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Review Articles

Diagnosis, toxicological mechanism, and detoxification for hepatotoxicity induced by pyrrolizidine alkaloids from herbal medicines or other plants

ORCID Icon, , & ORCID Icon
Pages 123-133 | Received 05 Dec 2023, Accepted 18 Jan 2024, Published online: 27 Feb 2024

References

  • Amin KA, Hashem KS, Al-Muzafar HM, Taha EM. 2014. Oxidative hepatotoxicity effects of monocrotaline and its amelioration by lipoic acid, S-adenosyl methionine and vitamin E. J Complement Integr Med. 11(1):35–41. doi: 10.1515/jcim-2013-0041.
  • Amin KA, Hassan MS, Awad EI-ST, Hashem KS. 2011. The protective effects of cerium oxide nanoparticles against hepatic oxidative damage induced by monocrotaline. Int J Nanomed. 6:143–149. doi: 10.2147/IJN.S15308.
  • Bekkers SCAM, Yazdani SK, Virmani R, Waltenberger J. 2010. Microvascular obstruction: underlying pathophysiology and clinical diagnosis. J Am Coll Cardiol. 55(16):1649–1660. doi: 10.1016/j.jacc.2009.12.037.
  • Cao YH, Liu M, Wu SY, Xu JJ, Wang WJ, Qi XM, Ren J, Sun JH, Chen J, Gong LK. 2022. Kupffer cells play a crucial role in monocrotaline-induced liver injury by producing TNF-alpha. Toxicology. 468:153101. doi: 10.1016/j.tox.2022.153101.
  • Chen Y, Ji LL, Wang HT, Wang ZT. 2009. Intracellular glutathione plays important roles in pyrrolizidine alkaloids-induced growth inhibition on hepatocytes. Environ Toxicol Pharmacol. 28(3):357–362. doi: 10.1016/j.etap.2009.06.002.
  • Chen Y, Wang WQ, Jia XL, Wang CH, Yang L, Wang ZT, Xiong AZ. 2022. Firm evidence for the detoxification of senecionine-induced hepatotoxicity via N-glucuronidation in UGT1A4-humanized transgenic mice. Food Chem Toxicol. 165:113185. doi: 10.1016/j.fct.2022.113185.
  • Chen Z, Huo JR, Yang L, Zhu HY. 2011. Effect of ligustrazine on mice model of hepatic veno-occlusive disease induced by Gynura segetum. J Gastroenterol Hepatol. 26(6):1016–1021. doi: 10.1111/j.1440-1746.2011.06661.x.
  • Cooper RA, Huxtable RJ. 1999. The relationship between reactivity of metabolites of pyrrolizidine alkaloids and extrahepatic toxicity. Proc West Pharmacol Soc. 42:13–16.
  • Copple BL, Banes A, Ganey PE, Roth RA. 2002. Endothelial cell injury and fibrin deposition in rat liver after monocrotaline exposure. Toxicol Sci. 65(2):309–318. doi: 10.1093/toxsci/65.2.309.
  • Copple BL, Woolley B, Banes A, Ganey PE, Roth RA. 2002. Anticoagulants prevent monocrotaline-induced hepatic parenchymal cell injury but not endothelial cell injury in the rat. Toxicol Appl Pharmacol. 180(3):186–196. doi: 10.1006/taap.2002.9394.
  • Copple BL, Ganey PE, Roth RA. 2003. Liver inflammation during monocrotaline hepatotoxicity. Toxicology. 190(3):155–169. doi: 10.1016/s0300-483x(03)00164-1.
  • Copple BL, Roth RA, Ganey PE. 2006. Anticoagulation and inhibition of nitric oxide synthase influence hepatic hypoxia after monocrotaline exposure. Toxicology. 225(2–3):128–137. doi: 10.1016/j.tox.2006.05.016.
  • Cuce G, Canbaz HT, Sozen ME, Yerlikaya FH, Kalkan S. 2017. Vitamin E and selenium treatment of monocrotaline induced hepatotoxicity in rats. Biotech Histochem. 92(1):59–67. doi: 10.1080/10520295.2016.1267798.
  • Danan G, Teschke R. 2015. RUCAM in drug and herb induced liver injury: the update. Int J Mol Sci. 17(1):14. doi: 10.3390/ijms17010014.
