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Vol. 26, Issue 5, 490-496, May 1998
Merck Frosst Centre for Therapeutic Research (J.M.S., P.E.M.,
S.H.D., B.P.K., P.P., J.A.Y., D.A.N.-G.), and
Drug Metabolism
Department, Merck Research (T.R.)
Induction of cytochromes P450 (P450s) by drugs can lead to
drug-drug interactions. Primary hepatocytes have been reported to
retain inducible P450s. To optimize the use of primary hepatocytes for
predicting induction of P450 (CYP 3A and 2B) expression in vivo, both culture conditions and expression of induction
potentials were investigated. In rat hepatocytes, basal CYP 3A1/2
expression was better maintained in cells cultured on Matrigel compared
with collagen when low concentrations of dexamethasone were used.
However, CYP 3A1/2 induction was not affected by either matrix. In
contrast, induction of CYP 2B1/2 by phenobarbital was markedly stronger in hepatocytes cultured on Matrigel. To further validate the in vitro model, Sprague-Dawley rats and isolated hepatocytes
cultured on Matrigel were exposed to a series of compounds. In an
attempt to minimize large variability between experiments, a novel
approach for calculating induction potential was applied. In
vitro results for CYP 3A1/2 and 2B1/2 induction correlated well
with those observed in vivo. In contrast with rat
hepatocytes, basal CYP 3A4 expression in human hepatocytes decreased
rapidly in cells cultured on either Matrigel or collagen. However, CYP
3A4 inducibility was retained in cells cultured on either matrix.
Interestingly, induction of CYP 3A4 in human hepatocytes by several
model compounds did not correlate with the induction of CYP 3A1/2 in
rat hepatocytes. This in vitro assay should facilitate the
demand for a fast and reproducible method for addressing P450 induction
by numerous compounds at the drug discovery stage.
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