Role of farnesoid X receptor in establishment of ontogeny of phase-I drug metabolizing enzyme genes in mouse liver

The expression of phase-I drug metabolizing enzymes in liver changes dramatically during postnatal liver maturation.Farnesoid X receptor(FXR) is critical for bile acid and lipid homeostasis in liver.However,the role of FXR in regulating ontogeny of phase-I drug metabolizing genes is not clear.Hence,we applied RNA-sequencing to quantify the developmental expression of phase-I genes in both Fxr-null and control(C57BL/6) mouse livers during development.Liver samples of male C57BL/6 and Fxr-null mice at6 different ages from prenatal to adult were used.The Fxr-null showed an overall effect to diminish the "day-1 surge" of phase-I gene expression,including cytochrome P450 s at neonatal ages.Among the 185 phase-I genes from 12 different families,136 were expressed,and differential expression during development occurred in genes from all 12 phase-I families,including hydrolysis: carboxylesterase(Ces),paraoxonase(Pon),and epoxide hydrolase(Ephx); reduction: aldoketo reductase(Akr),quinone oxidoreductase(Nqo),and dihydropyrimidine dehydrogenase(Dpyd); and oxidation: alcohol dehydrogenase(Adh),aldehyde dehydrogenase(Aldh),flavin monooxygenases(Fmo),molybdenum hydroxylase(Aox and Xdh),cytochrome P450(P450),and cytochrome P450 oxidoreductase(Por).The data also suggested new phase-I genes potentially targeted by FXR.These results revealed an important role of FXR in regulation of ontogeny of phase-I genes.

Epigenetic regulation of drug metabolism and transport

The drug metabolism is a biochemical process on modification of pharmaceutical substances through specialized enzymatic systems. Changes in the expression of drug-metabolizing enzyme genes can affect drug metabolism. Recently, epigenetic regulation of drug-metabolizing enzyme genes has emerged as an important mechanism. Epigenetic regulation refers to heritable factors of genomic modifications that do not involve changes in DNA sequence. Examples of such modifications include DNA methylation, histone modifications, and non-coding RNAs. This review examines the widespread effect of epigenetic regulations on genes involved in drug metabolism, and also suggests a network perspective of epigenetic regulation. The epigenetic mechanisms have important clinical implications and may provide insights into effective drug development and improve safety of drug therapy.

Antigenic Peptide Loading into Major Histocompatibility Complex Class I Is Driven by the Substrate N-Terminus

Major histocompatibility complex class I(MHC-I),a key element of the acquired immune system,plays essential roles in activating CD8^(+)T cells by recognizing intracellular antigens derived from pathogens and cancer.Assembly of MHC-I and antigen peptides is critical for the antigen presentation on the cell surface.However,the structural dynamics of antigenic peptide loading into MHC-I,at atomistic resolution,is still elusive.Here,by constructing a Markov state model(MSM)based onlarge scale all-atommolecular dynamics(MDs)simulations with an aggregated simulation time∼24μs,we reveal the detailed molecular mechanism underlying the peptide-loading dynamics into MHC-I and identify the key intermediates with associated thermodynamic/kinetic properties.Furthermore,we examine how the chaperone tapasin-binding protein related(TAPBPR)participates in promoting the peptide loading,and the results show that TAPBPR,by binding to the F pocket,allosterically modulates the structures of the distant pocket B,resulting in formation of a peptide-receptive conformation ideal for accommodating the incoming peptide N-terminus.This study provides fundamental structural insights for the peptide loading into MHC-I in both chaperone uncatalyzed and catalyzed contexts.