  • DeLeve LD, McCuskey RS, Wang X, Hu L, McCuskey MK, Epstein RB, Kanel GC. 1999. Characterization of a reproducible rat model of hepatic veno-occlusive disease. Hepatology. 29(6):1779–1791. doi: 10.1002/hep.510290615.
  • DeLeve LD, Valla DC, Garcia-Tsao G, American Association for the Study Liver Diseases. 2009. Vascular disorders of the liver. Hepatology. 49(5):1729–1764. doi: 10.1002/hep.22772.
  • DeLeve LD, Wang XD, Kanel GC, Ito Y, Bethea NW, McCuskey MK, Tokes ZA, Tsai J, McCuskey RS. 2003. Decreased hepatic nitric oxide production contributes to the development of rat sinusoidal obstruction syndrome. Hepatology. 38(4):900–908. doi: 10.1002/hep.1840380416.
  • Deleve LD, Wang XD, Tsai J, Kanel G, Strasberg S, Tokes ZA. 2003. Sinusoidal obstruction syndrome (veno-occlusive disease) in the rat is prevented by matrix metalloproteinase inhibition. Gastroenterology. 125(3):882–890. doi: 10.1016/s0016-5085(03)01056-4.
  • Dignan FL, Wynn RF, Hadzic N, Karani J, Quaglia A, Pagliuca A, Veys P, Potter MN, Haemato-oncology Task Force of British Committee for Standards in Haematology, British Society for Blood and Marrow Transplantation. 2013. BCSH/BSBMT guideline: diagnosis and management of veno-occlusive disease (sinusoidal obstruction syndrome) following haematopoietic stem cell transplantation. Br J Haematol. 163(4):444–457. doi: 10.1111/bjh.12558.
  • Edgar JA, Colegate SM, Boppré M, Molyneux RJ. 2011. Pyrrolizidine alkaloids in food: a spectrum of potential health consequences. Food Addit Contam Part A Chem Anal Control Expo Risk Assess. 28(3):308–324. doi: 10.1080/19440049.2010.547520.
  • Edgar JA, Molyneux RJ, Colegate SM. 2015. Pyrrolizidine alkaloids: potential role in the etiology of cancers, pulmonary hypertension, congenital anomalies, and liver disease. Chem Res Toxicol. 28(1):4–20. doi: 10.1021/tx500403t.
  • European Association for the Study of the Liver. 2016. EASL clinical practice guidelines: vascular diseases of the liver. J Hepatol. 64(1):179–202.
  • Fu PP, Xia QS, Lin G, Chou MW. 2004. Pyrrolizidine alkaloids–genotoxicity, metabolism enzymes, metabolic activation, and mechanisms. Drug Metab Rev. 36(1):1–55. doi: 10.1081/dmr-120028426.
  • Gao H, Ruan JQ, Chen J, Li N, Ke CQ, Ye Y, Lin G, Wang JY. 2015. Blood pyrrole-protein adducts as a diagnostic and prognostic index in pyrrolizidine alkaloid-hepatic sinusoidal obstruction syndrome. Drug Des Devel Ther. 9:4861–4868. doi: 10.2147/DDDT.S87858.
  • Gordon GJ, Coleman WB, Grisham JW. 2000. Induction of cytochrome P450 enzymes in the livers of rats treated with the pyrrolizidine alkaloid retrorsine. Exp Mol Pathol. 69(1):17–26. doi: 10.1006/exmp.2000.2308.
  • Guo TT, Li X, Yang XQ, Kong XQ, Liu H, Bai T, Xu KS, Ye J, Song YH. 2019. Gadoxetic acid-enhanced hepatobiliary-phase magnetic resonance imaging for pyrrolizidine alkaloid-induced hepatic sinusoidal obstruction syndrome and association with liver function. Sci Rep. 9(1):1231. doi: 10.1038/s41598-018-37775-1.
  • Haas M, Ackermann G, Küpper J-H, Glatt H, Schrenk D, Fahrer J. 2023. OCT1-dependent uptake of structurally diverse pyrrolizidine alkaloids in human liver cells is crucial for their genotoxic and cytotoxic effects. Arch Toxicol. 97(12):3259–3271. doi: 10.1007/s00204-023-03591-4.
