磺基转移酶及磺酸化代谢在药物研究中的进展

黄昊妍, 任光辉, 傅可嘉, 赵娣, 陈西敬, 张永杰

中国药学杂志 ›› 2021, Vol. 56 ›› Issue (3) : 169-174.

PDF(1564 KB)
PDF(1564 KB)
中国药学杂志 ›› 2021, Vol. 56 ›› Issue (3) : 169-174. DOI: 10.11669/cpj.2021.03.001
综述

磺基转移酶及磺酸化代谢在药物研究中的进展

  • 黄昊妍, 任光辉, 傅可嘉, 赵娣, 陈西敬*, 张永杰*
作者信息 +

Research Progress of Sulfotransferase and Sulfonation in Drug Metabolism

  • HUANG Hao-yan, REN Guang-hui, FU Ke-jia, ZHAO Di, CHEN Xi-jing*, ZHANG Yong-jie*
Author information +
文章历史 +

摘要

磺酸化代谢(又称硫酸化代谢)在药物的体内处置中发挥重要作用,是新药研发以及临床合理用药的重要基础。人磺基转移酶(又称硫酸转移酶)包含4个家族13个亚型,在体内具有广泛的底物,主要分布于肝、小肠、肾和肺等器官。对大多数底物而言,磺基转移酶介导的代谢常呈现典型的底物抑制特征;而低底物浓度水平通常会诱导酶的表达。体内磺酸化代谢由磺基转移酶催化小分子化合物结合3'-磷酸腺苷-5'-磷酸硫酸酯提供的磺酸基完成。一般情况下,磺酸化代谢介导药物或外源性异物的解毒过程,但在特殊药物代谢中产生毒性或不良反应。笔者综述了近年来磺基转移酶及磺酸化代谢在药物研究中的进展,以期为药物代谢的研究、新药研发与临床用药提供参考。

Abstract

Sulfonation metabolism plays an important role in the disposition of drugs in vivo, which are significantly influencing the development of new drugs and the rational application of drugs in the clinic practice. Human sulfotransferases (SULTs) are currently divided into 13 subtypes from 4 families, with a wide range of substrates in the body. They are mainly distributed in the liver, small intestine, kidney and lung. In addition, SULTs expression can be induced by various substrates, and most substrates can inhibit sulfotransferase to a certain extent at high concentrations. In vivo, sulfonation metabolism is catalyzed by the binding of sulfuryl group, which is provided by 3'-adenosine-5'-phosphoryl sulfate, to the xenobiotic or endobiotic substrates. In most cases, sulfonation leads to the detoxification and facilitate the excretion of substrates, whereas toxicity or adverse reactions in the metabolism of specific drugs. The later cases normally involve formation of chemically reactive metabolites. This article reviews the recent progress of SULTs and sulfonation in drug research and development, which may gain insights into the understanding of roles of SULTs and sulfonation in drug metabolism and safety assessment, thus facilitate development of new drugs and clinical drug usage.

关键词

磺基转移酶 / 磺酸化代谢 / 药物代谢 / 诱导与抑制 / 解毒与致毒

Key words

sulfotransferase / sulfonation / drug metabolism / induction and inhibition / detoxification and toxicity

引用本文

导出引用
黄昊妍, 任光辉, 傅可嘉, 赵娣, 陈西敬, 张永杰. 磺基转移酶及磺酸化代谢在药物研究中的进展[J]. 中国药学杂志, 2021, 56(3): 169-174 https://doi.org/10.11669/cpj.2021.03.001
HUANG Hao-yan, REN Guang-hui, FU Ke-jia, ZHAO Di, CHEN Xi-jing, ZHANG Yong-jie. Research Progress of Sulfotransferase and Sulfonation in Drug Metabolism[J]. Chinese Pharmaceutical Journal, 2021, 56(3): 169-174 https://doi.org/10.11669/cpj.2021.03.001
中图分类号: R969.1   

