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Vol. 30, Issue 12, 1400-1405, December 2002
Institute of Environmental Health Sciences, Wayne State University,
Detroit, Michigan (T.A.K., N.A.M.-H.); Department of Surgery, Wayne
State University, and Department of Veterans Affairs, Detroit, Michigan
(M.S.D.); and Department of Pathology, University of Pittsburgh Medical
Center, Pittsburgh, Pennsylvania (H.C., S.C.S.)
The effects of treatment with the 3-hydroxy-3-methylglutaryl
coenzyme A reductase (HMG-CoA reductase) inhibitors lovastatin, simvastatin, pravastatin, fluvastatin, and atorvastatin on the contents
of cytochrome P450 mRNAs were examined in primary cultures of human
hepatocytes prepared from three different livers. Treatment of 2- to
3-day-old human hepatocyte cultures with 3 × 10
5 M
lovastatin, simvastatin, fluvastatin, or atorvastatin for 24 h
increased the amounts of CYP2B6 and CYP3A mRNA by an average of 3.8- to
9.2-fold and 24- to 36-fold, respectively. In contrast, pravastatin
treatment had no effect on the mRNA level of either CYP2B6 or CYP3A,
although treatment with pravastatin did produce the expected
compensatory increase in HMG-CoA reductase mRNA content, indicating
effective inhibition of cholesterol biosynthesis. Although treatment
with the active (+), but not the inactive (
), enantiomer of
atorvastatin increased the amount of HMG-CoA reductase mRNA, treatment
with each enantiomer significantly induced both CYP2B6 and CYP3A mRNA
levels. Treatment of primary cultured rat hepatocytes with the
atorvastatin enantiomers effectively increased the amount of CYP3A
mRNA, but had no effect on CYP2B or CYP4A mRNA levels, in contrast to
fluvastatin, which increased both. Findings for P450 proteins by
Western blotting were consistent with the mRNA results. These findings
indicate that the ability of a drug to inhibit HMG-CoA reductase
activity does not predict its ability to produce P450 induction in
primary cultured human hepatocytes, and demonstrate that some, but not
all, of the effects of these drugs that occur in primary cultured rat
hepatocytes are conserved in human hepatocyte cultures.
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