Dynamics of Cytosine Methylation in the Proximal Promoters of CYP3A4 and CYP3A7 in Pediatric and Prenatal Livers

Drug Metabolism and Disposition : the Biological Fate of Chemicals
Carrie A VyhlidalJ Steven Leeder

Abstract

Members of the human CYP3A family of metabolizing enzymes exhibit developmental changes in expression whereby CYP3A7 is expressed in fetal tissues, followed by a transition to expression of CYP3A4 in the first months of life. Despite knowledge about the general pattern of CYP3A activity in human development, the mechanisms that regulate developmental expression remain poorly understood. Epigenetic changes, including cytosine methylation, have been suggested to play a role in the regulation of CYP3A expression. The objective of this study was to investigate changes in cytosine methylation of the CYP3A4 and CYP3A7 genes in human pediatric and prenatal livers. The methylation status of cytosine-phospho-guanine dinucleotides was determined in 16 pediatric liver samples using methyl-seq and confirmed by bisulfite sequencing of 48 pediatric and 34 prenatal liver samples. Samples were separated by age into five groups (prenatal, < 1 year of age, 1.8-6 years, 7-11 years, and 12-17 years). Methyl-seq anaylsis revealed that cytosines in the proximal promoter of CYP3A7 are hypomethylated in neonates compared with adolescents (P < 0.001). In contrast, a cytosine 383 base pair upstream of CYP3A4 is hypermethylated in liver samples from neon...Continue Reading

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Citations

Jun 16, 2016·Drug Metabolism and Disposition : the Biological Fate of Chemicals·J Steven Leeder, Bernd Meibohm
Oct 12, 2016·Drug Metabolism and Pharmacokinetics·Hang HeLi-Rong Zhang
Dec 30, 2018·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Joseph L Dempsey, Julia Yue Cui
Apr 21, 2018·Current Drug Discovery Technologies·Jacob Peedicayil
Dec 2, 2020·Expert Opinion on Drug Metabolism & Toxicology·Siavosh Naji-TalakarBhagwat Prasad
Mar 19, 2021·British Journal of Clinical Pharmacology·Brian D ChapronJ Steven Leeder

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