title: Baicalin Protects Mice from Aristolochic Acid I-Induced Kidney Injury by Induction of CYP1A through the Aromatic Hydrocarbon Receptor.
abstract: Exposure to aristolochic acid I (AAI) can lead to aristolochic acid nephropathy (AAN), Balkan endemic nephropathy (BEN) and urothelial cancer. The induction of hepatic CYP1A, especially CYP1A2, was considered to detoxify AAI so as to reduce its nephrotoxicity. We previously found that baicalin had the strong ability to induce CYP1A2 expression; therefore in this study, we examined the effects of baicalin on AAI toxicity, metabolism and disposition, as well as investigated the underlying mechanisms. Our toxicological studies showed that baicalin reduced the levels of blood urea nitrogen (BUN) and creatinine (CRE) in AAI-treated mice and attenuated renal injury induced by AAI. Pharmacokinetic analysis demonstrated that baicalin markedly decreased AUC of AAI in plasma and the content of AAI in liver and kidney. CYP1A induction assays showed that baicalin exposure significantly increased the hepatic expression of CYP1A1/2, which was completely abolished by inhibitors of the Aromatic hydrocarbon receptor (AhR), 3',4'-dimethoxyflavone and resveratrol, in vitro and in vivo, respectively. Moreover, the luciferase assays revealed that baicalin significantly increased the luciferase activity of the reporter gene incorporated with the Xenobiotic response elements recognized by AhR. In summary, baicalin significantly reduced the disposition of AAI and ameliorated AAI-induced kidney toxicity through AhR-dependent CYP1A1/2 induction in the liver.
authors.affiliation: Key Laboratory of Nuclear Medicine, Ministry of Health, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi 214063, Jiangsu, China. wangke@jsinm.org.
authors.forename: Ke
authors.initials: K
authors.lastname: Wang
authors.affiliation: Center for Drug Safety Evaluation and Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Graduate School of the Chinese Academy of Sciences, Shanghai 201203, China. shang320@hotmail.com.
authors.forename: Chenchen
authors.initials: C
authors.lastname: Feng
authors.affiliation: Center for Drug Safety Evaluation and Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Graduate School of the Chinese Academy of Sciences, Shanghai 201203, China. lifen_888@hotmail.com.
authors.forename: Chenggang
authors.initials: C
authors.lastname: Li
authors.affiliation: Center for Drug Safety Evaluation and Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Graduate School of the Chinese Academy of Sciences, Shanghai 201203, China. jyao@cdser.simm.ac.cn.
authors.forename: Jun
authors.initials: J
authors.lastname: Yao
authors.affiliation: Center for Drug Safety Evaluation and Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Graduate School of the Chinese Academy of Sciences, Shanghai 201203, China. cluseee@gmail.com.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Xie
authors.affiliation: Center for Drug Safety Evaluation and Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Graduate School of the Chinese Academy of Sciences, Shanghai 201203, China. lkgong@cdser.simm.ac.cn.
authors.forename: Likun
authors.initials: L
authors.lastname: Gong
authors.affiliation: Center for Drug Safety Evaluation and Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Graduate School of the Chinese Academy of Sciences, Shanghai 201203, China. djlover@gmail.com.
authors.forename: Yang
authors.initials: Y
authors.lastname: Luan
authors.affiliation: Center for Drug Safety Evaluation and Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Graduate School of the Chinese Academy of Sciences, Shanghai 201203, China. gzxing@cdser.simm.ac.cn.
authors.forename: Guozhen
authors.initials: G
authors.lastname: Xing
authors.affiliation: Key Laboratory of Nuclear Medicine, Ministry of Health, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi 214063, Jiangsu, China. zhuxue@jsinm.org.
authors.forename: Xue
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Center for Drug Safety Evaluation and Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Graduate School of the Chinese Academy of Sciences, Shanghai 201203, China. xmqi@cdser.simm.ac.cn.
authors.forename: Xinming
authors.initials: X
authors.lastname: Qi
authors.affiliation: Center for Drug Safety Evaluation and Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Graduate School of the Chinese Academy of Sciences, Shanghai 201203, China. jren@cdser.simm.ac.cn.
authors.forename: Jin
authors.initials: J
authors.lastname: Ren
mesh_terms: D058186:Acute Kidney Injury / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology* / Q000627:therapeutic use; D034341:Aristolochic Acids / Q000633:toxicity*; D001449:Balkan Nephropathy / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics / Q000378:metabolism*; D005419:Flavonoids / Q000494:pharmacology* / Q000627:therapeutic use; D056945:Hep G2 Cells; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018336:Receptors, Aryl Hydrocarbon / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D034341:Aristolochic Acids; D005419:Flavonoids; D018336:Receptors, Aryl Hydrocarbon; C038044:baicalin; C000228:aristolochic acid I; D019363:Cytochrome P-450 CYP1A1
keywords: CYP1A; aristolochic acid; aromatic hydrocarbon receptor; baicalin; kidney injury