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Vol. 27, Issue 8, 887-894, August 1999
University of Pittsburgh Medical Center, We have previously reported that paclitaxel (Taxol) is a
potent inducer of cytochrome P-450 (CYP) 3A protein and CYP3A mRNA in
human hepatocyte cultures. Here we report that Taxol increased CYP3A-dependent testosterone 6
-hydroxylation in intact hepatocytes. This effect was concentration-dependent, with maximal increase in
enzyme activity being observed at 10 µM Taxol. Treatment of hepatocyte cultures with concentrations of Taxol higher than 10 µM
caused a dose-dependent decrease in testosterone 6-hydroxylase activity, amount of CYP3A protein, and total protein synthesis. The
maximal CYP3A activity detected after treatment with Taxol or
rifampicin was similar in six separate human hepatocyte cultures, suggesting that the cultures have achieved a limit of maximally inducible CYP3A. The fold increase in enzyme activity, however, was
different and was inversely related to the level of expression in
untreated hepatocytes, with the greatest increases being observed in
the hepatocytes that expressed the lowest basal level of CYP3A. Pretreatment of hepatocytes with triacetyloleandomycin resulted in a
90% inhibition of testosterone 6-hydroxylase activity. Our results
demonstrate the use of human hepatocyte cultures to investigate the
induction of cytochrome P-450 by xenobiotics in intact cells and stress
the importance of large dose-response studies as well as the need to
assess toxicity in these investigations. The response to inducers of
CYP3A activity were very consistent among different hepatocyte donors.
Absolute values of testosterone 6-hydroxylase activity did not vary
more than 2- and 5-fold in induced and untreated hepatocytes, respectively.
Copyright © 1999 by The American Society for Pharmacology and Experimental Therapeutics
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