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Vol. 54, Issue 3, 474-484, September 1998
Institute of Chemical Toxicology, Wayne State University, Detroit,
Michigan 48201
The effects of treatment with squalestatin 1, a potent inhibitor of
squalene synthase, the first committed enzyme of sterol biosynthesis,
were examined on cytochrome P450 expression in primary cultured rat
hepatocytes and rat liver. Incubation of cultured hepatocytes with
squalestatin 1 caused marked accumulations (maximal elevations that
were ~25-100% of phenobarbital-elicited increases) of CYP2B mRNA
and immunoreactive protein but not of CYP1A, CYP3A, or CYP4A.
Squalestatin 1 treatment increased CYP2B and 3-hydroxy-3-methylglutaryl coenzyme A reductase mRNA content in hepatocyte cultures with comparable potencies (ED50 = 5.0 and 18 nM,
respectively), and significantly induced CYP2B (mRNA, immunoreactive
protein, and pentoxyresorufin O-dealkylase activity) in the livers of
treated rats, producing maximal increases at a dose of 25 mg/kg/day
that were ~32-87% of phenobarbital-induced increases. Squalestatin 1 treatment induced both CYP2B1 and CYP2B2 and activated reporter gene
expression in cultured hepatocytes transiently transfected with a
plasmid containing ~2.4 kb of CYP2B1 gene 5'-flanking region or containing a previously described phenobarbital-responsive region.
Coincubation of cultured hepatocytes with 25-hydroxycholesterol suppressed squalestatin 1-mediated CYP2B and 3-hydroxy-3-methylglutaryl coenzyme A mRNA induction with approximately the same potency. Treatment of cultures with SQ-34919, a structurally distinct squalene synthase inhibitor, produced the same selective CYP2B mRNA induction as
did squalestatin 1. These results suggest that inhibition of hepatic
sterol synthesis activates processes that culminate in increased CYP2B
gene transcription.
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