TY - JOUR
T1 - Drug metabolic activity of cultured hepatocytes can synchronize with bile acid concentration in the medium
AU - Sugihara, Nobuhiro
AU - Ise, Hirohiko
AU - Negishi, Naoki
AU - Nikaido, Toshio
AU - Akaike, Toshihiro
PY - 2002
Y1 - 2002
N2 - 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 μM 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 μM glycocholic acid. Bile acid controls the AMND activity in the transcription of hepatocytes.
AB - 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 μM 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 μM glycocholic acid. Bile acid controls the AMND activity in the transcription of hepatocytes.
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U2 - 10.1002/cbf.933
DO - 10.1002/cbf.933
M3 - Article
C2 - 11835266
AN - SCOPUS:0036181332
SN - 0263-6484
VL - 20
SP - 11
EP - 17
JO - Cell Biochemistry and Function
JF - Cell Biochemistry and Function
IS - 1
ER -