Introduction
Inherent features of disease and response to therapeutics are often clustered in individuals, families, and population groups. Yet, a broad approach to diagnosis and therapy has been adopted for the most history of medicine practice. Individual difference is widely existing in clinical practice. Personalized medicine is paid increasing attention after human genome sequencing[1], and linking genomic and clinical profiles of individual patients helps to understand their disease at a deeper level to develop more targeted therapies. Patients will get maximum benefit but minimum risk because of personalized medicine. The absorption, distribution, metabolism and excretion (ADME) process of drugs in human body is an important part which induces individual differences in medicine therapy[2]. The protein activity and abundance of drug-metabolizing enzymes and transporters are very important in ADME process.
Most of the personalized medicine relevant studies focus on the genetic polymorphism of ADME genes using pharmacogenetics. SLCO1B1 gene mutation (c.521T > C, p.Val174Ala) decreases the transportation of active simvastatin from portal circulation into the liver, leading to increased plasma concentration of simvastatin acid and an enhanced risk of myopathy adverse reaction[3]. A website was established to query drug pharmacokinetic data and to predict targeted ADME relevant protein, which integrates, genetic, proteomic, phenotypic and molecule interaction data[4]. However, the protein activity and abundance not only depend on the structure change caused by the change of DNA sequence, but also be regulated by the mRNA expression. Many studies explored the relationship between the expression of ADME genes and drug reaction difference from the perspective of epigenetics, especially DNA methylation[5]. Resistance to chemotherapeutics is associated with promoter hypermethylation of ABCG2[6]. Xu Hao et al. summarized the correlation between ADME gene expression and DNA methylation exact locations and explained individual differences in clinical treatment[7]. In addition, source of differences in DNA methylation levels of ADME genes between individuals is not clear. A large number of studies showed that non-genetic factors such as age, gender, race, diet, pathophysiological status, and combined drugs may affect drug efficacy and safety by regulating the PK process. Some non-genetic factors may affect the DNA methylation of genes. Dioxins and dietary factors affecting metabolic gene methylation have attracted much attention and been published[8, 9]. The cause of retinopathy in patients with hypercholesterolemia may be caused by hypermethylation of ABCA1[10]. Epigenetic can be a bridge connecting affecting factors and personalized medicine[11, 12]. This systematic review summarizes individual factors and their effects on methylation characteristics of gene related to drug metabolism, and aims to screen out the influential individual factors, to find possible signaling pathways or targets for individualized factors and to provide new insights into the causes of individualized differences in clinical treatment.