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Journal of Biochemistry Advance Access originally published online on July 25, 2007
Journal of Biochemistry 2007 142(4):443-452; doi:10.1093/jb/mvm152
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© 2007 The Japanese Biochemical Society.

Regulatory Factors Involved in Species-specific Modulation of Arylhydrocarbon Receptor (AhR)-dependent Gene Expression in Humans and Mice

Takehiro Suzuki and Keiko Nohara*

Environmental Health Sciences Division, National Institute for Environmental Studies, 16-2 Onogawa, Tsukuba 305-8506, Japan

*To whom correspondence should be addressed at. Environmental Health Sciences Division, National Institute for Environmental Studies, 16-2 Onogawa, Tsukuba 305-8506, Japan. Tel: +81-29-850-2500, Fax: +81-29-850-2574, E-mail: keikon{at}nies.go.jp

Received April 15, 2007; Accepted June 22, 2007


  Abstract

The arylhydrocarbon receptor (AhR) mediates toxicities of dioxins, including the most potent congener 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), by being translocated to the nucleus upon ligand-binding and inducing expression of target genes. Although the species-specific activity of the AhR is primarily attributable to species-specific AhR-ligand affinity, the precise mechanism has not been clarified. We investigated the modulation mechanisms of AhR in Hepa1c1c7 and HepG2 hepatoma cells, which were derived from high-affinity-AhR-expressing C57BL/6 mice and low-affinity-AhR-expressing humans, respectively. Although, consistent with their AhR affinities, TCDD induced a greater amount of cytochrome P450 1A1 (CYP1A1) mRNA, one of the most sensitive AhR-targets, in Hepa1c1c7 cells than in HepG2 cells immediately after exposure, both cells expressed a similar level of CYP1A1 mRNA from 4 h onward. A rapid decrease in the AhR protein after nuclear translocation in Hepa1c1c7 cells was suggested to contribute to suppression of CYP1A1 induction to the same level as in HepG2 cells. Different profiles of histone deacetylase 1 (HDAC1)-binding to the CYP1A1 promoter and histone acetylation between both cell lines and lower degradation rate of CYP1A1 mRNA in HepG2 cells were also implicated in regulating their target gene expression. These factors have been highly suggested to be involved in the species-specific modulation mechanism of AhR function.

Key Words: arylhydrocarbon receptor (AhR), CYP1A1, Hepa1c1c7, HepG2, TCDD

Abbreviations: AhR, arylhydrocarbon receptor; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; CYP1A1, cytochrome P4501A1; HDAC, histone deacetylase; Hsp90, heat shock protein 90; XAP2, hepatitis B virus X-associated protein; NLS, nuclear localization signal; ARNT, arylhydrocarbon receptor nuclear translocator; XRE, xenobiotic responsive element; TSA, trichostatin A; polII, RNA polymerase II; HAT, histone acetyltransferase; CBP, CREB binding protein; N-CoR, nuclear receptor corepressor


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