| Co-Investigator(Kenkyū-buntansha) |
SHIMIZU Shuji Kyushu University, Faculty of Medicine, Associate Professor, 医学部, 助教授 (70274454)
YAMAGUCHI Koji Kyushu University, Faculty of Medicine, Lecturer, 医学部, 講師 (50191226)
CHIJIIWA Kazuo Kyushu University, Graduate School of Medical Sciences, Associate Professor, 大学院・医学系研究科, 助教授 (90179945)
NOSHIRO Hirokazu Kyushu University, Faculty of Medicine, Assistant Professor, 医学部, 助手 (90301340)
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| Budget Amount *help |
¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 1999: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 1998: ¥1,600,000 (Direct Cost: ¥1,600,000)
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| Research Abstract |
The first study was designed to investigate dose and time-dependent effects of cholestyramine on hepatic bile acid synthesis in the hamster. Cholestyramine increases activities of hepatic cholesterol 7α-hydroxylase and serum levels of 7α-hydroxycholesterol. To examine if serum 7α -hydroxycholesterol level parallels with the enzyme activity, 0, 0.5, 1, 2, 4, and 10% of cholestyramine was administered to female golden Syrian hamsters for 28 days in the dose-dependent study and 2% cholestyramine for 0, 1, 3, 7, 14, 21, and 28 days in the time-dependent study. In the dose-dependent study, hepatic and serum cholesterol levels were significantly decreased dose-dependently when more than 0.5% of cholestyramine was fed for 28days. Cholestyramine increased the cholesterol 7α -hydroxylase activity in a dose-dependent manner, while the serum 7α -hydroxycholesterol level was essentially unchanged. No correlation was found between the serum level and the hepatic enzyme activity. In the time-depende
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nt study, hepatic and serum cholesterol levels markedly decreased when 2% cholestyramine was fed for longer than 3 day. Serum triglyceride level increased significantly for the first 7 days and then decreased. Cholesterol 7α -hydroxylase activity increased significantly as early as on day 1, became maximum on day 7, and then kept the significantly high values until day 28. The serum 7α -hydroxycholesterol level significantly increased for the first 7days and decreased to the pretreatment level thereafter. The serum 7α -hydroxycholesterol level significantly correlated with the serum cholesterol and triglyceride levels. We conclude that the serum 7α -hydroxycholesterol level does not always reflect the activity of hepatic cholesterol 7α -hydroxylase, when cholesterol metabolism is severely disturbed by cholestyramine.
The next study was performed in clinical patients who undergo partial hepatectomy. Bile acid synthesis is reported to be useful to assess the liver regeneration in partially hepatectomized rats. In order to examine if liver regeneration after partial hepatectomy in clinical patients might be also assessed by bile acid synthesis, a preliminary study was performed. Mean serum 7α -hydroxycholesterol level on day 0 was higher than the control value in human. The level was suppressed between day 1 and day 7, was increased on day 14, and then decreased on day 21. The chronological change of the serum levels was similar to that in the animal model, however no statistical difference could be observed among the postoperative days, because of large variations of data in clinical patients. Patients with preoperative biliary drainage had higher serum 7α -hydroxycholesterol level than patients without biliary drainage on day 0 had suppressed serum levels throughout the 21 days after hepatectomy. In patients whose liver resection rate was more than 50%, the serum levels were decreased on day 1 and kept the low level until 21 days after hepatectomy. In summary, the present study showed that the chronological change in mean serum 7α -hydroxycholesterol level after partial hepatectomy in clinical patients was similar to that of the two-third hepatectomy in rats. Presence of preoperative PTBD and the massive hepatic resection more than 50% of the liver may delay the recovery of bile acid synthesis after hepatectomy. However, serum 7α -hydroxycholesterol levels in each patient may not be used to predict the extent of liver regeneration, because of the very large variations in its levels in the clinical patients. Less
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