  • Hammad MA, Abdel-Bakky MS, Walker LA, Ashfaq MK. 2011. Oxidized low-density lipoprotein and tissue factor are involved in monocrotaline/lipopolysaccharide-induced hepatotoxicity. Arch Toxicol. 85(9):1079–1089. doi: 10.1007/s00204-011-0649-6.
  • Hammad MA, Abdel-Bakky MS, Walker LA, Ashfaq MK. 2013. Tissue factor antisense deoxyoligonucleotide prevents monocrotaline/LPS hepatotoxicity in mice. J Appl Toxicol. 33(8):774–783. doi: 10.1002/jat.2728.
  • Harb R, Xie GH, Lutzko C, Guo Y, Wang X, Hill CK, Kanel GC, DeLeve LD. 2009. Bone marrow progenitor cells repair rat hepatic sinusoidal endothelial cells after liver injury. Gastroenterology. 137(2):704–712. doi: 10.1053/j.gastro.2009.05.009.
  • He YS, Lian W, Ding L, Fan XY, Ma J, Zhang QY, Ding XX, Lin G. 2021. Lung injury induced by pyrrolizidine alkaloids depends on metabolism by hepatic cytochrome P450s and blood transport of reactive metabolites. Arch Toxicol. 95(1):103–116. doi: 10.1007/s00204-020-02921-0.
  • He YS, Ma J, Fan XY, Ding L, Ding XX, Zhang QY, Lin G. 2021. The key role of gut-liver axis in pyrrolizidine alkaloid-induced hepatotoxicity and enterotoxicity. Acta Pharm Sin B. 11(12):3820–3835. doi: 10.1016/j.apsb.2021.07.013.
  • He YS, Zhu L, Ma J, Lin G. 2021. Metabolism-mediated cytotoxicity and genotoxicity of pyrrolizidine alkaloids. Arch Toxicol. 95(6):1917–1942. doi: 10.1007/s00204-021-03060-w.
  • Hessel-Pras S, Braeuning A, Guenther G, Adawy A, Enge A-M, Ebmeyer J, Henderson CJ, Hengstler JG, Lampen A, Reif R. 2020. The pyrrolizidine alkaloid senecionine induces CYP-dependent destruction of sinusoidal endothelial cells and cholestasis in mice. Arch Toxicol. 94(1):219–229. doi: 10.1007/s00204-019-02582-8.
  • Hirata M, Tajima H, Miyashita T, Miyata T, Nakanuma S, Makino I, Hayashi H, Oyama K, Takamura H, Ninomiya I, et al. 2017. Extravasated platelet aggregation in the livers of rats with drug-induced hepatic sinusoidal obstruction syndrome. Mol Med Rep. 15(5):3147–3152. doi: 10.3892/mmr.2017.6407.
  • Huang ZL, Chen MW, Wei MJ, Lu B, Wu XJ, Wang ZT, Ji LL. 2019. Liver inflammatory injury initiated by DAMPs-TLR4-MyD88/TRIF-NFkappaB signaling pathway is involved in monocrotaline-induced HSOS. Toxicol Sci. 172(2):385–397. doi: 10.1093/toxsci/kfz193.
  • Huang ZL, Jing XQ, Sheng YC, Zhang JQ, Hao ZX, Wang ZT, Ji LL. 2019. (-)-Epicatechin attenuates hepatic sinusoidal obstruction syndrome by inhibiting liver oxidative and inflammatory injury. Redox Biol. 22:101117. doi: 10.1016/j.redox.2019.101117.
  • Huang ZL, Sheng YC, Chen MW, Hao ZX, Hu FF, Ji LL. 2018. Liquiritigenin and liquiritin alleviated MCT-induced HSOS by activating Nrf2 antioxidative defense system. Toxicol Appl Pharmacol. 355:18–27. doi: 10.1016/j.taap.2018.06.014.
  • Huang ZL, Zhao Q, Chen MW, Zhang JQ, Ji LL. 2019. Liquiritigenin and liquiritin alleviated monocrotaline-induced hepatic sinusoidal obstruction syndrome via inhibiting HSP60-induced inflammatory injury. Toxicology. 428:152307. doi: 10.1016/j.tox.2019.152307.
