TY - JOUR T1 - Circadian Regulation of Hepatic Cytochrome P450 2a5 by Peroxisome Proliferator-Activated Receptor Gamma JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.118.083071 SP - dmd.118.083071 AU - Jiangming Deng AU - Lianxia Guo AU - Baojian Wu Y1 - 2018/01/01 UR - http://dmd.aspetjournals.org/content/early/2018/08/28/dmd.118.083071.abstract N2 - Human CYP2A6 (mouse Cyp2a5) plays an important role in metabolism and detoxification of various drugs and chemicals. Here, we investigate a potential role of peroxisome proliferator-activated receptor gamma (Ppar-γ) in circadian regulation of Cyp2a5 enzyme. We first showed that Cyp2a5 mRNA and protein in mouse liver displayed robust circadian oscillations. Consistent with circadian protein pattern, Cyp2a5-mediated 7-hydroxylation of coumarin was circadian-time dependent. Formation of 7-hydroxycoumarin was more extensive at the dosing-time of ZT2 than ZT14. Interestingly, the nuclear receptor Ppar-γ was also a circadian gene. Circadian Ppar-γ protein level was strongly correlated with Cyp2a5 mRNA level (r = 0.989). Furthermore, Ppar-γ activation (by a selective agonist rosiglitazone) up-regulated Cyp2a5 expression in Hepa-1c1c7 cells, whereas Ppar-γ knockdown down-regulated Cyp2a5 expression. Also, Ppar-γ knockdown blunted the rhythmicity of Cyp2a5 mRNA in serum-shocked Hepa-1c1c7 cells. In addition, a combination of promoter truncation analysis, mobility shift and chromatin immunoprecipitation assays revealed that Ppar-γ directly bound to a PPAR response element (i.e., the -1418- to -1396-bp region) within Cyp2a5 promoter and activated the gene transcription. Taken together, Ppar-γ was a transcriptional activator of Cyp2a5 and its rhythmic expression contributed to circadian expression of Cyp2a5. ER -