Bioactivation of 3-n-Butylphthalide via Sulfation of Its Major Metabolite 3-Hydroxy-NBP: Mediated Mainly by Sulfotransferase 1A1

doi:10.1124/dmd.113.056218

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	Bioactivation of 3-n-Butylphthalide via Sulfation of Its Major Metabolite 3-Hydroxy-NBP: Mediated Mainly by Sulfotransferase 1A1
	Diao, Xingxing; Pang, Xiaoyan; Xie, Cen; Guo, Zitao; Zhong, Dafang; Chen, Xiaoyan
刊名	DRUG METABOLISM AND DISPOSITION
	2014-04
卷号	42 期号:4 页码:774-781
ISSN号	0090-9556
DOI	10.1124/dmd.113.056218
文献子类	Article
英文摘要	3-n-Butylphthalide (NBP) [(+/-)-3-butyl-1(3H)-isobenzofuranone] is an anti-cerebral-ischemia drug. Moderate hepatotoxicity has been observed in clinical applications. One of the major metabolites, 3-N-acetylcysteine-NBP, has been detected in human urine, indicating the formation of a reactive metabolite. We elucidated the formation mechanism of the reactive metabolite and its association with the hepatotoxicity of NBP. The in vitro incubations revealed that 3-glutathione-NBP (3-GSH-NBP) was observed only in fresh rat liver homogenate rather than in liver microsomes, liver cytosol, or liver 9,000g supernatant supplemented with NADPH and GSH. We also detected 3-GSH-NBP when 3'-phosphoadenosine-5'-phosphosulfate was added in GSH-fortified human liver cytosol (HLC). The formation of 3-GSH-NBP was 39.3-fold higher using 3-hydroxy-NBP (3-OH-NBP) as the substrate than NBP. The sulfotransferase (SULT) inhibitors DCNP (2,6-dichloro-4-nitrophenol) and quercetin suppressed 3-GSH-NBP formation in HLC by 75 and 82%, respectively, suggesting that 3-OH-NBP sulfation was involved in 3-GSH-NBP formation. Further SULT phenotyping revealed that SULT1A1 is the major isoform responsible for the sulfation. Dose-dependent toxicity was observed in primary rat hepatocytes exposed to 3-OH-NBP, with an IC50 of approximately 168 mu M. Addition of DCNP and quercetin significantly increased cell viability, whereas L-buthionine-sulfoximine (a GSH depleter) decreased cell viability. Overall, our study revealed the underlying mechanism for the bioactivation of NBP is as follows. NBP is first oxidized to 3-OH-NBP and further undergoes sulfation to form 3-OH-NBP sulfate. The sulfate spontaneously cleaves off, generating highly reactive electrophilic cations, which can bind either to GSH to detoxify or to hepatocellular proteins to cause undesirable side effects.
WOS关键词	TAMOXIFEN-DNA ADDUCTS ; CEREBRAL-BLOOD-FLOW ; PHENOL SULFOTRANSFERASE ; RAT HEPATOCYTES ; ISCHEMIC-STROKE ; VALPROIC ACID ; HUMAN LIVERS ; IDENTIFICATION ; HUMANS ; DL-3-N-BUTYLPHTHALIDE
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
WOS记录号	WOS:000332842500032
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/277146]
专题	上海药物代谢研究中心
通讯作者	Chen, Xiaoyan
作者单位	Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Diao, Xingxing,Pang, Xiaoyan,Xie, Cen,et al. Bioactivation of 3-n-Butylphthalide via Sulfation of Its Major Metabolite 3-Hydroxy-NBP: Mediated Mainly by Sulfotransferase 1A1[J]. DRUG METABOLISM AND DISPOSITION,2014,42(4):774-781.
APA	Diao, Xingxing,Pang, Xiaoyan,Xie, Cen,Guo, Zitao,Zhong, Dafang,&Chen, Xiaoyan.(2014).Bioactivation of 3-n-Butylphthalide via Sulfation of Its Major Metabolite 3-Hydroxy-NBP: Mediated Mainly by Sulfotransferase 1A1.DRUG METABOLISM AND DISPOSITION,42(4),774-781.
MLA	Diao, Xingxing,et al."Bioactivation of 3-n-Butylphthalide via Sulfation of Its Major Metabolite 3-Hydroxy-NBP: Mediated Mainly by Sulfotransferase 1A1".DRUG METABOLISM AND DISPOSITION 42.4(2014):774-781.