Small Heterodimer Partner Regulates Circadian Cytochromes p450 and Drug-Induced Hepatotoxicity

Abstract

The role of small heterodimer partner (SHP) in regulation of xenobiotic detoxification remains elusive. Here, we uncover a critical role for SHP in circadian regulation of cytochromes P450 (CYPs) and drug-induced hepatotoxicity. <b>Methods:</b> The mRNA and protein levels of CYPs in the livers of wild-type and SHP^-/- mice were measured by quantitative real-time polymerase chain reaction and Western blotting, respectively. Regulation of CYP by SHP was investigated using luciferase reporter, mobility shift, chromatin immunoprecipitation, and/or co-immunoprecipitation assays. <b>Results:</b> The circadian rhythmicities of xenobiotic-detoxifying CYP mRNAs and proteins were disrupted in SHP-deficient mice. Of note, SHP ablation up-regulated <i>Cyp2c38</i> and <i>Cyp2c39</i>, whereas it down-regulated all other <i>CYP</i> genes. Moreover, SHP regulated the expression of <i>CYP</i> genes through different mechanisms. SHP repressed Lrh-1/Hnf4α to down-regulate Cyp2c38, E4bp4 to up-regulate Cyp2a5, Dec2/HNF1α axis to up-regulate Cyp1a2, Cyp2e1 and Cyp3a11, and Rev-erbα to up-regulate Cyp2b10, Cyp4a10 and Cyp4a14. Furthermore, SHP ablation sensitized mice to theophylline (or mitoxantrone)-induced toxicity. Higher level of toxicity was correlated with down-regulated metabolism and clearance of theophylline (or mitoxantrone). In contrast, SHP ablation blunted the circadian rhythmicity of acetaminophen-induced hepatotoxicity and alleviated the toxicity by down-regulating Cyp2e1-mediated metabolism and reducing formation of the toxic metabolite. Toxicity alleviation by SHP ablation was also observed for aflatoxin B1 due to reduced formation of the toxic epoxide metabolite. <b>Conclusion:</b> SHP participates in circadian regulation of CYP enzymes, thereby impacting xenobiotic metabolism and drug-induced hepatotoxicity.