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.