从脂质代谢途径探讨中药雷公藤“物-效/毒-靶”关联性的研究现状与展望

doi:10.19803/j.1672-8629.20220734

摘要/Abstract

摘要： 目的从机体脂质代谢角度出发,分析归纳中药雷公藤效/毒相关物质基础的作用途径,探讨其“物-效/毒-靶”关联性,以寻找雷公藤药效和毒性成分的创新研究方法与视角。方法收集并梳理近年来雷公藤制剂及其活性物质在脂质代谢调控方面的相关文献,在药性理论指导上,结合临床用药实际情况与实验研究结果,构建“物-效/毒-靶”关联性的分析模式。结果雷公藤制剂及活性物质通过参与调控脂肪酸代谢、磷脂类代谢以及固醇类代谢在内的多个关键脂质代谢环节发挥药效作用,但同时也可诱发脂质过氧化物堆积、磷脂类代谢紊乱、胆汁酸淤积等负面途径的致毒反应。结论从脂肪代谢途径解析“物-效/毒-靶”关联性有利于指导临床合理用药。

关键词: 雷公藤, 脂质代谢, “物-效/毒-靶”关联, 脂肪酸代谢, 磷脂类代谢, 固醇类代谢, 中药药性理论

Abstract: Objective To analyze the lipid metabolic pathways related to the efficacy and/or toxicity of Tripterygium wilfordii’s and to explore the component-effect/toxicity-target correlations. Methods Recent literature on the regulation of lipid metabolism by Tripterygium wilfordii preparations and its active components was collected and reviewed. An analytical model for component-effect/toxicity-target correlations was established based on theories of pharmacology, clinical use and experimental research. Results Tripterygium wilfordii preparations and its active components proved to exert therapeutic effects by regulating multiple key processes of lipid metabolism, including fatty acid metabolism, phospholipid metabolism and steroid metabolism while inducing various toxic effects due to lipid peroxidation, phospholipid metabolism disorders and bile acid accumulation. Conclusion The analysis of the component-effect/toxicity-target correlations from perspective of lipid metabolism pathways can help to better understand and evaluate its effectiveness and safety, which will facilitate rational medications in clinical practice.

Key words: Tripterygium wilfordii, lipid metabolism, component-effect/toxicity-target correlations, fatty acid metabolism, phospholipid metabolism, steroid metabolism, theories of traditional Chinese medicine properties

中图分类号:

R961
R994.11

丁子禾, 张彦琼, 林娜. 从脂质代谢途径探讨中药雷公藤“物-效/毒-靶”关联性的研究现状与展望[J]. 中国药物警戒, 2023, 20(5): 489-495.

DING Zihe, ZHANG Yanqiong, LIN Na. Component-effect/toxicity-target correlations of Tripterygium wilfordii in terms of lipid metabolism[J]. Chinese Journal of Pharmacovigilance, 2023, 20(5): 489-495.

