Study on the mechanism of lethal and serious drug-induced adverse event in fetus

胎儿致死性严重药物不良事件机制研究

• 批准号: 20390157
• 负责人: KITADA Mitsukazu
• 金额: $ 11.9万
• 依托单位: Chiba University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2008
• 资助国家: 日本
• 起止时间: 2008 至 2010
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-20390157/
• 关键词: 医薬品副作用; 薬物相互作用; 胎児毒性; 心臓停止; DHEA-S; 遺伝子多型; CYP3A7; STS; 心機能とステロイド

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.

脱氢双足剂3-硫酸盐（DHEA-S）在怀孕期间起着重要作用，并在临床上用作药剂（硫酸番茄酮）来治疗日本宫颈成熟不足的孕妇。然而，在将硫酸硫酸硫酸盐给准妈妈施用后，已经报告了几例胎儿死亡。我们发现，在该类固醇与体内的生理相关浓度下，CYP3A7.2可能大大降低了DHEA-S代谢的能力。我们发现了STS基因的六个新型SNP。然而，假定的调节区域中存在的5SNP不会影响转录活性，而V476M似乎对酶的转录后表达和硫酸硫酸硫酸硫磺酶活性对DHEA-S的影响几乎没有影响。另一方面，在所有外显子中都没有非同义的SNP，但是在SLC22A11基因的5'Fanking区域中发现了一个已知的SNP（-18T> C）。记者基因测定的结果表明，SNP似乎没有给SLC22A11基因的转录活性发生很大变化。尽管提出，由于遗传多态性引起的这些蛋白质的功能缺乏似乎会影响胎儿或胎儿 - 置换单位中DHEA-S的药代动力学，但在这项研究中，在STS和SLC22A11基因中发现与DHEA-S诱导的胎儿死亡直接相关的多态性。

项目成果

Six Novel Single Nucleotide Polymorphisms of the Steroid Sulfatase Gene in a Japanese Population.

日本人群中类固醇硫酸酯酶基因的六种新的单核苷酸多态性。

• 发表时间: 2010
• 期刊: Drug Metab Pharmacokinet. 25(4)
• 作者: Matsumoto J;Ariyoshi N;Ishii I;Kitada M
• 通讯作者: Kitada M

The Prevalence in Carrier of CYP3A7*2 Variant in Japanese, and Effects Substitution of CYP3A7 on the Metabolism of DHEA-S in vitro.

日本人CYP3A7*2 变异体携带者的流行情况以及CYP3A7 替代对DHEA-S 体外代谢的影响。

• 发表时间: 2008
• 作者: 有吉範高;ら;et al
• 通讯作者: et al

CYP3A7多型の機能解析に関する論文は J Steroid Biochem Mot Bio1 に投稿中である。

一篇关于 CYP3A7 多态性功能分析的论文目前正在提交给 J Steroid Biochem Mot Bio1。

妊婦への子宮頚管熟化薬投与における胎児突然死の原因究明に関する研究(第2報)

孕妇服用促宫颈成熟药物引起胎儿猝死原因的调查研究（第二次报告）

• 发表时间: 2011
• 作者: 松本准、有吉範高;ら
• 通讯作者: ら

Six Novel Single Nucleotide Polymorphisms of the Steroid Sulfatase Geneina Japanese Population.

日本人群类固醇硫酸酯酶 Geneina 的六种新型单核苷酸多态性。

• 发表时间: 2010
• 期刊: Drug Metab Pharmacokinet.
• 作者: Matsumoto J;Ariyoshi N;Ishii I;Kitada M.
• 通讯作者: Kitada M.