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.