Discussion
Personalized medicine is attached more and more importance since late
1990s. Personalized medicine can better cope with individual differences
in the therapy, thus bringing better clinical outcomes to patients.
Individual difference is mainly caused by the ADME process of drugs in
human body, especially caused by drug-metabolizing enzymes and
transporters. These protein activities are regulated by kinds of
individual factors, such as genetic polymorphism, medicine combination
and age. On the other hand, changes in epigenetic characteristics of
genes can cause differences in mRNA expression. Epigenetic differences,
especially DNA methylation, in ADME genes have attracted more and more
attention, but the upstream regulatory factors and mechanism still
unclear. Studies showed non-genetic factors may affect the DNA
methylation level of genes. This systematic review was conducted to
summarizes individual factors and their effects on methylation of ADME
genes and to provide insights into the inner mechanism.
The systemic review searched all studies from 2000 till now and 63
articles were included totally. Half of all studies (n=32) were cohort
study of population. We summarized six aspects of individual factors
from the perspective of personalized medicine: parental exposure,
environmental pollutants exposure, obesity and diet, drugs, gender and
others. Common individual factors, for example, high fat diet, obesity
and smoking left marks on the DNA methylation. Most studies reported
significant changes in methylation results, and fewer published no
significant results. Publication bias may exist. Whether the CpG sites
were reported was not related to publishing year or sample size, but may
be related to detection method and experimental funds. The factor with
the largest number of studies and the largest sample size was obesity.
The possible reason was that obesity has become a major global concern,
and over-weight people are easier to collect. Some individual factors
had a central tendency on methylated ADME genes and CpG sites, for
instance, BMI and ABCG1. However, several key ADME genes, such as
CYP2C19, CYP2D6 and CYP3A5, were not involved. The reason might be that
the initiators of these studies focused on pathogenesis, while the
impact of individual factors on drug metabolism via epigenetic
regulating could be paid more attention.
Although most studies included did not explore deeply into mechanism,
they provided a new sight of how individual factor influence human
metabolism. Yang Song et al. reported arsenic led ABCA1 hypermethylation
via reactive oxygen species (ROS)
pathway[77].
Arsenic-treated cells were found hypermethylation of the ABCG1 promoter
and a dose-dependent decrease in ROS generation. Two conceptual models
was proposed to explain the arsenic-induced methylation process, but
neither model satisfactorily represented each step of the
process[78].
S-adenosylmethionine (AdoMet) was the methyl group donor in both models.
Dioxins induced CYP1A1 promoter demethylation via aryl hydrocarbon
receptor (Ahr)[29].
Ahr is a highly conserved nuclear receptor that mediates toxic response
to environmentally persistent organic pollutants, PAHs included. Using
siRNA knockout method, Tet2, Tet3, and Tdg were also found play
important role in the process. Besides, changes in methylation can be
used as markers for cancer detection, side effects, or drug efficacy.
There is evidence that resistance to chemotherapeutics is associated
with promoter hypermethylation of
ABCG2[6].
Various epidrugs were developed reverse epigenetic markers, for example,
DNMT inhibitors, Vidaza (5-Azacytidine) and Dacogen (Decitabine), will
lead to global methylation level
alteration[79,
80]. However, epidrugs were unspecific
and bring many concerns in clinical application because of apparent
cytotoxicity during
treatment[81]. At
present, in addition to epidrugs, changes in our personal behavior
habits could also change some epigenetic markers. Kaliman et al. found
that intensive practice of mindfulness meditation could lead to
alterations of H4ac and H3K4me3, as well as a decreased expression of
RIPK2 and COX2 compared to control
group[82]. Either
epidurgs or behavior’s impact on ADME genes methylation has not been
reported yet.
Recommendation for the future research
The included studies had some drawback and weakness. Cohort study or
clinical controlled trial are more recommended, and as many samples as
possible should be included. Experiments should provide both raw and
processed data to ensure rigor. It is best to use mathematical models to
quantify the weights of influencing factors. The mechanisms how
individual factors influence epigenetics and more individual factors
should be studied.
Strengths and limitations
The strengths of the research are that research types and research
objects are listed. We can figure out the current research stages.
Moreover, we classify and analyze the research on individualized
factors, and propose six aspects of common individualized factors for
the first time. We not only describe the results of various experiments,
but also search papers to make a conjecture about the possible mechanism
pathway.
The limitations of the research are that most studies only published the
correlation, we do not know the causal relationship between the factors
and DNA methylation. Furthermore, the regulatory mechanism behind that
is still unclear. There may be a complex network regulation mechanism,
and DNA methylation epigenetics is only one of the pathways. Some
studies did not exclude the mixed factors. Our findings are based on
included studies. Positive results are more likely to be published, so
our findings may be biased.