Effects of various inducers on the expression of cytochromes P-450 IIC8, 9, 10 and IIIA in cultured adult human hepatocytes.
Primary cultures of adult human hepatocytes were used to determine the capability of the human liver to respond to phenobarbital, 3-methylcholanthrene, troleandomycin and rifampicin, four compounds known to be potent inducers of hepatic cytochrome P-450 in various animal species. Both mRNA and corresponding protein of two major isoenzymes, that is, P-450 IIC8, 9, 10 and P-450 IIIA, were measured after daily exposure to the drugs for 3 days. Phenobarbital and rifampicin were found to increase the levels of P-450 IIC8, 9, 10 mRNA and protein while troleandomycin and 3-methylcholanthrene were ineffective. Different effects were obtained for P-450 IIIA. Both mRNA and related protein were markedly increased by troleandomycin and rifampicin and decreased by 3-methylcholanthrene. mRNAs were slightly increased by phenobarbital. The results demonstrate that human hepatocytes retain drug-inducible P-450 isoenzymes in primary culture and represent a unique approach to investigate regulation of human liver drug metabolizing enzymes.
Morel
F
F
Unité de Recherches Hépatologiques, INSERM U 49, Hôpital Pontchaillou, 35033 Rennes Cédex, France.
Beaune
P
P
Ratanasavanh
D
D
Flinois
J P
JP
Guengerich
F P
FP
Guillouzo
A
A