RT Journal Article SR Electronic T1 The Use of Human Hepatocyte Cultures to Study the Induction of Cytochrome P-450 JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 887 OP 894 VO 27 IS 8 A1 Vsevolod E. Kostrubsky A1 Vinod Ramachandran A1 Raman Venkataramanan A1 Kenneth Dorko A1 James E. Esplen A1 Shimin Zhang A1 Jacqueline F. Sinclair A1 Steven A. Wrighton A1 Stephen C. Strom YR 1999 UL http://dmd.aspetjournals.org/content/27/8/887.abstract AB 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 6β-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 6β-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 6β-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 6β-hydroxylase activity did not vary more than 2- and 5-fold in induced and untreated hepatocytes, respectively. The American Society for Pharmacology and Experimental Therapeutics