Circadian Clock–Controlled Drug Metabolism: Implications for Chronotherapeutics

Abstract

Dependence of drug metabolism on dosing time has long been recognized. However, only recently are the underlying mechanisms for circadian drug metabolism being clarified. Diurnal rhythmicity in expression of drug-metabolizing enzymes is believed to be a key factor determining circadian metabolism. Supporting the notion that biological rhythms are generated and maintained by the circadian clock, a number of diurnal enzymes are under the control of the circadian clock. In general, circadian clock genes generate and regulate diurnal rhythmicity in drug-metabolizing enzymes via transcriptional actions on one or two of three cis-elements (i.e., E-box, D-box, and Rev-erb response element or RAR-related orphan receptor response element). Additionally, cycling or clockcontrolled nuclear receptors such as hepatocyte nuclear factor 4a and peroxisome proliferator-activated receptor g are contributors to diurnal enzyme expression. These newly discovered mechanisms for each of the rhythmic enzymes are reviewed in this article. We also discuss how the rhythms of enzymes are translated to circadian pharmacokinetics and drug chronotoxicity, which has direct implications for chronotherapeutics. Our discussion is also extended to two diurnal transporters (P-glycoprotein and multidrug resistance-associated protein 2) that have an important role in drug absorption. Although the experimental evidence is lacking in metabolism-based chronoefficacy, circadian genes (e.g., Reverba) as drug targets are shown to account for diurnal variability in drug efficacy. SIGNIFICANCE STATEMENTSignificant progress has been made in understanding the molecular mechanisms for generation of diurnal rhythmicity in drugmetabolizing enzymes. In this article, we review the newly discovered mechanisms for each of the rhythmic enzymes and discuss how the rhythms of enzymes are translated to circadian pharmacokinetics and drug chronotoxicity, which has direct implications for chronotherapeutics.

Oscillating lncRNA Platr4 regulates NLRP3 inflammasome to ameliorate nonalcoholic steatohepatitis in mice

“…Circadian expression of most genes is driven by molecular components of circadian clock via transcriptional actions on their cis- elements (E-box, D-box and RevRE or RORE) 35 , 36 . We thus investigated the roles of these three cis- elements in rhythmic expression of Platr4 using Bmal1 -/- , E4bp4 -/- and Rev-erbα -/- mice.…”

“…Circadian gene expression is mainly driven by the molecular components of circadian clock via direct transcriptional actions on their cis- elements (E-box, D-box and RevRE or RORE) 35 , 36 . Alternatively, an indirect mechanism has been proposed for generation of rhythmic gene expression by circadian clock 35 . This mechanism involves cycling transcriptional factors (TFs) (including nuclear receptors) as the intermediates.…”

“…The rhythms of clock-output cycling TFs are propagated to their downstream target genes. Examples of such cycling TFs are aryl hydrocarbon receptor, peroxisome proliferator-activated receptor gamma (Ppar-γ), hepatocyte nuclear factor 4α (Hnf4α), and Hnf1α 35 , 51 . Our finding that Platr4 regulates the circadian rhythmicity in Nlrp3 inflammasome pathway herein leads to a proposal of an additional mechanism for circadian regulation of immune genes.…”

Circadian rhythms: influence on physiology, pharmacology, and therapeutic interventions

“…Rapid advances in molecular biology techniques [e.g., molecular cloning, gene editing, and chromatin immunoprecipitation (ChIP) analysis] have revealed both direct and indirect mechanisms of core clock gene regulation of circadian drug metabolizing enzyme transcription. Bmal1 and Clock generate circadian rhythmicity in Cyp2a4/5, Ugt1a1, Fmo5, and Sult1a1 expression by direct transcriptional activation upon binding to E-box elements in the promoter regions of these target genes [100,101]. In addition, Bmal1/Clock also regulate expression of drug-metabolizing enzymes through indirect mechanisms.…”

“…For example, Bmal1 regulates diurnal expression of Cyp3a11 through DBP and HNF4a, two direct targets of Bmal1 and activators of Cyp3a11 [102]. Lu and colleagues have recently published an excellent review on this topic and summarize mechanistic studies that provide a strong link between molecular clock output genes and hepatic drug metabolism [100].…”