参考文献

[1] KLAASSEN C D, BOLES J W. Sulfation and sulfotransferases 5: the importance of 3'-phosphoadenosine 5'-phosphosulfate (PAPS) in the regulation of sulfation[J]. FASEB J, 1997, 11(6):404-418.
[2] GLATT H. Sulfotransferases in the bioactivation of xenobiotics[J]. Chem-Biol Interact, 2001, 129(1-2):141-170.
[3] WILLIAMSON G, CLIFFORD M N. Role of the small intestine, colon and microbiota in determining the metabolic fate of polyphenols[J]. Biochem Pharmacol, 2017, 139:24-39.
[4] COOK I, WANG T, FALANY C N, et al. High accuracy in silico sulfotransferase models[J]. J Biol Chem, 2013, 288(48):34494-34501.
[5] STACHEL N, SKOPP G. Identification and characterization of sulfonyltransferases catalyzing ethyl sulfate formation and their inhibition by polyphenols[J]. Int J Legal Med, 2016, 130(1):139-146.
[6] EBMEIER C C, ANDERSON R J. Human thyroid phenol sulfotransferase enzymes 1A1 and 1A3: activities in normal and diseased thyroid glands, and inhibition by thyroid hormones and phytoestrogens[J]. J Clin Endocr Metab, 2004, 89(11):5597-5605.
[7] LIANG S C, XIA Y L, HOU J, et al. Methylation, glucuronidation, and sulfonation of daphnetin in human hepatic preparations in vitro: metabolic profiling, pathway comparison, and bioactivity analysis[J]. J Pharm SCI-US, 2016, 105(2):808-816.
[8] HUI Y, YASUDA S, LIU M Y, et al. On the sulfation and methylation of catecholestrogens in human mammary epithelial cells and breast cancer cells[J]. Biol Pharm Bull, 2008, 31(4):769-773.
[9] HASHIGUCHI T, KUROGI K, SHIMOHIRA T, et al. Δ4-3-ketosteroids as a new class of substrates for the cytosolic sulfotransferases[J]. BBA-Gen Subj, 2017, 1861(11):2883-2890.
[10] KUROGI K, CHEPAK A, HANRAHAN M T, et al. Sulfation of opioid drugs by human cytosolic sulfotransferases: metabolic labeling study and enzymatic analysis[J]. Eur J Pharm Sci, 2014, 62:40-48.
[11] BAI Q, XU L, KAKIYAMA G, et al. Sulfation of 25-hydroxycholesterol by SULT2B1b decreases cellular lipids via the LXR/SREBP-1c signaling pathway in human aortic endothelial cells[J]. Atherosclerosis, 2011, 214(2):350-356.
[12] FUDA H, JAVITT N B, MITAMURA K, et al. Oxysterols are substrates for cholesterol sulfotransferase[J]. J Lipid Res, 2007, 48(6):1343-1352.
[13] TIBBS Z E, ROHN-GLOWACKI K J, CRITTENDEN F, et al. Structural plasticity in the human cytosolic sulfotransferase dimer and its role in substrate selectivity and catalysis[J]. Drug Metab Pharmacokinet, 2015, 30(1):3-20.
[14] ILANA B, CHEN G, DOTAN A, et al. The molecular basis for the broad substrate specificity of human sulfotransferase 1A1[J]. PLoS One, 2011, 6(11):e26794.
[15] GAMAGE N U, DUGGLEBY R G, BARNETT A C, et al. Structure of a human carcinogen-converting enzyme, SULT1A1-structural and kinetic implications of substrate inhibition[J]. J Biol Chem, 2003, 278(9):7655-7662.
[16] BARNETT A C, TSVETANOV S, GAMAGE N, et al. Active site mutations and substrate inhibition in human sulfotransferase 1A1 and 1A3[J]. J Biol Chem, 2004, 279(18):18799-18805.
[17] NISHIMUTA H, TSUJIMOTO M, OGURA K, et al. Inhibitory effects of various beverages on ritodrine sulfation by recombinant human sulfotransferase isoforms SULT1A1 and SULT1A3[J]. Pharm Res-Dordr, 2005, 22(8):1406-1410.
[18] GULCAN H O, DUFFEL M W. Substrate inhibition in human hydroxysteroid sulfotransferase SULT2A1: studies on the formation of catalytically non-productive enzyme complexes[J]. Arch Biochem Biophys, 2011, 507(2):232-240.
[19] SUIKO M, KUROGI K, HASHIGUCHI T, et al. Updated perspectives on the cytosolic sulfotransferases (SULTs) and SULT-mediated sulfation[J]. Biosci Biotechnol Biochem, 2017, 81(1):63-72.
[20] DUANMU Z, WECKLE A, KOUKOURITAKI S B, et al. Developmental expression of Aryl, estrogen, and hydroxysteroid sulfotransferases in pre-and postnatal human liver[J]. J Pharmacol Exp Ther, 2006, 316(3):1310-1317.
[21] DUNIEC-DMUCHOWSKI Z, RONDINI E A, TIBBS Z E, et al. Expression of the orphan cytosolic sulfotransferase SULT1C3 in human intestine: characterization of the transcript variant and implications for function[J]. Drug Metab Dispos, 2014, 42(3):352-360.
[22] HIGASHI Y, FUDA H, YANAI H, et al. Expression of cholesterol sulfotransferase (SULT2B1b) in human skin and primary cultures of human epidermal keratinocytes[J]. J Invest Dermatol, 2004, 122(5):1207-1213.
