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

Dec 18, 2018Theranostics

Small Heterodimer Partner Controls Daily Liver Enzymes and Drug-Related Liver Damage

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Circadian Biology on OpenScience ↗PubMed ↗DOI ↗

Abstract

SHP ablation resulted in disrupted circadian rhythms of xenobiotic-detoxifying cytochrome P450 enzymes in mice.

SHP-deficient mice exhibited altered levels of various cytochrome P450 mRNAs and proteins.
The absence of SHP led to up-regulation of some genes and down-regulation of others involved in drug metabolism.
SHP regulates cytochrome P450 expression through distinct pathways involving different regulatory proteins.
Mice lacking SHP showed increased sensitivity to theophylline and mitoxantrone, indicating heightened drug toxicity.
In contrast, SHP ablation reduced hepatotoxicity from acetaminophen and aflatoxin B1 by modulating metabolic pathways.

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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.The mRNA and protein levels of CYPs in the livers of wild-type and SHPmice 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.The circadian rhythmicities of xenobiotic-detoxifying CYP mRNAs and proteins were disrupted in SHP-deficient mice. Of note, SHP ablation up-regulatedand, whereas it down-regulated all othergenes. Moreover, SHP regulated the expression ofgenes 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.SHP participates in circadian regulation of CYP enzymes, thereby impacting xenobiotic metabolism and drug-induced hepatotoxicity. Methods: Results: Conclusion: -/-Cyp2c38Cyp2c39CYP CYP

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

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