Studies on the prediction of fetal toxicity caused by drugs
| Project/Area Number |
09470522
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (B)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
応用薬理学・医療系薬学
|
|---|
| Research Institution | Chiba University |
|---|
Principal Investigator |
KITADA Mitsukazu Chiba University, Hospital Pharmacy, Professor, 医学部・附属病院, 教授 (90110345)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
ISHII Itsuko Chiba University, Clinical Pharmacology, Assistant, 薬学部, 助手 (00202929)
OHMORI Shigeru Chiba University, Hospital Pharmacy, Associate Professor, 医学部・附属病院, 助教授 (70169069)
|
|---|
| Project Period (FY) |
1997 – 1998
|
| Project Status |
Completed (Fiscal Year 1998)
|
| Budget Amount *help |
¥10,600,000 (Direct Cost: ¥10,600,000)
Fiscal Year 1998: ¥4,400,000 (Direct Cost: ¥4,400,000)
Fiscal Year 1997: ¥6,200,000 (Direct Cost: ¥6,200,000)
|
|---|
| Keywords | CYP / CYP3A7 / steroid metabolism / drug metabolism / fetal toxicity / CYP3A |
|---|
| Research Abstract |
Human CYP3A4, CYP3A7 and their chimera CYPs expressed in TN5 or SF9 cells using baculovirus were used for the characterization of human fetal CYP3A7 in steroid metabolism, especially dehydroepiandrosterone (DHEA) and DHEA 3-sulfate (DHEA-3S).
(1) Expression levels of CYP3A enzymes and their chimera enzymes in insect cells and the stability of expressed proteins were different among these GYP enzymes. Exogenous NADPH-cytochrome P450 reductase and cytochrome b5 were essential to obtain the maximal activities for 16 - hydtoxylations of DHEA.and DHEA-3S.
(2) It was suggested that the amino acid residues from 210 to 279 in CYP3A7 were important to hydroxylate DHEA and DHEA-3S at 16 position.
(3) Computer model of CYP3A7 indicated that the protein was stabilized to bind with DHEA and DHEA-3S to form the hydrogen bond at Asp214 with hydroxyl group (DHEA) or -OSO3H (DHEA-3S) at Asp2l4 (oxygen of -CONH2 in Asp).
(4) From the kinetic studies, it was suggested that the region from 40 to 109 amino acids residues in CYP3A7 might be important to interact with NADPH-cytochrome P450 reductase and the region from 210 to 279 amino acid residues might be interact with alpha-naphthoflavone.
|
Report
(3 results)
Research Products
(6 results)
