Host: The Japanese Society of Toxicology
Name : The 49th Annual Meeting of the Japanese Society of Toxicology
Date : June 30, 2022 - July 02, 2022
The expression and function of some xenobiotic transporters varies according to the time of day, causing the dosing time-dependent changes in drug disposition and toxicity. P-glycoprotein (P-gp), encoded by the ABCB1 gene, is suggested to be rhythmically expressed in kidneys, because renal elimination of several P-gp substrates, including metal drugs, varies depending on administration time. The circadian clock system regulates the abundance of proteins at nearly all stages of the gene expression process. Among post-transcriptional regulation mechanism, adenosine-to-inosine (A-to-I) RNA editing catalyzed by ADAR is the most prevalent nucleotide conversion in mammal. RNA editing and splicing are two major RNA processes that diversify transcriptomes in eukaryotes. We recently demonstrated that ADAR regulates the circadian expression of P-gp in human renal proximal tubular epithelial cells (RPTECs) by modulating the splicing of ABCB1 pre-mRNA. After synchronization of the cellular circadian clock by dexamethasone treatment, the expression of both ADAR and P-gp exhibited a significant 24-h oscillation in RPTECs. The temporal increase in ADAR levels prevented the production of aberrant spliced transcripts of the ABCB1 gene, thereby promoting the maturation of its mRNA. The time-dependent difference in the ADAR-mediated maturation of ABCB1 mRNA seemed to cause the circadian expression of P-gp. Recently, we also found that ADAR participates in the control of other xenobiotic transporter expression by regulating the production of circular RNA. In this symposium, we introduce the pleiotropic roles of ADAR in the circadian regulation of xenobiotic transporters and summarize the mechanism underlying the time-dependent changes in xenobiotic detoxification.