  • Ji LL, Chen Y, Liu TY, Wang ZT. 2008. Involvement of Bcl-xL degradation and mitochondrial-mediated apoptotic pathway in pyrrolizidine alkaloids-induced apoptosis in hepatocytes. Toxicol Appl Pharmacol. 231(3):393–400. doi: 10.1016/j.taap.2008.05.015.
  • Ji LL, Chen Y, Wang ZT. 2008. Protection of S-adenosyl methionine against the toxicity of clivorine on hepatocytes. Environ Toxicol Pharmacol. 26(3):331–335. doi: 10.1016/j.etap.2008.06.007.
  • Ji LL, Liu TY, Chen Y, Wang ZT. 2009. Protective mechanisms of N-acetyl-cysteine against pyrrolizidine alkaloid clivorine-induced hepatotoxicity. J Cell Biochem. 108(2):424–432. doi: 10.1002/jcb.22269.
  • Ji LL, Liu TY, Wang ZT. 2010. Pyrrolizidine alkaloid clivorine induced oxidative injury on primary cultured rat hepatocytes. Hum Exp Toxicol. 29(4):303–309.
  • Jiang KY, Zhang Y, Ye XL, Xiong F, Chen Y, Jia XL, Zhang YX, Yang L, Xiong AZ, Wang ZT. 2022. Bear bile powder attenuates senecionine-induced hepatic sinusoidal obstruction syndrome in mice. Chin J Nat Med. 20(4):270–281. doi: 10.1016/S1875-5364(22)60169-9.
  • Jing XQ, Zhang JQ, Huang ZL, Sheng YC, Ji LL. 2018. The involvement of Nrf2 antioxidant signalling pathway in the protection of monocrotaline-induced hepatic sinusoidal obstruction syndrome in rats by (+)-catechin hydrate. Free Radic Res. 52(4):402–414. doi: 10.1080/10715762.2018.1437914.
  • Kan XF, Ye J, Rong XX, Lu ZW, Li X, Wang Y, Yang L, Xu KS, Song YH, Hou XH. 2016. Diagnostic performance of contrast-enhanced CT in pyrrolizidine alkaloids-induced hepatic sinusoidal obstructive syndrome. Sci Rep. 6(1):37998. doi: 10.1038/srep37998.
  • Kaufman CS, Cretcher MR. 2021. Transjugular liver biopsy. Tech Vasc Interv Radiol. 24(4):100795. doi: 10.1016/j.tvir.2021.100795.
  • Li WW, Cheng T, Jiang TT, Zhou MY, Gong BW, Zhao GD, Li J, Tan R, Yang XJ, Joshi K, et al. 2022. Hepatic RNA adduction derived from metabolic activation of retrorsine in vitro and in vivo. Chem Biol Interact. 365:110047. doi: 10.1016/j.cbi.2022.110047.
  • Li YS, Bao J, Xu Y, Wang TL. 2020. [Clinicopathological analysis of 16 cases of pyrrolizidine alkaloids-associated hepatic sinusoidal obstruction syndrome]. Zhonghua Gan Zang Bing Za Zhi. 28(4):332–337.
  • Liang QN, Sheng YC, Jiang P, Ji LL, Xia YY, Min Y, Wang ZT. 2011a. The difference of glutathione antioxidant system in newly weaned and young mice liver and its involvement in isoline-induced hepatotoxicity. Arch Toxicol. 85(10):1267–1279. doi: 10.1007/s00204-011-0664-7.
  • Liang QN, Sheng YC, Jiang P, Ji LL, Xia YY, Min Y, Wang ZT. 2011b. The gender-dependent difference of liver GSH antioxidant system in mice and its influence on isoline-induced liver injury. Toxicology. 280(1-2):61–69. doi: 10.1016/j.tox.2010.11.010.
  • Lin G, Nnane IP, Cheng TY. 1999. The effects of pretreatment with glycyrrhizin and glycyrrhetinic acid on the retrorsine-induced hepatotoxicity in rats. Toxicon. 37(9):1259–1270. doi: 10.1016/s0041-0101(98)00263-3.