[23] GEESE W J, RAFTOGIANIS R B. Biochemical characterization and tissue distribution of human SULT2B1[J]. Biochem Biophys Res Commun, 2001, 288(1):280-289.
[24] GARCIA P L, HOSSAIN M I, ANDRABI S A, et al. Generation and characterization of SULT4A1 mutant mouse models[J]. Drug Metab Dispos, 2018, 46(1): 41-45.
[25] YEH C T, YEN G C. Involvement of p38 MAPK and Nrf2 in phenolic acid-induced P-form phenol sulfotransferase expression in human hepatoma HepG2 cells[J]. Carcinogenesis, 2006, 27(5):1008-1017.
[26] ALNOUTI Y, KLAASSEN C D. Regulation of sulfotransferase enzymes by prototypical microsomal enzyme inducers in mice[J]. J Pharmacol Exp Ther, 2008, 324(2):612-621.
[27] JAMES M O, AMBADAPADI S. Interactions of cytosolic sulfotransferases with xenobiotics[J]. Drug Metab Rev, 2013, 45(4):401-414.
[28] COOK I, WANG T, LEYH T S. Isoform-specific therapeutic control of sulfonation in humans[J]. Biochem Pharmacol, 2019, 159:25-31.
[29] RASOOL M I, BAIRAM A F, GOHAL S A, et al. Effects of the human SULT1A1 polymorphisms on the sulfation of acetaminophen, O-desmethylnaproxen, and tapentadol[J]. Pharmacol Rep, 2019, 71(2):257-265.
[30] ZHOU J, ZHANG Y, LI N, et al. A systematic metabolic pathway identification of common gardenia fruit (gardeniae fructus) in mouse bile, plasma, urine and feces by HPLC-Q-TOF-MS/MS[J]. J Chromatogr B, 2020, 1145:122100.
[31] XIONG A Z, YANG L, ZHANG F, et al. Identification of metabolites of senecionine, a hepatotoxic pyrrolizidine alkaloid, by liquid chromatography/tandem mass spectrometry [J]. Chin Pharm J(中国药学杂志), 2012,47(1):54-60.
[32] FAN Y F, FENG Q, TANG L, et al. Study on sulfation metabolism of scutellarein in FVB/NCrlVr mice[J]. Chin Pharm J(中国药学杂志), 2012, 47(18): 1493-1497.
[33] REN G, CHEN H, ZHANG M, et al. Determination of oroxylin A, oroxylin A 7-O-glucuronide, and oroxylin A sodium sulfonate in Beagle dogs via ultra-high-performance liquid chromatography/tandem mass spectrometry: application in a pharmacokinetic study[J]. J Sep Sci, 2020, 43(12):2290-2300.
[34] REN G, CHEN H, ZHANG M, et al. Pharmacokinetics, tissue distribution and excretion study of oroxylin A, oroxylin A 7-O-glucuronide and oroxylin A sodium sulfonate in rats after administration of oroxylin A[J]. Fitoterapia, 2020, 142:104480.
[35] DIAO X, PANG X, XIE C, et al. Bioactivation of 3-n-butylphthalide via sulfation of its major metabolite 3-hydroxy-NBP: mediated mainly by sulfotransferase 1A1[J]. Drug Metab Dispos, 2014, 42(4):774-781.
[36] LI R, LI W, YOU Y, et al. Metabolic activation and cytotoxicity of aloe-emodin mediated by sulfotransferases[J]. Chem Res Toxicol, 2019, 32(6):1281-1288.
[37] ZHOU S, LI W, TIAN M, et al. Metabolic activation of pirfenidone mediated by cytochrome P450s and sulfotransferases[J]. J Med Chem, 2020, 63(15):8059-8068.
[38] OKUNO Y, BONALA R, ATTALURI S, et al. Bioactivation mechanisms of N-hydroxyaristolactams: nitroreduction metabolites of aristolochic acids[J]. Environ Mol Mutagen, 2019, 60(9):792-806.
[39] SHARMA A M, KLARSKOV K, UETRECHT J. Nevirapine bioactivation and covalent binding in the skin[J]. Chem Res Toxicol, 2013, 26(3):410-421.
[40] KREIS P. Human phenol sulfotransferases hP-PST and hM-PST activate propane 2-nitronate to a genotoxicant[J]. Carcinogenesis, 2000, 21(2):295-299.
[41] BENDADANI C, MEINL W, MONIEN B, et al. Determination of sulfotransferase forms involved in the metabolic activation of the Genotoxicant 1-hydroxymethylpyrene using bacterially expressed enzymes and genetically modified mouse models[J]. Chem Res Toxicol, 2014, 27(6):1060-1069.
[42] LI Y, CHEN Z, PAONESSA J D, et al. Strong impact of sulfotransferases on DNA adduct formation by 4-aminobiphenyl in bladder and liver in mice[J]. Cancer Med, 2018, 7(11):5604-5610.
[43] ARLT V M, MEINL W, FLORIAN S, et al. Impact of genetic modulation of SULT1A enzymes on DNA adduct formation by aristolochic acids and 3-nitrobenzanthrone[J]. Arch Toxicol, 2017, 91(4):1957-1975.

基金

国家自然科学基金项目资助(81473272,81503148,82003877);中央高校基本科研业务费专项资金项目资助(2632018PT02,2632020ZD01);中国药科大学“双一流”创新团队项目资助(CPU2018GY29,CPU2018GF11);江苏省自然科学基金项目资助(BK20190557)
PDF(1564 KB)

1746

Accesses

0

Citation

Detail

段落导航
相关文章

/