参考文献

[1] ZHANG Y, MAO X, LI W, et al.Tripterygium wilfordii: an inspiring resource for rheumatoid arthritis treatment[J]. Med Res Rev, 2021, 41(3): 1337-1374.
[2] WU D, MENG YH, YANG BY, et al.Application of lipidomics to the study of traditional Chinese medicine[J]. Chinese Herbal Medicine(中草药), 2020, 51(21): 9.
[3] ZHOU YQ, ZHOU W, YUE LX, et al.Development of celastrol involved in the regulation of lipid metabolism[J]. Med Lead(医药导报), 2021, 40(12): 6.
[4] XIE T, ZHOU XP, LIN LL, et al.Metabolomics study of attenuated compound herb pair of Tripterygium wilfordii based on “heterogeneous phase system”[J]. Journal of Chinese Traditional Medicine(中国中药杂志), 2016, 41(6): 6.
[5] WU H, YU XH, MA GC, et al.Lc-ms-based metabolomics study of hepatotoxicity reduction by liquorice gunning Tripterygium wilfordii Hook F.[J]. Chinese Herbal Medicine(中草药), 2020, 51(21): 5501-5508.
[6] LONG C, YANG Y, WANG Y, et al.Role of glutamine-glutamate/GABA cycle and potential target GLUD2 in alleviation of rheumatoid arthritis by Tripterygium hypoglaucum (levl.) Hutch based on metabolomics and molecular pharmacology[J]. J Ethnopharmacol, 2021, 281: 114561.
[7] ZHANG K, PACE S, JORDAN PM, et al.Beneficial modulation of lipid mediator biosynthesis in innate immune cells by antirheumatic glycosides[J]. Biomolecules, 2021, 11(5): 746.
[8] HUANG R, GUO F, LI Y, et al.Activation of AMPK by triptolide alleviates nonalcoholic fatty liver disease by improving hepatic lipid metabolism, inflammation and fibrosis[J]. Phytomedicine, 2021, 92: 153739.
[9] WANG X, XU M, PENG Y, et al.Triptolide enhances lipolysis of adipocytes by enhancing ATGL transcription via upregulation of p53[J]. Phytother Res, 2020, 34(12): 3298-3310.
[10] ZHAO Q, TANG P, ZHANG T, et al.Celastrol ameliorates acute liver injury through modulation of PPARα[J]. Biochem Pharmacol, 2020, 178: 114058.
[11] SHI Y, JIANG S, ZHAO T, et al.Celastrol suppresses lipid accumulation through LXRα/ABCA1 signaling pathway and autophagy in vascular smooth muscle cells[J]. Biochem Biophys Res Commun, 2020, 532(3): 466-474.
[12] SUN Y, SONG YY, ZHANG C, et al.AMPK signaling pathway activation by celastrol inhibits proliferation of hepatoma HepG2 cells[J]. China Pharmacist(中国药师), 2021, 24(11): 1961-1966, 1982.
[13] DONG Y, LU H, LI Q, et al.(5R)-5-hydroxytriptolide ameliorates liver lipid accumulation by suppressing lipid synthesis and promoting lipid oxidation in mice[J]. Life Sci, 2019, 232: 116644.
[14] WANG Z, QU L, ZHANG J, et al.Evaluation of quantity-ect/toxicity mechanism of Tripterygium glycoside tablets on delayed type hypersensitivity model based on targeted sphingolipidomics and transcriptomics[J]. Journal of Pharmaceutical Sciences(药学学报), 2018, 53(11): 1868-1378.
[15] QIAN Q, GAO Y, XUN G, et al.Synchronous investigation of the mechanism and substance basis of tripterygium glycosides tablets on anti-rheumatoid arthritis and hepatotoxicity[J]. Appl Biochem Biotechnol, 2022, 194(11): 5333-5352.
[16] LIU Y.Explored biomarkers of psoriasis vulgaris based on metabolomics approach and investigated the effect of drugs on the markers[D]. Guangzhou: Jinan University, 2017.
[17] ZHU Y, ZHANG L, ZHANG X, et al.Tripterygium wilfordii glycosides ameliorates collagen-induced arthritis and aberrant lipid metabolism in rats[J]. Front Pharmacol, 2022, 13: 938849.
[18] ZHANG T, ZHAO Q, XIAO X, et al.Modulation of lipid metabolism by celastrol[J]. J Proteome Res, 2019, 18(3): 1133-1144.
[19] LIU M, CHEN M, LUO Y, et al.Lipidomic profiling of ipsilateral brain and plasma after celastrol post-treatment in transient middle cerebral artery occlusion mice model[J]. Molecules, 2021, 26(14): 4124.
[20] WANG R, GU X, DAI W, et al.A lipidomics investigation into the intervention of celastrol in experimental colitis[J]. Mol Biosyst, 2016, 12(5): 1436-1444.
[21] LI H, XING X, ZHANG X, et al.Effects of triptolide on the sphingosine kinase-Sphingosine-1-phosphate signaling pathway in colitis-associated colon cancer[J]. Int Immunopharmacol, 2020, 88: 106892.
[22] LI JF, QU F, ZHENG SJ, et al.Elevated plasma sphingomyelin (d18:1/22:0) is closely related to hepatic steatosis in patients with chronic hepatitis C virus infection[J]. Eur J Clin Microbiol Infect Dis, 2014, 33(10): 1725-1732.
[23] LIU J, WAN L, HUANG CB, et al.Effect of Xinfeng capsule on lipoprotein metabolism in patients with rheumatoid arthritis[J]. Journal of Integrated Traditional Chinese and Western Medicine(中国中西医结合杂志), 2015, 35(9): 1060-1064.
[24] KANG MJ, KWON EB, YUK HJ, et al.Tripterygium regelii decreases the biosynthesis of triacylglycerol and cholesterol in HepG2 cells[J]. Biosci Biotechnol Biochem, 2017, 81(12): 2285-2291.
[25] WANG XQ, PAN ZB, GAO RH, et al.Effects of Huo Fang root tablets combined with valsartan on renal function and lipid metabolism indexes in patients with diabetic nephropathy[J]. Chinese General Practice(中华全科医学), 2016, 14(11): 3.
