Induction of P450 1A by 3-methylcholanthrene protects mice from aristolochic acid-I-induced acute renal injury

doi:10.1093/ndt/gfn262

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 药物安全性评价中心

	Induction of P450 1A by 3-methylcholanthrene protects mice from aristolochic acid-I-induced acute renal injury
	Xue, Xiang 1,2; Xiao, Ying 1,2; Zhu, Hongli 3; Wang, Hui 1; Liu, Yongzhen1 ; Xie, Tianpei 3; Ren, Jin1
刊名	NEPHROLOGY DIALYSIS TRANSPLANTATION
	2008-10
卷号	23 期号:10 页码:3074-3081
关键词	aristolochic acid nephropathy P450 1A 3-methylcholanthrene
ISSN号	0931-0509
DOI	10.1093/ndt/gfn262
文献子类	Article
英文摘要	Background. Cytochrome P450 1A, an enzyme known to metabolize polycyclic aromatic hydrocarbons (PAHs), participates in the metabolism of aristolochic acid I (AAI) in liver and kidney microsomes isolated from humans and rodents. This study was designed to investigate whether P450 1A plays a role in AAI-induced renal injury in C57BL/6 mice. Methods. Separate groups of mice were given AAI (10 mg/kg and 20 mg/kg) or pretreatment with 3-methylcholanthrene (3-MC, an agent known to induce P450 1A expression in many species including rodents) at 60 mg/kg given at 24 h before AAI injection. Renal function and histopathology were determined at the 3rd day following the high dose of AAI and at the 14th day following the low dose of AAI treatment. For both doses, we determined in vivo AAI clearances and pharmacokinetic parameters. We also determined in vitro P450 1A1/2 activity and the ability of liver microsomes from 3-MC-treated and vehicle-treated mice to metabolize AAI. Finally, the effect of 3-MC on protein levels of P450 1A1/2 in both liver and kidney was measured by western blotting. Results. Pretreatment with 3-MC greatly protected mice against renal failure induced by AAI. In vivo AAI clearance was more rapid in 3-MC-pretreated mice than in the vehicle-pretreated mice. In addition, the P450 1A1/2 activity and the ability to metabolize AAI in hepatic microsomes isolated from 3-MC-treated mice were much greater than in vehicle-treated mice. Western blotting showed that protein levels of hepatic P450 1A1/2 were greatly increased in 3-MC-treated mice than in vehicle-treated mice. Conclusion. These results demonstrated that the induction of hepatic P450 1A1/2 protected against AAI-induced kidney injury through faster in vivo clearance of AAI and suggested an important role for hepatic P450s in the detoxification of AAI-induced renal injury.
资助项目	National Grand Fundamental Research 973 Program of China[2006CB504700]
WOS关键词	CHINESE HERBS NEPHROPATHY ; INTERSTITIAL FIBROSIS ; UROTHELIAL CARCINOMA ; REDUCTIVE ACTIVATION ; FANCONIS-SYNDROME ; CYTOCHROME-P450 ; DNA ; FAILURE ; ADDUCTS ; TOXICITY
WOS研究方向	Transplantation ; Urology & Nephrology
语种	英语
出版者	OXFORD UNIV PRESS
WOS记录号	WOS:000259330500010
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/272798]
专题	药物安全性评价中心中科院受体结构与功能重点实验室新药研究国家重点实验室
通讯作者	Ren, Jin
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 2.Chinese Acad Sci, Grad Sch, Shanghai 201203, Peoples R China; 3.Shanghai TenGen Biomed Co, Shanghai, Peoples R China
推荐引用方式 GB/T 7714	Xue, Xiang,Xiao, Ying,Zhu, Hongli,et al. Induction of P450 1A by 3-methylcholanthrene protects mice from aristolochic acid-I-induced acute renal injury[J]. NEPHROLOGY DIALYSIS TRANSPLANTATION,2008,23(10):3074-3081.
APA	Xue, Xiang.,Xiao, Ying.,Zhu, Hongli.,Wang, Hui.,Liu, Yongzhen.,...&Ren, Jin.(2008).Induction of P450 1A by 3-methylcholanthrene protects mice from aristolochic acid-I-induced acute renal injury.NEPHROLOGY DIALYSIS TRANSPLANTATION,23(10),3074-3081.
MLA	Xue, Xiang,et al."Induction of P450 1A by 3-methylcholanthrene protects mice from aristolochic acid-I-induced acute renal injury".NEPHROLOGY DIALYSIS TRANSPLANTATION 23.10(2008):3074-3081.