DNA methylation and the regulation of P450 enzymes and transporters:implications for interindividual variability in response to drugs

Abstract

Abstract: Gene polymorphisms of Cytochrome P450 enzymes and transporters have been recognized as causes of interindividual variability in response to drugs. But some inconsistencies of the gene polymorphism and the phenotype of certain metabolic enzymes, transporter genotype can not be completely explained on the basis of genetic polymorphisms.Parmacoepigeneties is to study the relationship between genetic factors and drug therapy from the perspective of epigenetics and offer new explanation for interindividual variations in drug response.P450 enzymes and transporters are subject to epigenetic control. The most common epigenetic mechanism is DNA methylation, which does not change the genetic code, but might affect gene expression.Since the maintenance of its genome sequence, DNA methylation can be used to explain some inconsistencies of the gene polymorphism and the phenotype. In this overview,we summarize the newest advancement of the regulation of DNA methylation in epigenetic mechanisms of P450 enzymes and transporter gene expression.

Key words: Cytochrome P450, Transporters, DNA methylation, Interindividual Variability

CLC Number:

R968

YANG Jie, TAN Jie , ZOU Jian-jun, ZHOU Jun-shan, XIE Hai-tang. DNA methylation and the regulation of P450 enzymes and transporters:implications for interindividual variability in response to drugs[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2010, 15(11): 1294-1299.

