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Vol. 62, Issue 5, 1177-1186, November 2002
Institute of Environmental Health Sciences, Wayne State University,
Detroit, Michigan
Because our previous studies indicated that squalestatin 1 treatment
induces CYP2B expression in primary cultures of rat hepatocytes as a
direct consequence of squalene synthase inhibition, we investigated possible underlying mechanisms. Cotransfection of cultured
Sprague-Dawley male rat hepatocytes with each of the three sterol
regulatory element binding protein (SREBP) transcription factors failed
to induce luciferase expression from a squalestatin 1-responsive CYP2B1
reporter plasmid. Squalestatin 1 treatment of primary hepatocyte cultures from male Wistar-Kyoto rats produced a greater induction of
CYP2B mRNA than occurred in cultures from female rats, consistent with
the previously demonstrated response dimorphism that has been
attributed to differences in constitutive androstane receptor (CAR)
levels. Cotransfection of female Wistar-Kyoto rat hepatocyte cultures
with plasmid expressing either mouse or rat CAR restored squalestatin
1-inducible CYP2B1-reporter expression. Cotransfection of
Sprague-Dawley rat hepatocyte cultures with plasmid expressing rat CAR
lacking the C-terminal AF-2 subdomain inhibited squalestatin 1-inducible CYP2B1-reporter expression. Squalestatin 1-mediated CYP2B
mRNA induction in rat hepatocyte cultures was completely abolished by
pretreatment with the 3-hydroxymethyl-3-glutaryl CoA reductase
inhibitor pravastatin and was rescued by mevalonate supplementation,
whereas phenobarbital-mediated induction was unaffected by these
treatments. Finally, direct addition of
trans,trans-farnesol to the culture medium caused the
rapid induction of CYP2B mRNA. These results indicate that squalestatin
1 treatment induces CYP2B expression, not by inhibiting sterol
synthesis and activating SREBPs, but by evoking the accumulation of an
endogenous isoprenoid and activating CAR.
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