DNA methylation dynamics in the hepatic CYP3A4 gene promoter.
The CYP3A4 gene, encoding the major drug metabolizing enzyme in humans, exhibits a high interindividual variation in hepatic expression that can lead to interindividual differences in drug metabolism and associated adverse drug effects. Much of the interindividual variability in CYP3A4 remains unexplained. In the present study we investigated the role of DNA methylation in influencing the interindividual CYP3A4 expression. Individual CpG methylation within the ∼12 kb CYP3A4 regulatory region was investigated in 72 adult as well as in 7 fetal human livers using bisulfite sequencing. We identified highly variable CpG methylation sites in adult livers, which correspond to important CYP3A4 transcription factor binding sites including the proximal promoter, XREM and CLEM4 as well as in separate C/EBP and HNF4α binding regions. CpG hypermethylation within these regulatory regions was observed in fetal livers when compared to adult livers. This data suggests that dynamic DNA methylation elements are likely associated with key regulatory CYP3A4 promoter regions and may potentially contribute to the commonly observed interindividual expression of CYP3A4 as well as the hepatic developmental shift in its expression. The findings provide novel insight to CYP3A4 regulation with possible implications for understanding interindividual differences in drug response.
Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, SE-171 77 Stockholm, Sweden. marina.kacevska@ki.se
Marina
M
Kacevska
Maxim
M
Ivanov
Annika
A
Wyss
Silva
S
Kasela
Lili
L
Milani
Anders
A
Rane
Magnus
M
Ingelman-Sundberg
D000328:Adult; D018899:CpG Islands / Q000235:genetics; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D019175:DNA Methylation; D004742:Enhancer Elements, Genetic / Q000235:genetics; D005260:Female; D005333:Fetus / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D006801:Humans; D007223:Infant; D008099:Liver / Q000254:growth & development / Q000378:metabolism*; D008297:Male; D011401:Promoter Regions, Genetic / Q000235:genetics*
D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human