JLM.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Disclaimer
The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Conflict of interest
The authors declare that they have no conflicts of interest.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
ESM 1
(PDF 748 kb)
About this article
Cite this article
Kronfol, M.M., Jahr, F.M., Dozmorov, M.G. et al. DNA methylation and histone acetylation changes to cytochrome P450 2E1 regulation in normal aging and impact on rates of drug metabolism in the liver. GeroScience 42, 819–832 (2020). https://doi.org/10.1007/s11357-020-00181-5
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11357-020-00181-5