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J.Health Sci., 50(3), 226-234, 2004
Possible Involvement of Chlorinated Ethylenes in
Arylhydrocarbon Receptor-Related Induction of Cytochrome P4501A1
(CYP1A1) in Human Hepatoma HepG2 Cells
Akinori Uesugi,a Takayuki
Nakahama,*, a Shigeki
Shimba,b Masakatsu
Tezuka,b and Yoshio Inouyea
aFaculty of Pharmaceutical Sciences, Toho University, 2-2-1
Miyama, Funabashi, Chiba 274-8510, Japan and
bCollege of Pharmacy, Nihon University, 7-7-1 Narashinodai, Funabashi,
Chiba 274-8555, Japan
In our previous study, chlorinated ethylenes (CEs) such as tetrachloroethylene (PCE),
trichloroethylene (TCE) and 1,1-dichloroethylene
(1,1-DCE) were found to suppress CYP1A1 activity in
rats. In the present study, the effects of CEs on
CYP1A1 activity, CYP1A1 mRNA expression and the binding of nuclear proteins to the xenobiotic
response element (XRE) were investigated in rat hepatocytes and human hepatoma HepG2 cells.
Unexpectedly, CYP1A1 activity was enhanced in the cells cultured in the presence of CEs,
suggesting that the suppressive effect of CEs
in vivo is indirect. Well consistent with the enhanced enzymatic
activity, the expression of CYP1A1 mRNA was increased by all CEs. Furthermore, the induction by
3-methylchoranthrene (3-MC) was reversed in the presence of individual CEs, implying cross-talk
between the induction mechanisms of PAHs and CEs.
In a luciferase reporter assay of transcription under
the control of 4 repeats of XRE, a 2.5-fold increase
was induced in HepG2 cells by CEs in the case of 1,1-DCE-treatment, while a 11-fold increase was
observed in the cells treated with 3-MC. In HepG2 cells transfected with plasmids expressing aryl
hydrocarbon receptor (AhR) antisense mRNA, in which the AhR-expression level was reduced by
approximately 40%, no increase in luciferase activity
was observed following the CE-treatment, though a 15-fold induction was observed in the presence
of 3-MC. As for the nuclear XRE-binding proteins in the presence of CEs analyzed with the gel
mobility shift assay, the band-intensity peaked 3 hr after
the PCE-, TCE- and 3-MC-treatments. The metabolic activation might be responsible for the 3-hr
delay to attain the maximal band-intensity in the case of 1,1-DCE.
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