Phenobarbital induces cytochrome P-450- and cytochrome P-448-dependent monooxygenases in rat hepatoma cells.
The induction by phenobarbital (PB) of aldrin epoxidase (AE) and aryl hydrocarbon hydroxylase (AHH), markers of cytochrome P-450- and cytochrome P-448-dependent monooxygenases, was studied in cell lines derived from Reuber H35 rat hepatoma which differ widely in their degree of differentiation. The following results were obtained: (1) PB induced AE 2-6-fold and AHH 2-4-fold in the differentiated clones, Fao, 2sFou, and C2Rev7 during an exposure period of 72 h. The barbiturate increased AHH but not AE in the dedifferentiated clone H5, the poorly differentiated line H4IIEC3/T, and in the well differentiated line H4IIEC3/G-. (2) Continuous presence of the barbiturate was required for maintaining the induction of the two monooxygenase activities in C2Rev7 cells. (3) Maximum induction of AE was observed at a PB concentration of 1.5-3.0 mM. (4) The effects of 7,8-benzoflavone on AHH-activities induced by phenobarbital in C2Rev7 and H5 cells suggested that they are mediated by cytochrome P-450- and cytochrome P-448-dependent monooxygenase forms, respectively. Thus, the flavonoid had only a slight inhibitory effect on PB-induced AHH in C2Rev7 cells, but strongly inhibited PB-induced AHH in H5 cells. The induction of AE and of 7,8-benzoflavone-inhibitable AHH in 2sFou cells indicated that PB is capable of inducing cytochromes P-450 and cytochrome P-448 in the same cell.
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000201:enzymology*; D002460:Cell Line; D003577:Cytochrome P-450 Enzyme System; D004790:Enzyme Induction; D007700:Kinetics; D008113:Liver Neoplasms; D006899:Mixed Function Oxygenases / Q000096:biosynthesis* / Q000378:metabolism; D009245:NADH Dehydrogenase / Q000096:biosynthesis; D010105:Oxygenases / Q000096:biosynthesis*; D010634:Phenobarbital / Q000494:pharmacology*; D051381:Rats
D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C019647:aldrin epoxidase; D010105:Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C027270:cytochrome P448-dependent mono-oxygenase; D009245:NADH Dehydrogenase; D010634:Phenobarbital