[26] YAN HY.Clinical observation of Kunxian capsule in the treatment of chronic glomerulonephritis[D]. Chengdu: Chengdu University of Traditional Chinese Medicine, 2020.
[27] LUO L, YANG T.Triptolide inhibits the progression of atherosclerosis in apolipoprotein E/mice[J]. Exp Ther Med, 2016, 12(4): 2307-2313.
[28] ZHANG CJ, ZHU N, LONG J, et al.Celastrol induces lipophagy via the LXRα/ABCA1 pathway in clear cell renal cell carcinoma[J]. Acta Pharmacol Sin, 2021, 42(9): 1472-1485.
[29] XING CH, ZHANG JC, ZHANG FJ.Effect of Tripterygium glycoside tablets on serum lipids in mice fed a high-fat diet[J]. Chinese Journal of Modern Applied Pharmacy(中国现代应用药学), 2018, 35(9): 1351-1354.
[30] WANG YH, JIANG S, SHI YN, et al.Celastrol activates LXR by α/ABCA1 pathway and autophagy inhibit lipid accumulation in macrophages[J]. Progress in Biochemistry and Biophysics(生物化学与生物物理进展), 2021, 48(7): 836-456.
[31] ZHOU F, GONG TW, WANG J, et al.Clinical efficacy and mechanism of Tripterygium wilfordii multi glycoside combined with methotrexate in rheumatoid arthritis: a review[J]. Medical Science Journal of Central South China(中南医学科学杂志), 2018, 46(3): 257-259, 266.
[32] WANG C, HUANG J, JIANG ZZ, et al.The role of steroid hormones in rheumatoid arthritis research progress[J]. Journal of China Pharmaceutical University(中国药科大学学报), 2015, 46(6): 757-633.
[33] LI J, LU Y, XIAO C, et al.Comparison of toxic reaction of Tripterygium wilfordii multiglycoside in normal and adjuvant arthritic rats[J]. J Ethnopharmacol, 2011, 135(2): 270-277.
[34] MA M, CHEN XY, GU C, et al.Biochemical changes of oxidative stress in premature ovarian insufficiency induced by tripterygium glycosides[J]. Int J Clin Exp Pathol, 2014, 7(12): 8855-8861.
[35] CHANG LJ, LI ZJ, LI Q, et al.Serum metabolomics analysis of nephrotoxicity induced by Tripterygium Wilfordii in rats[J]. Chinese Journal of Experimental Traditional Medical Formulae(中国实验方剂学杂志), 2016, 22(24): 89-94.
[36] LI C, ZHANG C, ZHU C, et al.Inflammation aggravated the hepatotoxicity of triptolide by oxidative stress, lipid metabolism disorder, autophagy, and apoptosis in zebrafish[J]. Front Pharmacol, 2022, 13: 949312.
[37] JIANG Z, HUANG X, HUANG S, et al.Sex-related differences of lipid metabolism induced by triptolide: the possible role of the lxrα/srebp-1 signaling pathway[J]. Front Pharmacol, 2016, 7: 87.
[38] MA B, QI H, LI J, et al.Triptolide disrupts fatty acids and peroxisome proliferator-activated receptor (PPAR) levels in male mice testes followed by testicular injury: a GC-MS based metabolomics study[J]. Toxicology, 2015, 336: 84-95.
[39] CHENG Y, CHEN G, WANG L, et al.Triptolide-induced mitochondrial damage dysregulates fatty acid metabolism in mouse sertoli cells[J]. Toxicol Lett, 2018, 292: 136-150.
[40] LIU X, CHEN C, HAN D, et al.SLC7A11/GPX4 Inactivation-mediated ferroptosis contributes to the pathogenesis of triptolide-induced cardiotoxicity[J]. Oxid Med Cell Longev, 2022: 3192607.
[41] YANG J, SUN L, WANG L, et al.Activation of Sirt1/FXR signaling pathway attenuates triptolide-induced hepatotoxicity in rats[J]. Front Pharmacol, 2017, 8: 260.
[42] YANG F, ZHUO L, ANANDA S, et al.Role of reactive oxygen species in triptolide-induced apoptosis of renal tubular cells and renal injury in rats[J]. J Huazhong Univ Sci Technolog Med Sci, 2011, 31(3): 335-341.
[43] LIU C, ZHANG C, WANG W, et al.Integrated metabolomics and network toxicology to reveal molecular mechanism of celastrol induced cardiotoxicity[J]. Toxicol Appl Pharmacol, 2019, 383: 114785.
[44] NAM TG.Lipid peroxidation and its toxicological implications[J]. Toxicol Res, 2011, 27(1): 1-6.
[45] Tian YG, SU XH, Li LIU LL, et al.An overview of studies on hepatotoxicity of Tripterygium Wilfordii in the past 20 years[J]. China Journal of Chinese Materia Medica(中国中药杂志), 2019, 44(16): 399-405.
[46] KAZAN K, KALAIPANDIAN S.Ferroptosis: yet another way to die[J]. Trends Plant Sci, 2019, 24(6): 479-481.
[47] HUANG Y, FU JF, SHI HB, et al.Metformin prevents non-alcoholic fatty liver disease in rats: role of phospholipase A2/lysophosphatidylcholine lipoapoptosis pathway in hepatocytes[J]. Chinese Journal of Pediatrics(中华儿科杂志), 2011, 49(2): 139-145.
[48] DENG XY, MA X.Mechanism of liver injury and its therapeutic progress[J]. Pharmacy and Clinics of Chinese Materia Medica(中药与临床), 2022, 13(5): 118-123, 128.
[49] NOEL OF, STILL CD, ARGYROPOULOS G, et al.Bile acids, FXR, and metabolic effects of bariatric surgery[J]. J Obes, 2016: 4390254.
[50] ZHANG B, LYU JT, ZHANG XM, et al.Traditional Chinese Medicine property-based understanding of toxicity, efficacy and pharmacovigilance[J]. Chinese Journal of Pharmacovigilance(中国药物警戒), 2021, 18(5): 5.