  • Lin G, Wang JY, Li N, Li M, Gao H, Ji Y, Zhang F, Wang HL, Zhou Y, Ye Y, et al. 2011. Hepatic sinusoidal obstruction syndrome associated with consumption of Gynura segetum. J Hepatol. 54(4):666–673. doi: 10.1016/j.jhep.2010.07.031.
  • Liu F, Rong XX, Guo H, Xu D, Liu C, Meng LL, Yang XY, Guo TT, Kan XF, Song YH. 2020. Clinical characteristics, CT signs, and pathological findings of pyrrolizidine alkaloids-induced sinusoidal obstructive syndrome: a retrospective study. BMC Gastroenterol. 20(1):30. doi: 10.1186/s12876-020-1180-0.
  • Liu TY, Chen Y, Wang ZY, Ji LL, Wang ZT. 2010. Pyrrolizidine alkaloid isoline-induced oxidative injury in various mouse tissues. Exp Toxicol Pathol. 62(3):251–257. doi: 10.1016/j.etp.2009.04.008.
  • Liu ZL, Liang S, Wei XH, Du XF, Zhang J. 2022. Defibrotide improved the outcome of monocrotaline induced rat hepatic sinusoidal obstruction syndrome. BMC Gastroenterol. 22(1):525. doi: 10.1186/s12876-022-02523-3.
  • Lu SC. 2009. Regulation of glutathione synthesis. Mol Aspects Med. 30(1–2):42–59. doi: 10.1016/j.mam.2008.05.005.
  • Lu Y, Ma J, Song ZJ, Ye Y, Fu PP, Lin G. 2018. The role of formation of pyrrole-ATP synthase subunit beta adduct in pyrrolizidine alkaloid-induced hepatotoxicity. Arch Toxicol. 92(11):3403–3414. doi: 10.1007/s00204-018-2309-6.
  • Ma J, Zhang CY, He YS, Chen XM, Lin G. 2022. Fasting augments pyrrolizidine alkaloid-induced hepatotoxicity. Arch Toxicol. 96(2):639–651. doi: 10.1007/s00204-021-03193-y.
  • Ma J, Zhang W, He YS, Zhu L, Zhang CY, Liu J, Ye Y, Zhuge YZ, Lin G. 2021. Clinical application of pyrrole-hemoglobin adducts as a biomarker of pyrrolizidine alkaloid exposure in humans. Arch Toxicol. 95(2):759–765. doi: 10.1007/s00204-020-02947-4.
  • Miyata T, Tajima H, Hirata M, Nakanuma SI, Makino I, Hayashi H, Oyama K, Miyashita T, Takamura H, Ninomiya I, et al. 2018. Phosphodiesterase III inhibitor attenuates rat sinusoidal obstruction syndrome through inhibition of platelet aggregation in Disse’s space. J Gastroenterol Hepatol. 33(4):950–957. doi: 10.1111/jgh.14004.
  • Mohty M, Malard F, Abecassis M, Aerts E, Alaskar AS, Aljurf M, Arat M, Bader P, Baron F, Bazarbachi A, et al. 2015. Sinusoidal obstruction syndrome/veno-occlusive disease: current situation and perspectives-a position statement from the European Society for Blood and Marrow Transplantation (EBMT). Bone Marrow Transplant. 50(6):781–789. doi: 10.1038/bmt.2015.52.
  • Nakamura K, Hatano E, Narita M, Miyagawa-Hayashino A, Koyama Y, Nagata H, Iwaisako K, Taura K, Uemoto S. 2012. Sorafenib attenuates monocrotaline-induced sinusoidal obstruction syndrome in rats through suppression of JNK and MMP-9. J Hepatol. 57(5):1037–1043. doi: 10.1016/j.jhep.2012.07.004.
  • Ni HM, Williams JA, Ding WX. 2015. Mitochondrial dynamics and mitochondrial quality control. Redox Biol. 4:6–13. doi: 10.1016/j.redox.2014.11.006.
  • Okuno M, Hatano E, Nakamura K, Miyagawa-Hayashino A, Kasai Y, Nishio T, Seo S, Taura K, Uemoto S. 2015. Regorafenib suppresses sinusoidal obstruction syndrome in rats. J Surg Res. 193(2):693–703. doi: 10.1016/j.jss.2014.08.052.
