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Drug metabolic activity of cultured hepatocytes can synchronize with bile acid concentration in the medium
Author(s) -
Sugihara Nobuhiro,
Ise Hirohiko,
Negishi Naoki,
Nikaido Toshio,
Akaike Toshihiro
Publication year - 2002
Publication title -
cell biochemistry and function
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.933
H-Index - 61
eISSN - 1099-0844
pISSN - 0263-6484
DOI - 10.1002/cbf.933
Subject(s) - glycocholic acid , bile acid , biochemistry , cytochrome p450 , cyp3a , secretion , biology , chemistry , cholic acid , metabolism
The regulation of drug metabolic activity of cultured hepatocytes can be applied to the evaluation of pharmacokinetics, analysis of drug delivery and the bioartificial liver system. It is very difficult to maintain the drug metabolic activity mediated by cytochrome P‐450 (CYP) 3A. Recently we found that the CYP3A aminopyrine N‐demethylase (AMND) activity of hepatocytes cultured on collagen surface oscillated with culture time. This phenomenon was related to the concentration of bile acid in the culture medium. CYP3A, multidrug resistant gene 2 (MDR2) and heat shock protein 84 (HSP84) mRNA appeared in a manner corresponding to this oscillation. When a large quantity of bile acid was taken up into hepatocytes from the medium, low AMND activity was observed, and these proteins did not appear. When bile acid was secreted and the bile acid concentration inside the hepatocytes was low, high AMND activity was obtained, and these proteins appeared. In order to clarify the mechanism of oscillation between AMND activity and bile acid, 8 μ M glycocholic acid was added to the culture medium 15 h before the measurement. No oscillation in AMND activity was observed in the presence of 8 μ M glycocholic acid. Bile acid controls the AMND activity in the transcription of hepatocytes. Copyright © 2001 John Wiley & Sons, Ltd.