Effect of model inducers on cytochrome P450 activities of human hepatocytes in primary culture.
The dealkylations of 7-ethoxy- and 7-pentoxyresorufin,p-nitrophenol hydroxylation, and regio- and stereoselective hydroxylation of testosterone were measured to study the stability and inducibility of cytochrome P450 activities in cultured human hepatocytes. The results showed that human hepatocytes in primary culture retain the ability to increase specific cytochrome P450 activities upon incubation with inducers. 3-Methylcholanthrene produced a strong increase (6- to 21-fold over control) in 7-ethoxyresorufin O-deethylase activity and a small enhancement (1.5- to 2.5-fold) of the p-nitrophenol hydroxylation rate. Incubation of cells with phenobarbital resulted in moderate increases in 7-pentoxyresorufin O-depentylation (1.5- to 2-fold) and in testosterone hydroxylation 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-hydroxylations of testosterone. Treatment of hepatocytes with dexamethasone produced 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) formation showing the greatest enhancement. Clofibric acid exposure resulted in 1.5- to 3-fold increases in 7-pentoxyresorufin O-depentylase and in testosterone 6 beta- and 2 beta-hydroxylase activities. Isosafrol selectively increased 7-ethoxyresorufin O-deethylase activity (2- to 3-fold), and it moderately reduced the other activities studied.
Donato
M T
MT
Unidad de Hepatología Experimental, Hospital Universitario La Fe, Valencia, Spain.
Castell
J V
JV
Gómez-Lechón
M J
MJ
D000328:Adult; D000368:Aged; D002478:Cells, Cultured; D002995:Clofibric Acid / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D004790:Enzyme Induction; D000431:Ethanol / Q000494:pharmacology; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000096:biosynthesis* / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology*; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology; D008875:Middle Aged; D009596:Nitrophenols / Q000378:metabolism; D010078:Oxazines / Q000378:metabolism; D010084:Oxidation-Reduction; D010634:Phenobarbital / Q000494:pharmacology; D012451:Safrole / Q000494:pharmacology; D013379:Substrate Specificity; D013739:Testosterone / Q000378:metabolism
D007527:Isoenzymes; D009596:Nitrophenols; D010078:Oxazines; D000431:Ethanol; D013739:Testosterone; D002995:Clofibric Acid; D008748:Methylcholanthrene; C007649:ethoxyresorufin; D003907:Dexamethasone; C044943:pentoxyresorufin; D003577:Cytochrome P-450 Enzyme System; D012451:Safrole; C015959:isosafrole; C024836:4-nitrophenol; D010634:Phenobarbital