  • Otaka F, Ito Y, Goto T, Eshima K, Amano H, Koizumi W, Majima M. 2020. Platelets prevent the development of monocrotaline-induced liver injury in mice. Toxicol Lett. 335:71–81. doi: 10.1016/j.toxlet.2020.10.007.
  • Otaka F, Ito Y, Inoue T, Ohkubo H, Nishizawa N, Kojo K, Betto T, Yamane S, Narumiya S, Koizumi W, et al. 2019. Thromboxane A (2) receptor signaling in endothelial cells attenuates monocrotaline-induced liver injury. Toxicol Appl Pharmacol. 381:114733. doi: 10.1016/j.taap.2019.114733.
  • Periasamy S, Hsu DZ, Chen SY, Yang SS, Chandrasekaran VRM, Liu MY. 2011. Therapeutic sesamol attenuates monocrotaline-induced sinusoidal obstruction syndrome in rats by inhibiting matrix metalloproteinase-9. Cell Biochem Biophys. 61(2):327–336. doi: 10.1007/s12013-011-9215-3.
  • Peterka M, Sarin S, Roeder E, Wiedenfeld H, Halaskova M. 1994. Differing embryotoxic effects of senecionine and senecionine-N-oxide on the chick embryo. Funct Dev Morphol. 4(2):89–92.
  • Qin L, D’Alessandro-Gabazza CN, Aoki S, Gil-Bernabe P, Yano Y, Takagi T, Boveda-Ruiz D, Ramirez Marmol AY, San Martin Montenegro VT, Toda M, et al. 2010. Pulmonary hypertension is ameliorated in mice deficient in thrombin-activatable fibrinolysis inhibitor. J Thromb Haemost. 8(4):808–816. doi: 10.1111/j.1538-7836.2010.03751.x.
  • Takeuchi M, Oda S, Tsuneyama K, Yokoi T. 2018. Comprehensive analysis of serum microRNAs in hepatic sinusoidal obstruction syndrome (SOS) in rats: implication as early phase biomarkers for SOS. Arch Toxicol. 92(9):2947–2962. doi: 10.1007/s00204-018-2269-x.
  • Tan YW, Zheng SN. 2023. Clinicopathological characteristics and diagnosis of hepatic sinusoidal obstruction syndrome caused by Tusanqi-Case report and literature review. Open Med (Wars). 18(1):20230737. doi: 10.1515/med-2023-0737.
  • Teschke R, Danan G. 2020. Worldwide use of RUCAM for causality assessment in 81,856 idiosyncratic DILI and 14,029 HILI cases published 1993-mid 2020: a comprehensive analysis. Medicines (Basel). 7(10):62. doi: 10.3390/medicines7100062.
  • Teschke R, Eickhoff A, Schulze J, Danan G. 2021. Herb-induced liver injury (HILI) with 12,068 worldwide cases published with causality assessments by Roussel Uclaf Causality Assessment Method (RUCAM): an overview. Transl Gastroenterol Hepatol. 6:51. doi: 10.21037/tgh-20-149.
  • Teschke R, Vongdala N, Quan NV, Quy TN, Xuan TD. 2021. Metabolic toxification of 1,2-unsaturated pyrrolizidine alkaloids causes human hepatic sinusoidal obstruction syndrome: the update. Int J Mol Sci. 22(19):10419. doi: 10.3390/ijms221910419.
  • Tu MJ, Li LP, Lei HM, Ma ZY, Chen ZJ, Sun SY, Xu SY, Zhou H, Zeng S, Jiang HD. 2014. Involvement of organic cation transporter 1 and CYP3A4 in retrorsine-induced toxicity. Toxicology. 322:34–42. doi: 10.1016/j.tox.2014.04.007.
  • Tu MJ, Sun SY, Wang K, Peng XY, Wang RH, Li LP, Zeng S, Zhou H, Jiang HD. 2013. Organic cation transporter 1 mediates the uptake of monocrotaline and plays an important role in its hepatotoxicity. Toxicology. 311(3):225–230. doi: 10.1016/j.tox.2013.06.009.
