PURPOSE: To examine the potential of cultured human liver slices to predict cytochrome P450 (CYP) inducibility, regarding global and zonal CYP expression, together with drug-induced histologic changes. METHODS: We first assessed whether CYP2B6, 3A4, and 2C9 expression was maintained in cultured liver slices. Cultured hepatocytes were used as the reference culture system. Then we tested the effects of phenobarbital and cyclophosphamide on CYP expression in both models. RESULTS: Morphologic features are preserved in slices. Basal CYP expression declines with time in culture in both models. Slices display the same region specificity of CYP2B6, 2C9, and 3A4 expression as intact liver. CYP2B6 and 3A4 mRNA, apoprotein, and enzyme-related activities were induced by phenobarbital and cyclophosphamide, whereas CYP2C9 apoprotein was not. Their immunoreactivities were also increased, while their zonal distribution was preserved on slice tissue sections. Microsomal enzyme induction was confirmed by histology. CONCLUSIONS: Cultured human liver slices are an attractive alternative to hepatocyte culture for the prediction of human CYP isoenzyme induction by xenobiotics.
PURPOSE: To examine the potential of cultured human liver slices to predict cytochrome P450 (CYP) inducibility, regarding global and zonal CYP expression, together with drug-induced histologic changes. METHODS: We first assessed whether CYP2B6, 3A4, and 2C9 expression was maintained in cultured liver slices. Cultured hepatocytes were used as the reference culture system. Then we tested the effects of phenobarbital and cyclophosphamide on CYP expression in both models. RESULTS: Morphologic features are preserved in slices. Basal CYP expression declines with time in culture in both models. Slices display the same region specificity of CYP2B6, 2C9, and 3A4 expression as intact liver. CYP2B6 and 3A4 mRNA, apoprotein, and enzyme-related activities were induced by phenobarbital and cyclophosphamide, whereas CYP2C9 apoprotein was not. Their immunoreactivities were also increased, while their zonal distribution was preserved on slice tissue sections. Microsomal enzyme induction was confirmed by histology. CONCLUSIONS: Cultured human liver slices are an attractive alternative to hepatocyte culture for the prediction of humanCYP isoenzyme induction by xenobiotics.
Authors: L Gervot; B Rochat; J C Gautier; F Bohnenstengel; H Kroemer; V de Berardinis; H Martin; P Beaune; I de Waziers Journal: Pharmacogenetics Date: 1999-06
Authors: E G Schuetz; J D Schuetz; S C Strom; M T Thompson; R A Fisher; D T Molowa; D Li; P S Guzelian Journal: Hepatology Date: 1993-11 Impact factor: 17.425
Authors: M VandenBranden; S A Wrighton; S Ekins; J S Gillespie; S N Binkley; B J Ring; M G Gadberry; D C Mullins; S C Strom; C B Jensen Journal: Drug Metab Dispos Date: 1998-11 Impact factor: 3.922
Authors: Shivaani Kummar; Jiuping Ji; Robert Morgan; Heinz-Josef Lenz; Shannon L Puhalla; Chandra P Belani; David R Gandara; Deborah Allen; Brian Kiesel; Jan H Beumer; Edward M Newman; Larry Rubinstein; Alice Chen; Yiping Zhang; Lihua Wang; Robert J Kinders; Ralph E Parchment; Joseph E Tomaszewski; James H Doroshow Journal: Clin Cancer Res Date: 2012-02-03 Impact factor: 12.531
Authors: Kajsa P Persson; Susanne Ekehed; Charlotta Otter; E S Mareike Lutz; Jane McPheat; Collen M Masimirembwa; Tommy B Andersson Journal: Pharm Res Date: 2006-11-22 Impact factor: 4.200
Authors: R K Kelley; J Hwang; M J M Magbanua; L Watt; J H Beumer; S M Christner; S Baruchel; B Wu; L Fong; B M Yeh; A P Moore; A H Ko; W M Korn; S Rajpal; J W Park; M A Tempero; A P Venook; E K Bergsland Journal: Br J Cancer Date: 2013-09-10 Impact factor: 7.640
Authors: Sumera Karim; Evaggelia Liaskou; Samuel Hadley; Janine Youster; Jeff Faint; David H Adams; Patricia F Lalor Journal: Toxicol Sci Date: 2013-01-08 Impact factor: 4.849