EFFECT OF MODEL INDUCERS ON CYTOCHROME-P450 ACTIVITIES OF HUMAN HEPATOCYTES IN PRIMARY CULTURE

The dealkylations of 7-ethoxy- and 7-pentoxyresorufin, p-nitrophenol h ydroxylation, and regio- and stereoselective hydroxylation of testoste rone were measured to study the stability and inducibility of cytochro me P450 activities in cultured human hepatocytes. The results showed t hat human hepatocytes in primary culture retain the ability to increas e specific cytochrome P450 activities upon incubation with inducers. 3 -Methylcholanthrene produced a strong increase (6- to 21-fold over con trol) in 7-ethoxyresorufin O-deethylase activity and a small enhanceme nt (1.5- to 2.5-fold) of the p-nitrophenol hydroxylation rate. Incubat ion of cells with phenobarbital resulted in moderate increases in 7-pe ntoxyresorufin O-depentylation (1.5- to 2-fold) and in testosterone hy droxylation at 16 alpha (1.5- to 4.5-fold) and 16 beta (1.3- to 4-fold ) positions. Ethanol specifically increased p-nitrophenol hydroxylase activity (1.5- to 3.5-fold) and reduced 15 beta- and 6 beta-hydroxylat ions of testosterone. Treatment of hepatocytes with dexamethasone prod uced an increase of almost all the activities studied, with 6 beta- (2 - to 3-fold) and 16 beta-hydroxytestosterone (1.4- to 2.4-fold) format ion showing the greatest enhancement, Clofibric acid exposure resulted in 1.5- to 3-fold increases in 7-pentoxyresorufin O-depentylase and i n testosterone 6 beta- and 2 beta-hydroxylase activities. Isosafrol se lectively increased 7-ethoxyresorufin O-deethylase activity (2- to 3-f old), and it moderately reduced the other activities studied.