2010 Fiscal Year Final Research Report
Study on the mechanism of lethal and serious drug-induced adverse event in fetus
| Project/Area Number |
20390157
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (B)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Applied pharmacology
|
|---|
| Research Institution | Chiba University |
|---|
Principal Investigator |
KITADA Mitsukazu Chiba University, 医学部附属病院, 教授 (90110345)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
ARIYOSHI Noritaka 千葉大学, 医学部附属病院, 准教授 (00243957)
|
|---|
| Co-Investigator(Renkei-kenkyūsha) |
ISHII Itsuko 千葉大学, 大学院・薬学研究院, 准教授 (00202929)
|
|---|
| Project Period (FY) |
2008 – 2010
|
| Keywords | 医薬品副作用 / 薬物相互作用 |
|---|
| Research Abstract |
Dehydroepiandrosterone-3-sulfate (DHEA-S) plays important roles during pregnancy and is clinically used as an agent (prasterone sulfate) to treat pregnant woman with cervical ripening deficiency in Japan. However, several cases of fetal death have been reported after administration of prasterone sulfate to expectant mothers. We found that CYP3A7.2 may have considerably reduced capacity for the metabolism of DHEA-S at a physiologically relevant concentration of this steroid in vivo. We discovered six novel SNPs of the STS gene. However, 5SNPs present in postulated regulatory regions did not affect transcriptional activity, and V476M appeared to have little effect on both posttranscriptional expression of the enzyme and sulfatase activity toward DHEA-S. On the other hand, there was no non-synonymous SNP in all of exons, but one known SNP (-18T>C) was found in 5'-flanking region of the SLC22A11 gene. The result of reporter gene assay revealed that the SNP did not appear to give considerable change in transcriptional activity of the SLC22A11 gene. Although it was suggested that functional deficiency of these proteins due to genetic polymorphisms appear to affect pharmacokinetics of DHEA-S in fetal or fetal-placental unit, no polymorphism directly related to DHEA-S-induced fetal death was found in the STS and SLC22A11 genes in this study.
|