References

[1] Mega JL, Close SL, Wiviott SD, et al. Cytochrome P450 polymorphisms and response to clopidogrel[J]. N Engl J Med, 2009,360(4):354-362.
[2] Mlubb MD, Innocenti F.Mechanisms of genetic regulation in gene expression: examples from drug metabolizing enzymes and transporters[J].Wiley Interdiscip Rev Syst Biol Med, 2010 Sep 23. [Epub ahead of print].
[3] Magnus IS, Sarah CS, Alvin G, et al. Influence of cytochrome P450 polymorphisms on drug therapies: Pharmacogenetic, pharmacoepigenetic and clinical aspects[J].Pharmacol Ther, 2007,116(3):496-526.
[4] Jacob Peedicayil.Pharmacoepigenetics and pharmacoepigenomics[J].Pharmacogenomics,2008, 9(12):1785.
[5] Bestor TH. The DNA methyltransferases of mammals[J]. Hum Mol Genet, 2000,9(16): 2395-2402.
[6] Rountree MR, Bachman KE, Herman JG, et al. DNA methylation, chromatin inheritance, and cancer[J]. Oncogene, 2001, 20(24):3156-3165.
[7] Bird AP. CpG-rich islands and the function of DNA methyaltion[J]. Nature, 1986, 321 (6067):209-213.
[8] Jones PA, Takai D.The role of DNA methylation in mammalian epigenetics[J].Science, 2001,293(5532): 1068-1070.
[9] Tokizane T, Shiina H, Igawa M, et al. Cytochrome P4501B1 is overexpressed and regulated by hypomethylation in prostate cancer[J]. Clin Cancer Res, 2005, 11(6):5793-5801.
[10] Shiraishi M, Oates AJ, Sekiya T.An overview of the analysis of DNA methylation in mammalian genomes[J]. Biol Chem, 2002, 383(6):893-906.
[11] Esteller M. Relevance of DNA methylation in the management of cancer[J]. Lancet Oncol , 2003,4(6): 351-358.
[12] Padjen K, Ratnam S, Storb U. DNA methylation precedes chromatin modifications under the influence of the strain-specific modifier Ssm1[J]. Mol Cell Biol, 2005, 25 (11):4782-4791.
[13] Okino ST, Pookot D, Li LC, et al. Epigenetic inactivation of the dioxin-responsive cytochrome P450 1A1 gene in human prostate cancer[J].Cancer Res, 2006, 66 (15):7420-7428
[14] Nakajima M, Iwanari M, Yokoi T. Effects of histone deacetylation and DNA methylation on the constitutive and TCDD-inducible expressions of the human CYP1 family in MCF-7 and HeLa cells[J]. Toxicol Lett, 2003,144(2):247-256.
[15] Anttila S,Hakkola J,Tuominen P. Methylation of cytochrome P4501A1 promoter in the lung is associated with tobacco smoking[J].CancerRes, 2003, 63(24):8623-8628.
[16] Hammons GJ, Yan SY, Jin B. Specific site methylation in the 5'-flanking region of CYP1A2 interindividual differences in human livers[J].Life Sci, 2001, 69(7):839-845.
[17] Jin B,Park DW,Nam KW, et al. CpG methylation of the mouse CYP1A2 promoter[J].Toxicol Lett, 2004, 152 (1):11-18
[18] Widschwendter M, Siegmund KD, Muller HM, et al. Association of breast cancer DNA methylation profiles with hormone receptor status and response to tamoxifen[J]. Cancer Res, 2004, 64 (11):3807-3813.
[19] 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[J]. Biochem Pharmacol, 1992,43 (8):1876-1879.
[20] Umeno M, Song BJ, Kozak C, et al. The rat P450 2E1 gene: complete intron and exon sequence, chromosome mapping, and correlation of developmental expression with specific 5′ cytosine demethylation[J]. J Biol Chem, 1988, 263 (10):4956-4962.
[21] Botto F, Seree E, el KS, et al. Tissue-specific expression and methylation of the human CYP2E1 gene[J]. Biochem Pharmacol, 1994, 48 (6):1095-1103.
[22] Vieira I, Sonnier M, Cresteil T. Developmental expression of CYP2E1 in the human liver. Hypermethylation control of gene expression during the neonatal period[J]. Eur J Biochem, 1996,238 (2): 476-483.
[23] Fraga MF, Ballestar E, Paz MF, et al. Epigenetic differences arise during the lifetime of monozygotic twins[J]. Proc Natl Acad Sci USA ,2005,102 (30):10604-10609.
[24] Cooney CA, Dave AA, Wolff GL. Maternal methyl supplements in mice affect epigenetic variation and DNA methylation of offspring [J]. J Nutr, 2002, 132 (8 Suppl): 2393S-2400S.
[25] Gomez A, Karlgren M, Edler D, et al. Expression of CYP2W1 in colon tumors: regulation. by gene methylation[J]. Pharmacogenomics, 2007, 8 (10):1315-1325.
[26] Karlgren M, Gomez A, Stark K, et al. Tumor-specific expression of the novel cytochrome P450 enzyme, CYP2W1[J]. Biochem Biophys Res Commun, 2006, 341 (2):451-458.
[27] Chung I, Karpf AR, Muindi JR, et al. Epigenetic silencing of CYP24 in tumor-derived endothelial cells contributes to selective growth inhibition by calcitriol[J].J Biol Chem, 2007, 282 (12):8704-8714.
[28] Bailey-Dell KJ, Hassel B, Doyle LA, et al. Promoter characterization and genomic organization of the human breast cancer resistance protein (ATP- binding cassette transporter G2)gene[J].Biochim Biophys Acta, 2001,1520(3):234-241.
[29] Burger H, Foekens JA, Look MP, et al.RNA expression of breast cancer resistance protein, lung resistance-related protein, multidrug resistance-associated proteins 1 and 2, and multidrug resistance gene 1 in breast cancer: correlation with chemotherapeutic response[J].Clin Cancer Res, 2003,9(2):827-836.
[30] Kenneth KW, Zhan Z,Susan EB.Aberrant promoter methylation of the ABCG2 gene in renal carcinoma[J]. Mol Cell Biol, 2006, 26(22):8572-8585.
[31] Joel GT, Jana L.ABCG2 expression, function, and promoter methylation in human multiple myeloma[J].Blood, 2006, 108(12):3881-3889.
[32] Hirofumi N, Yoichi N, Hiroshi S,et al.Methylation status of breast cancer resistance protein detected by methylation-specific polymerase chain reaction analysis is correlated inversely with its expression in drug-resistant lung cancer cells[J]. Cancer, 2008,112(5):1122-1130.
[33] Kusaba H, Nakayama M, Harada T. Association of 5'CpG demethylation and altered chromatin structure in the promoter region with transcriptional activation of the multidrug resistance 1 gene in human cancer cells[J]. Eur J Biochem, 1999, 262(3):924-932.
[34] Baker EK, Johnstone RW, Zalcberg JR. Epigenetic changes to the MDR1 locus in response to chemotherapeutic drugs[J].Oncogene, 2005,24(54):8061-8075.
[35] 余长永, 张勇, 邹建军, 等. 氯吡格雷抵抗原因及对策的研究进展[J].中国临床药理学与治疗学, 2009,14(10):1168-1173.
[36] 刘昭前, 周宏灏. 个体化药物治疗的新时代[J].中国临床药理学与治疗学, 2007,12(1):1-6.