The role of breast cancer resistance protein (Bcrp/Abcg2) in triptolide-induced testis toxicity

doi:10.1039/c5tx00058k

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	The role of breast cancer resistance protein (Bcrp/Abcg2) in triptolide-induced testis toxicity
	Li, Chunzhu 1; Xing, Guozhen 2; Maeda, Kazuya 3; Wu, Chunyong 4; Gong, Likun2 ; Sugiyama, Yuichi 3; Qi, Xinming2 ; Ren, Jin2 ; Wang, Guangji 1
刊名	TOXICOLOGY RESEARCH
	2015
卷号	4 期号:5 页码:1260-1268
ISSN号	2045-452X
DOI	10.1039/c5tx00058k
文献子类	Article
英文摘要	Triptolide has been intensively studied in numerous preclinical and clinical assessments for immunosuppressive and anti-tumor activities. However, further clinical use is limited by the cumulative toxicity of triptolide in the testis and the mechanisms are poorly understood. In this study, we found significant triptolide accumulation in the testis, and further investigated the role of efflux transporters in its accumulation and toxicity. Chronic administration of triptolide induced time- and dose-dependent testicular injury and resulted in the accumulation of triptolide in the liver and testis, but not in the plasma. Using transporter-expressed cells, triptolide efflux was found in BCRP-expressing cells, which could be blocked by novobiocin (an inhibitor of BCRP) in accumulation assays. Triptolide also displayed apically directed transport across BCRP-expressing cell layers in transwell assays, strongly supporting that triptolide is a substrate of BCRP. Bcrp knockout mice (Bcrp(-/-)) were further used to examine the effects of triptolide. Knockout of Bcrp aggravated triptolide-induced testicular injury and increased the testis content and testis to plasma ratio of triptolide in Bcrp(-/-) mice. Notably, triptolide decreased the transcript and protein levels of Bcrp in the testis, which may be due to the downregulation of RNA polymerase II. In conclusion, as a substrate of BCRP, triptolide decreased the expression of Bcrp and RNA polymerase II in the testis, and further increased the testis content and enhanced its testicular toxicity, which contributes to the cumulative toxicity of triptolide in the testis.
资助项目	National Natural Science Foundation of China[81102496] ; National Key Technologies RD Program[2012ZX09302-003] ; National Key Technologies RD Program[2012ZX09301-001006]
WOS关键词	ORGANIC ANION TRANSPORTERS ; NATURAL-PRODUCT TRIPTOLIDE ; CELL-DEATH ; MOUSE SPERMATOGENESIS ; INHIBITION ; BARRIER ; GENE ; BCRP ; RATS ; TRANSCRIPTION
WOS研究方向	Toxicology
语种	英语
出版者	ROYAL SOC CHEMISTRY
WOS记录号	WOS:000360052000012
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/276713]
专题	药物安全性评价中心
通讯作者	Li, Chunzhu
作者单位	1.China Pharmaceut Univ, State Key Lab Nat Med, Key Lab Drug Metab & Pharmacokinet, Nanjing, Jiangsu, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab New Drug Res, Ctr Drug Safety Evaluat & Res, Beijing 100864, Peoples R China; 3.Univ Tokyo, Grad Sch Pharmaceut Sci, Tokyo, Japan; 4.China Pharmaceut Univ, Sch Pharm, Dept Pharmaceut Anal, Nanjing, Jiangsu, Peoples R China
推荐引用方式 GB/T 7714	Li, Chunzhu,Xing, Guozhen,Maeda, Kazuya,et al. The role of breast cancer resistance protein (Bcrp/Abcg2) in triptolide-induced testis toxicity[J]. TOXICOLOGY RESEARCH,2015,4(5):1260-1268.
APA	Li, Chunzhu.,Xing, Guozhen.,Maeda, Kazuya.,Wu, Chunyong.,Gong, Likun.,...&Wang, Guangji.(2015).The role of breast cancer resistance protein (Bcrp/Abcg2) in triptolide-induced testis toxicity.TOXICOLOGY RESEARCH,4(5),1260-1268.
MLA	Li, Chunzhu,et al."The role of breast cancer resistance protein (Bcrp/Abcg2) in triptolide-induced testis toxicity".TOXICOLOGY RESEARCH 4.5(2015):1260-1268.