| Project/Area Number |
03670148
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| Research Category |
Grant-in-Aid for General Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Research Field |
Pathological medical chemistry
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| Research Institution | School of Medicine Keio University |
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Principal Investigator |
IMAI Michiyo Keio Univ. Sch. of Med. Assistant, 医学部, 助手 (30129340)
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| Co-Investigator(Kenkyū-buntansha) |
MUKAI Kuniaki Keio Univ. Sch. of Med. Assistant, 医学部, 助手 (80229913)
OGISHIMA Tadashi Keio Univ. Sch. of Med. Assistant, 医学部, 助手 (70177153)
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| Project Period (FY) |
1991 – 1992
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| Project Status |
Completed (Fiscal Year 1992)
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| Budget Amount *help |
¥2,000,000 (Direct Cost: ¥2,000,000)
Fiscal Year 1992: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 1991: ¥1,000,000 (Direct Cost: ¥1,000,000)
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| Keywords | aldosterone / aldosterone producing adenome / cytochrome P-450aldo / aldosterone synthase / adrenal cortex / angiotensin II / cytochrome P-450_<ll>beta / corticosteroid / アルドステロン産生腫瘍 / シトクロムP-450 / シトクロムP・450aldo / 転写調節因子 / 原発性アルドステロン症 / ホルモン産生腫瘍 / チトクロ-ムPー450 / 遺伝子クロ-ニング / 遺伝子転写制御 |
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| Research Abstract |
In 1989, we successfully purified a cytochrome P-450 which converts deoxycorticosterone efficiently to aldosterone from the zona glomerulosa of rat adrenal cortex(J.Biol. Chcm. 264, 10935). The new cytochrome was distinguishable from cytochrome P-450_<ll>beta responsible for the formation of cortisol or corticosterone from the same substrate. Thus, production of minerallo-and glucocorticoids are catalyzed by different enzymes in rat adrenal cortex, in contrast to the case of bovine adrenal cortex where the hormons are synthesized by a single enzyme cytochrome P-450_<ll>beta. On the basis of such findings, we investigated in this study the mechanism of aldosterone formation in human adrenal cortex with special emphasis on that in aldosterone producing adenoma. The results obtained are summarized as follows.
(1) In human adrenal cortex, there exist two distinct cytochromes P-450, i. e. cytochrome P-450aldo and cytochrome P-450_<ll>beta as in rat adrenocortex.
(2) The cytochrome P-450aldo is exessively expressed in aldosterone producing adenoma.
(3) Using rats as a model, stimulation of aldosterone production by angiotensin II was due to the stimulation of the de novo synthesis of cytochrome P-450aldo through the activation of transcription.
(4) Immunocytochemical studies with specific antibodies proved that cytochrome P-450aldo and cytochrome P-450_<ll>beta are localized exclusively in the zona glomerulosa and fasciculata-reticularis, respectively.
(5) Rat genes which encode cytochrome P-450aldo and cytochrome P-450_<ll>beta, respectively, were isolated and structures of their 5'-flanking regions were charecterized.
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