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Vol. 31, Issue 4, 421-431, April 2003
XenoTech, LLC, Lenexa, Kansas (A.M., R.A.G., K.M.C., D.R.M.,
L.A.B., L.A.K., A.D.D., M.C., A.P.); Department of Surgery, University
of Kansas Medical Center, Kansas City, Kansas (J.F.); Stine-Haskell
Research Center, the DuPont Pharmaceuticals Company, Newark, Delaware
(M.D.R., L.G.); School of Pharmacy, Division of Pharmaceutics,
University of North Carolina-Chapel Hill, North Carolina, (E.L.L.); Byk
Gulden, Konstanz, Germany (K.Z.); Cephalon, Inc., West Chester,
Pennsylvania (P.R.); Sepracor, Inc., Marlborough, Massachusetts (P.K.);
SUGEN, Inc., S. San Francisco, California (L.A., G.W.); and Pfizer,
Inc., Groton, Connecticut (L.Y.).
Cultured human hepatocytes are a valuable in vitro system for
evaluating new molecular entities as inducers of cytochrome P450
(P450) enzymes. The present study summarizes data obtained from
62 preparations of cultured human hepatocytes that were treated with
vehicles (saline or dimethylsulfoxide, 0.1%), 
-naphthoflavone (33 µM), phenobarbital (100 or 250 µM), isoniazid (100 µM) and/or rifampin (20 or 50 µM), and examined for the expression of P450 enzymes based on microsomal activity toward marker substrates, or in
the case of CYP2C8, the level of immunoreactive protein. The results
show that CYP1A2 activity was markedly induced by -naphthoflavone
(on average 13-fold, n = 28 preparations), and weakly induced by phenobarbital (1.9-fold, n = 25)
and rifampin (2.3-fold, n = 22); CYP2A6 activity
tended to be increased with phenobarbital (n = 7)
and rifampin (n = 3) treatments, but the effects
were not statistically significant; CYP2B6 was induced by phenobarbital
(6.5-fold, n = 13) and rifampin (13-fold,
n = 14); CYP2C8 was induced by phenobarbital
(4.0-fold, n = 4) and rifampin (5.2-fold,
n = 4); CYP2C9 was induced by phenobarbital (1.8-fold, n = 14) and rifampin (3.5-fold,
n = 10); CYP2C19 was markedly induced by rifampin
(37-fold, n = 10), but relatively modestly by
phenobarbital (7-fold, n = 9); CYP2D6 was not
significantly induced by phenobarbital (n = 5) or
rifampin (n = 5); CYP2E1 was induced by
phenobarbital (1.7-fold, n = 5), rifampin
(2.2-fold, n = 5), and isoniazid (2.3-fold,
n = 5); and, CYP3A4 was induced by phenobarbital
(3.3-fold, n = 42) and rifampin (10-fold,
n = 61), but not by -naphthoflavone. Based on
these observations, we generalize that -naphthoflavone induces
CYP1A2 and isoniazid induces CYP2E1, whereas rifampin and, to a lesser
extent phenobarbital, tend to significantly and consistently induce
enzymes of the CYP2A, CYP2B, CYP2C, CYP2E, and CYP3A subfamilies but
not the 2D subfamily.
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