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Dose-dependent difference of nuclear receptors involved in murine liver hypertrophy by piperonyl butoxide

Yohei Sakamoto1, Midori Yoshida, Kei Tamura

  • 1Division of Pathology, National Institute of Health Sciences.

The Journal of Toxicological Sciences
|November 13, 2015
PubMed

Insights

High doses of piperonyl butoxide (PBO) induce liver hypertrophy through constitutive androstane receptor (CAR)-independent and -dependent pathways. Lower PBO doses primarily rely on CAR for liver changes.

Area of Science:

  • Toxicology
  • Molecular Biology
  • Pharmacology

Background:

  • Nuclear receptors are critical regulators of chemical-induced liver hypertrophy in rodents.
  • Constitutive androstane receptor (CAR) is a key nuclear receptor involved in xenobiotic metabolism and liver adaptation.

Purpose of the Study:

  • To investigate the role of CAR and other nuclear receptors in mouse liver hypertrophy induced by varying doses of piperonyl butoxide (PBO).
  • To elucidate the dose-dependent mechanisms of PBO-induced liver hypertrophy and the involvement of nuclear receptors.

Main Methods:

  • Administration of PBO (200, 1,000, or 5,000 ppm) to wild-type and CAR-knockout mice for one week.
  • Assessment of liver weight, hepatocellular hypertrophy, and expression of key genes (Cyp3a11, Cyp2b10) and proteins (CYP3A, CYP2B).

Main Results:

  • High-dose PBO (5,000 ppm) caused liver hypertrophy in both wild-type and CAR-knockout mice, with increased Cyp3a11 mRNA and CYP3A protein, suggesting a CAR-independent pathway (possibly PXR).
  • Wild-type mice at 5,000 ppm showed enhanced hypertrophy and CYP2B staining, indicating a localized CAR contribution.
  • Lower PBO dose (1,000 ppm) induced liver weight increase and hypertrophy predominantly in wild-type mice, with elevated Cyp2b10 mRNA and CYP2B staining, highlighting CAR's essential role.

Conclusions:

  • PBO-induced liver hypertrophy exhibits dose-dependent effects on nuclear receptor involvement.
  • High-dose PBO triggers both CAR-dependent and -independent pathways, while lower doses primarily activate CAR-mediated responses.
  • Understanding the dose-response relationship is crucial for deciphering the role of nuclear receptors in chemical-induced liver hypertrophy.

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