  • Wang WQ, Yang X, Chen Y, Ye XL, Jiang KY, Xiong AZ, Yang L, Wang ZT. 2020. Seneciphylline, a main pyrrolizidine alkaloid in Gynura japonica, induces hepatotoxicity in mice and primary hepatocytes via activating mitochondria-mediated apoptosis. J Appl Toxicol. 40(11):1534–1544. doi: 10.1002/jat.4004.
  • Wang X, Kanel GC, DeLeve LD. 2000. Support of sinusoidal endothelial cell glutathione prevents hepatic veno-occlusive disease in the rat. Hepatology. 31(2):428–434. doi: 10.1002/hep.510310224.
  • Wang XJ, Zhang W, Yang YF, Zhuge YZ, Xiong AZ, Yang L, Wang ZT. 2021. Blood microRNA signatures serve as potential diagnostic biomarkers for hepatic sinusoidal obstruction syndrome caused by Gynura japonica containing pyrrolizidine alkaloids. Front Pharmacol. 12:627126. doi: 10.3389/fphar.2021.627126.
  • Wang ZT, Ma J, He YS, Miu KK, Yao S, Tang CP, Ye Y, Lin G. 2022. Nrf2-mediated liver protection by 18beta-glycyrrhetinic acid against pyrrolizidine alkaloid-induced toxicity through PI3K/Akt/GSK3beta pathway. Phytomedicine. 102:154162. doi: 10.1016/j.phymed.2022.154162.
  • Wang ZT, Ma J, Yao S, He YS, Miu KK, Xia QS, Fu PP, Ye Y, Lin G. 2022. Liquorice extract and 18beta-glycyrrhetinic acid protect against experimental pyrrolizidine alkaloid-induced hepatotoxicity in rats through inhibiting cytochrome P450-mediated metabolic activation. Front Pharmacol. 13:850859. doi: 10.3389/fphar.2022.850859.
  • Xiao L, Hu LL, Chu HK, Chen LY, Yan JJ, Wang WJ, Yang XQ, Zhu QJ, Du F, Song YH, et al. 2022. Retrorsine cooperates with gut microbiota to promote hepatic sinusoidal obstruction syndrome by disrupting the gut barrier. J Clin Transl Hepatol. 10(6):1086–1098. doi: 10.14218/JCTH.2021.00398.
  • Yamazaki H, Tajima H, Yamamoto Y, Munesue S, Okazaki M, Ohbatake Y, Nakanuma S, Makino I, Miyashita T, Takamura H, et al. 2022. Thrombopoietin accumulation in hepatocytes induces a decrease in its serum levels in a sinusoidal obstruction syndrome model. Mol Med Rep. 25(6):201. doi: 10.3892/mmr.2022.12717.
  • Yang MB, Ruan JQ, Fu PP, Lin G. 2016. Cytotoxicity of pyrrolizidine alkaloid in human hepatic parenchymal and sinusoidal endothelial cells: firm evidence for the reactive metabolites mediated pyrrolizidine alkaloid-induced hepatotoxicity. Chem Biol Interact. 243:119–126. doi: 10.1016/j.cbi.2015.09.011.
  • Yang MB, Ruan JQ, Gao H, Li N, Ma J, Xue JY, Ye Y, Fu PP, Wang JY, Lin G. 2017. First evidence of pyrrolizidine alkaloid N-oxide-induced hepatic sinusoidal obstruction syndrome in humans. Arch Toxicol. 91(12):3913–3925. doi: 10.1007/s00204-017-2013-y.
  • Yang X, Wang H, Ni HM, Xiong AZ, Wang ZT, Sesaki H, Ding WX, Yang L. 2017. Inhibition of Drp1 protects against senecionine-induced mitochondria-mediated apoptosis in primary hepatocytes and in mice. Redox Biol. 12:264–273. doi: 10.1016/j.redox.2017.02.020.
  • Yang XQ, Ye J, Li X, Li Q, Song YH. 2019. Pyrrolizidine alkaloids-induced hepatic sinusoidal obstruction syndrome: pathogenesis, clinical manifestations, diagnosis, treatment, and outcomes. World J Gastroenterol. 25(28):3753–3763. doi: 10.3748/wjg.v25.i28.3753.
