Combined Influence of Genetic Polymorphism and DNA Methylation on ABCB1 Expression and Function in Healthy Chinese Males.
OBJECTIVE
It is well known that the expression and function of ATP-binding cassette transporter B1 (ABCB1) show high interindividual variability, but the reasons have not yet been fully elucidated. In this study, combined influence of genetic polymorphism and DNA methylation on ABCB1 mRNA expression and digoxin pharmacokinetics in healthy Chinese males was analyzed.


METHODS
A total of 93 subjects who were homozygous for the ABCB1 1236-2677-3435 TTT or CGC haplotype were enrolled in this study. DNA methylation status of the ABCB1 promoter and ABCB1 mRNA expression level in exfoliated intestinal epithelial cells were analyzed using bisulfite sequencing PCR and real-time PCR. The pharmacokinetics of digoxin in subjects were investigated after administration of a single oral dose of digoxin 0.5 mg.


RESULTS
The DNA methylation levels of ABCB1 promoter showed no significant difference between TTT/TTT and CGC/CGC carriers (P = 0.54). Subjects with TTT/TTT haplotype pair and high methylation status (TTT/TTT-HM) showed a significantly lower ABCB1 mRNA level compared to other subjects. Compared with TTT/TTT-HM subgroup, the area under the plasma concentration-time curve from time zero to 72 h (AUC0-72) of digoxin was decreased by 26.9 %, the maximum plasma concentration (Cmax) was decreased by 25 % and the apparent oral clearance (CL/F) was increased by 21.2 % in CGC/CGC-LM subgroup. The values of time to maximum concentration (tmax) and terminal elimination half-life (t1/2) showed no significant difference.


CONCLUSIONS
Both genetic polymorphism and DNA methylation variation should be taken into consideration to explain the interindividual variability in ABCB1 expression and function more clearly.
Institute of Life Sciences, Chongqing Medical University, Chongqing, 400016, People's Republic of China. lxwu2008@126.com.
Lan-Xiang
LX
Wu
Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai, 200090, People's Republic of China.
Hong-Bo
HB
Zhao
Institute of Life Sciences, Chongqing Medical University, Chongqing, 400016, People's Republic of China.
Chun-Jie
CJ
Wen
Institute of Life Sciences, Chongqing Medical University, Chongqing, 400016, People's Republic of China.
Ying
Y
Li
Institute of Life Sciences, Chongqing Medical University, Chongqing, 400016, People's Republic of China.
Ying-Ying
YY
Shao
Institute of Life Sciences, Chongqing Medical University, Chongqing, 400016, People's Republic of China.
Zhu
Z
Yang
Institute of Life Sciences, Chongqing Medical University, Chongqing, 400016, People's Republic of China.|Pharmacogenetics Research Institute, Institute of Clinical Pharmacology, Central South University, Changsha, 410078, People's Republic of China.
Hong-Hao
HH
Zhou
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000328:Adult; D044466:Asian People / Q000235:genetics*; D019175:DNA Methylation; D004077:Digoxin / Q000097:blood / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D006239:Haplotypes; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D004077:Digoxin
PLoS Genet. 2010 Jul 22;6(7):e1001033
20661447
Anticancer Res. 2012 Oct;32(10):4439-44
23060570
Handb Exp Pharmacol. 2011;(201):285-97
21103973
Pharmacology. 2008;82(3):221-7
18810246
Pharmacogenomics J. 2011 Oct;11(5):315-25
21625253
FASEB J. 2010 Sep;24(9):3135-44
20385621
FEBS Lett. 2014 Nov 17;588(22):4112-9
25042036
Pharmacogenomics. 2008 Dec;9(12):1801-8
19072639
J Gastrointest Dig Syst. 2011 Dec 16;8(1):1-6
23519721
Pharmacogenet Genomics. 2011 Mar;21(3):152-61
20216335
Nucleic Acids Res. 2010 Jul;38(12):3880-90
20194112
J Clin Pharmacol. 2014 Jan;54(1):3-13
24166743
J Clin Pharmacol. 2003 Oct;43(10):1101-7
14517192
Pharmacogenet Genomics. 2013 Sep;23(9):463-9
23820292
J Clin Pharmacol. 2006 Mar;46(3):373-9
16490813
Oncogene. 2005 Dec 1;24(54):8061-75
16091741
Placenta. 2008 Mar;29 Suppl A:S29-35
18031808
Br J Clin Pharmacol. 2015 Nov;80(5):1109-21
25940551
Hepatology. 2006 Jul;44(1):62-74
16799996
Cancer Res. 2014 Jan 15;74(2):598-608
24305879
Mol Cancer. 2010 Mar 25;9:68
20338046
Ann Hum Biol. 2015 Jan;42(1):1-9
25413580
J Pharm Sci. 2011 Sep;100(9):3875-83
21523786
Cell Mol Life Sci. 2004 Mar;61(6):682-99
15052411
Pharmacogenet Genomics. 2005 Oct;15(10):693-704
16141795
Pharmacogenomics J. 2007 Jun;7(3):154-79
16969364
Curr Drug Metab. 2004 Feb;5(1):11-9
14965248
Genome Res. 2013 Sep;23(9):1363-72
23908385
Leuk Res. 2011 Jan;35(1):73-9
20488541
Clin Pharmacol Ther. 2002 Nov;72(5):572-83
12426521
Pharmacogenomics J. 2010 Dec;10(6):489-504
20125118
Clin Biochem. 2010 Feb;43(3):307-13
19833118
Clin Pharmacokinet. 2010 Apr;49(4):223-37
20214407