Induction of cytochrome P450 2B6 and 3A4 expression by phenobarbital and cyclophosphamide in cultured human liver slices.
OBJECTIVE
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.
Drug Safety Evaluation, Aventis Pharma SA, Vitry-sur-Seine, France. helene.martin@ifrance.com
Hélène
H
Martin
Jean-Pierre
JP
Sarsat
Isabelle
I
de Waziers
Chantal
C
Housset
Pierre
P
Balladur
Philippe
P
Beaune
Véronique
V
Albaladejo
Carole
C
Lerche-Langrand
D000328:Adult; D000368:Aged; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis* / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D003520:Cyclophosphamide / Q000378:metabolism* / Q000493:pharmacokinetics; D065702:Cytochrome P-450 CYP2B6; D065729:Cytochrome P-450 CYP2C9; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000187:drug effects / Q000235:genetics; D004790:Enzyme Induction / Q000187:drug effects* / Q000235:genetics; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D010089:Oxidoreductases, N-Demethylating; D010634:Phenobarbital / Q000378:metabolism* / Q000493:pharmacokinetics
D003520:Cyclophosphamide; D003577:Cytochrome P-450 Enzyme System; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; C104464:CYP3A protein, human; D065702:Cytochrome P-450 CYP2B6; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D010634:Phenobarbital