  • Yee SB, Ganey PE, Roth RA. 2003. The role of Kupffer cells and TNF-alpha in monocrotaline and bacterial lipopolysaccharide-induced liver injury. Toxicol Sci. 71(1):124–132. doi: 10.1093/toxsci/71.1.124.
  • Yee SB, Hanumegowda UM, Hotchkiss JA, Ganey PE, Roth RA. 2003. Role of neutrophils in the synergistic liver injury from monocrotaline and bacterial lipopolysaccharide exposure. Toxicol Sci. 72(1):43–56. doi: 10.1093/toxsci/kfg019.
  • Yee SB, Harkema JR, Ganey PE, Roth RA. 2003. The coagulation system contributes to synergistic liver injury from exposure to monocrotaline and bacterial lipopolysaccharide. Toxicol Sci. 74(2):457–469. doi: 10.1093/toxsci/kfg129.
  • Yee SB, Kinser S, Hill DA, Barton CC, Hotchkiss JA, Harkema JR, Ganey PE, Roth RA. 2000. Synergistic hepatotoxicity from coexposure to bacterial endotoxin and the pyrrolizidine alkaloid monocrotaline. Toxicol Appl Pharmacol. 166(3):173–185. doi: 10.1006/taap.2000.8968.
  • Zhang F, Zhou Y, Yang X, Xiong AZ, Wang ZT, Yang L. 2019. Gynura rhizoma containing pyrrolizidine alkaloids induces the hepatic sinusoidal obstruction syndrome in mice via upregulating fibrosis-related factors. Acta Pharmacol Sin. 40(6):781–789. doi: 10.1038/s41401-018-0155-y.
  • Zhang J, Sheng Y, Shi L, Zheng Z, Chen M, Lu B, Ji L. 2017. Quercetin and baicalein suppress monocrotaline-induced hepatic sinusoidal obstruction syndrome in rats. Eur J Pharmacol. 795:160–168. doi: 10.1016/j.ejphar.2016.12.015.
  • Zhang W, Liu L, Zhang M Zhang F, Peng CY, Zhang B, Chen J, Li L, He J, Xiao JQ, Feng YH, et al. 2021. Validation of the Nanjing criteria for diagnosing pyrrolizidine alkaloids-induced hepatic sinusoidal obstruction syndrome. J Clin Transl Hepatol. 9(3):345–352.
  • Zheng ZY, Shi L, Sheng YC, Zhang JQ, Lu B, Ji LL. 2016. Chlorogenic acid suppresses monocrotaline-induced sinusoidal obstruction syndrome: the potential contribution of NFkappaB, Egr1, Nrf2, MAPKs and PI3K signals. Environ Toxicol Pharmacol. 46:80–89. doi: 10.1016/j.etap.2016.07.002.
  • Zhu L, Xue JY, He YS, Xia QS, Fu PP, Lin G. 2022. Correlation investigation between pyrrole-DNA and pyrrole-protein adducts in male ICR mice exposed to retrorsine, a hepatotoxic pyrrolizidine alkaloid. Toxins (Basel). 14(6):377. doi: 10.3390/toxins14060377.
  • Zhu L, Zhang CY, Li DP, Chen HB, Ma J, Gao H, Ye Y, Wang JY, Fu PP, Lin G. 2021. Tu-San-Qi (Gynura japonica): the culprit behind pyrrolizidine alkaloid-induced liver injury in China. Acta Pharmacol Sin. 42(8):1212–1222. doi: 10.1038/s41401-020-00553-9.
  • Zhu L, Zhang CY, Zhang W, Xia QS, Ma J, He X, He YS, Fu PP, Jia W, Zhuge YZ, et al. 2021. Developing urinary pyrrole-amino acid adducts as non-invasive biomarkers for identifying pyrrolizidine alkaloids-induced liver injury in human. Arch Toxicol. 95(10):3191–3204. doi: 10.1007/s00204-021-03129-6.
  • Zhuge YZ, Liu YL, Xie WF, Zou XP, Xu JM, Wang JY, Chinese Society of Gastroenterology Committee of Hepatobiliary Disease. 2019. Expert consensus on the clinical management of pyrrolizidine alkaloid-induced hepatic sinusoidal obstruction syndrome. J Gastroenterol Hepatol. 34(4):634–642. doi: 10.1111/jgh.14612.

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