Interindividual epigenetic variation in ABCB1 promoter and its relationship with ABCB1 expression and function in healthy Chinese subjects.
OBJECTIVE
Interindividual epigenetic variation is likely to be an important mechanism contributing to the interindividual variability in the expression and function of ATP-binding cassette, sub-family B, member 1 (ABCB1). The aim of the present study was to explore the effect of interindividual epigenetic variability in the ABCB1 promoter on ABCB1 expression and function in healthy Chinese subjects.


METHODS
Using bisulfite sequencing polymerase chain reaction (PCR) and chromatin immunoprecipitation assays, the DNA methylation and histone acetylation status of the ABCB1 promoter in stool DNA and exfoliated colonic epithelial cells of 157 healthy Chinese male volunteers was analysed. ABCB1 mRNA levels in colonic epithelial cells were detected by real-time PCR. The digoxin pharmacokinetics in subjects with different epigenetic profiles was investigated after a single oral administration of digoxin (0.5 mg).


RESULTS
The methylation levels of ABCB1 promoter in stool DNA showed a significant interindividual variation, from 0.84% to 18.05%. A high methylation level of the ABCB1 promoter was closely related to the low levels of acetylated histone H3 and ABCB1 mRNA expression. In the high methylation group, the area under the concentration-time curves (AUC(0-4 h) and AUC(0-10 h) ) of digoxin was increased by 19% [95% confidence interval (CI) 10%, 31%; P = 0.024] and 13% (95% CI 8%, 26%; P = 0.026), respectively, and the peak concentration (Cmax ) of digoxin was increased by 30% (95% CI 12%, 41%; P = 0.021) compared with the low methylation group.


CONCLUSIONS
The epigenetic modifications of the ABCB1 promoter show high interindividual variability in healthy Chinese subjects, and are closely related to the interindividual variation in ABCB1 mRNA expression and digoxin 0-4 h plasma concentrations in vivo.
Institute of life sciences, Chongqing Medical University, Chongqing, P.R. China.
Lan-Xiang
LX
Wu
Institute of life sciences, Chongqing Medical University, Chongqing, P.R. China.
Chun-Jie
CJ
Wen
Institute of life sciences, Chongqing Medical University, Chongqing, P.R. China.
Ying
Y
Li
Institute of life sciences, Chongqing Medical University, Chongqing, P.R. China.
Xue
X
Zhang
Institute of life sciences, Chongqing Medical University, Chongqing, P.R. China.
Ying-Ying
YY
Shao
Institute of life sciences, Chongqing Medical University, Chongqing, P.R. China.
Zhu
Z
Yang
Institute of life sciences, Chongqing Medical University, Chongqing, P.R. China.|Pharmacogenetics Research Institute, Institute of Clinical Pharmacology, Central South University, Changsha, Hunan, P.R. China.
Hong-Hao
HH
Zhou
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D000107:Acetylation; D000293:Adolescent; D000328:Adult; D000483:Alleles; D044466:Asian People / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics*; D004077:Digoxin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D044127:Epigenesis, Genetic; D004847:Epithelial Cells / Q000378:metabolism; D005838:Genotype; D064368:Healthy Volunteers; D006657:Histones / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis; D055815:Young Adult
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D006657:Histones; D012333:RNA, Messenger; D004077:Digoxin
ABCB1; digoxin; epigenetic; expression; interindividual variation