Nuclear receptor CAR specifically activates the two-pore K+ channel Kcnk1 gene in male mouse livers, which attenuates phenobarbital-induced hepatic hyperplasia

Toxicol Sci. 2013 Mar;132(1):151-61. doi: 10.1093/toxsci/kfs338. Epub 2013 Jan 4.


KCNK1, a member of the family of two-pore K(+) ion channels, is specifically induced in the livers of male mice after phenobarbital treatment. Here, we have determined the molecular mechanism of this male-specific activation of the Kcnk1 gene and characterized KCNK1 as a phenobarbital-inducible antihyperplasia factor. Upon activation by phenobarbital, nuclear receptor CAR binds the 97-bp response element (-2441/-2345) within the Kcnk1 promoter. This binding is observed in the livers of male mice, but not in the livers of female mice and requires the pituitary gland, because hypophysectomy abrogates it. Hyperplasia further progressed in the livers of Kcnk1 ( -/- ) male mice compared with those of Kcnk1 ( +/+ ) males after phenobarbital treatment. Thus, KCNK1 suppresses phenobarbital-induced hyperplasia. These results indicate that phenobarbital treatment induces KCNK1 to elicit a male-specific and growth-suppressing signal. Thus, KCNK1 and Kcnk1 ( -/- ) mice provide an experimental tool for further investigation into the molecular mechanism of CAR-mediated promotion of the development of hepatocellular carcinoma in mice.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Chromatin Immunoprecipitation
  • Constitutive Androstane Receptor
  • DNA Primers
  • Female
  • Hyperplasia / chemically induced*
  • Hyperplasia / genetics
  • Liver / drug effects*
  • Liver / metabolism
  • Male
  • Mice
  • Mice, Inbred C3H
  • Mice, Inbred C57BL
  • Molecular Sequence Data
  • Phenobarbital / toxicity*
  • Potassium Channels, Tandem Pore Domain / genetics*
  • Promoter Regions, Genetic
  • Real-Time Polymerase Chain Reaction
  • Receptors, Cytoplasmic and Nuclear / physiology*


  • Constitutive Androstane Receptor
  • DNA Primers
  • Kcnk1 protein, mouse
  • Potassium Channels, Tandem Pore Domain
  • Receptors, Cytoplasmic and Nuclear
  • Phenobarbital