Epigenetic Mechanisms Contribute to Intraindividual Variations of Drug Metabolism Mediated by Cytochrome P450 Enzymes

Abstract

Significant interindividual and intraindividual variations on cytochrome P450 (CYP)-mediated drug metabolism exist in the general population globally. Genetic polymorphisms are one of the major contribution factors for interindividual variations, but epigenetic mechanisms mainly contribute to intraindividual variations, including DNA methylation, histone modifications, microRNAs (miRNAs), and long non-coding RNAs (lncRNAs). The current review provides analysis of advanced knowledge in the last decade on contributions of epigenetic mechanisms to intraindividual variations on CYP-mediated drug metabolism in several situations, including (1) ontogeny, the developmental changes of CYP expression in individuals from neonates to adults; (2) increased activities of CYP enzymes induced by drug treatment; (3) increased activities of CYP enzymes in adult ages induced by drug treatment at neonate ages; and (4) decreased activities of CYP enzymes in individuals with drug-induced liver injury (DILI). Furthermore, current challenges, knowledge gaps, and future perspective of the epigenetic mechanisms in development of CYP pharmacoepigenetics are discussed. In conclusion, epigenetic mechanisms have been proven to contribute to intraindividual variations of drug metabolism mediated by CYP enzymes in age development, drug induction, and DILI conditions. The knowledge has helped understanding how intraindividual variation are generated. Future studies are needed to develop CYP-based pharmacoepigenetics to guide clinical applications for precision medicine with improved therapeutic efficacy and reduced risk of adverse drug reactions (ADRs) and toxicity.

Therapeutic potential of natural antisense transcripts and various mechanisms involved for clinical applications and disease prevention

“…One intriguing characteristic of NATs is their ability to encode concise open reading frames (ORFs) that lead to the production of peptides with unique biological functions, as seen in Figure 4 . One notable instance of this phenomena pertains to HNF4A-AS1, also known as hepatocyte nuclear factor 4 alpha antisense RNA 1 [ 58 ]. This particular entity encompasses a peptide consisting of 51 amino acids, often denoted as sPEP1.…”