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Vol. 302, Issue 2, 475-482, August 2002
La Jolla Institute for Molecular Medicine, San Diego, California
(J.L.R., L.M., S.W.A.); Institute for Biomedical Research, Hackensack
University Medical Center, Hackensack, New Jersey (K.D., J.M.L.); and
Department of Pathology, University of Pittsburgh, Pittsburgh,
Pennsylvania (S.S.)
Although CYP2C8, CYP2C9, and CYP2C19 play an important role in drug
biotransformation, factors influencing the expression and activity of
these CYP2C P450s in human liver remain largely undefined. We used
primary cultures of human hepatocytes from 15 subjects to assess the
inducibility of CYP2C enzyme expression by prototypical inducer agents,
including rifampicin, dexamethasone, and phenobarbital. After culture
for 72 h in serum-free medium on collagen, Western
blotting revealed that CYP2C9 was the only CYP2C enzyme expressed at
appreciable levels in untreated hepatocytes. Subsequent treatment with
25 µM rifampicin for 48 h elicited marked increases in CYP2C8
(700 ± 761%), CYP2C19 (854%), and CYP2C9 (209 ± 176%)
protein content versus a 550 ± 170% enhancement of CYP3A4 enzyme
levels. Parallel increases in CYP2C mRNAs, measured by Northern
blotting and/or RNase protection, were found in rifampicin-treated hepatocytes, with CYP2C8, CYP2C9, and CYP2C19 transcripts exhibiting increases of 688 ± 635, 207 ± 49, and 230 ± 60%,
respectively, versus an 8.8-fold enhancement of CYP3A4 mRNA levels.
Dexamethasone (10 µM) treatment enhanced CYP2C8 mRNA (360 ± 100%) and protein (274%) content, although this steroid had less
effect on CYP2C9 and CYP2C19 transcripts (23 ± 21% and 21 ± 36%, respectively) and enzyme levels (55 and 143%, respectively).
Phenobarbital (100 µM) was a powerful inducer of CYP2C9 (850%) and
CYP2C19 (735%) mRNA content, and also increased CYP2C8 (610%) and
CYP3A4 (205%) transcripts. Our results show that CYP2C enzyme
expression in human hepatocytes is highly inducible by rifampicin,
dexamethasone, and phenobarbital. Because these xenobiotics are ligands
and/or activators of the pregnane X receptor and/or constitutive
androstane receptor, such orphan nuclear receptors and their response
elements may partake in regulating CYP2C gene expression in humans.
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