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Mini-Reviews in Medicinal Chemistry

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ISSN (Print): 1389-5575
ISSN (Online): 1875-5607

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Mini-Review Article

Research and Progress of Probucol in Nonalcoholic Fatty Liver Disease

Author(s): Ke-qian Chen, Bo-yi Ke, Lu Cheng, Meng-ting Guan, Zong-bao Wang and Shu-zhi Wang*

Volume 23, Issue 19, 2023

Published on: 27 March, 2023

Page: [1905 - 1911] Pages: 7

DOI: 10.2174/1389557523666230324092842

Price: $65

Abstract

With the development of the social economy over the last 30 years, non-alcoholic fatty liver disease (NAFLD) is affected by unhealthy living habits and eating styles and has gradually become an increasingly serious public health problem. It is very important to investigate the pathogenesis and treatment of NAFLD for the development of human health. Probucol is an antioxidant with a bis-phenol structure. Although probucol is a clinically used cholesterol-lowering and antiatherosclerosis drug, its mechanism has not been elucidated in detail. This paper reviews the chemical structure, pharmacokinetics and pharmacological research of probucol. Meanwhile, this paper reviews the mechanism of probucol in NAFLD. We also analyzed and summarized the experimental models and clinical trials of probucol in NAFLD. Although current therapeutic strategies for NAFLD are not effective, we hope that through further research on probucol, we will be able to find suitable treatments to solve this problem in the future.

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[1]
Zhou, J.; Zhou, F.; Wang, W.; Zhang, X.J.; Ji, Y.X.; Zhang, P.; She, Z.G.; Zhu, L.; Cai, J.; Li, H. Epidemiological features of NAFLD from 1999 to 2018 in China. Hepatology, 2020, 71(5), 1851-1864.
[http://dx.doi.org/10.1002/hep.31150] [PMID: 32012320]
[2]
Carlsson, B.; Lindén, D.; Brolén, G.; Liljeblad, M.; Bjursell, M.; Romeo, S.; Loomba, R. The emerging role of genetics in precision medicine for patients with non-alcoholic steatohepatitis. Aliment. Pharmacol. Ther., 2020, 51(12), 1305-1320.
[http://dx.doi.org/10.1111/apt.15738] [PMID: 32383295]
[3]
Pafili, K.; Roden, M. Nonalcoholic fatty liver disease (NAFLD) from pathogenesis to treatment concepts in humans. Mol. Metab., 2021, 50, 101122.
[http://dx.doi.org/10.1016/j.molmet.2020.101122] [PMID: 33220492]
[4]
Raza, S.; Rajak, S.; Upadhyay, A.; Tewari, A.; Anthony Sinha, R. Current treatment paradigms and emerging therapies for NAFLD/NASH. Front. Biosci., 2021, 26(2), 206-237.
[http://dx.doi.org/10.2741/4892] [PMID: 33049668]
[5]
Yamashita, S.; Masuda, D.; Matsuzawa, Y. Did we abandon probucol too soon? Curr. Opin. Lipidol., 2015, 26(4), 304-316.
[http://dx.doi.org/10.1097/MOL.0000000000000199] [PMID: 26125504]
[6]
Heeg, J.F.; Hiser, M.F.; Satonin, D.K.; Rose, J.Q. Pharmacokinetics of probucol in male rats. J. Pharm. Sci., 1984, 73(12), 1758-1763.
[http://dx.doi.org/10.1002/jps.2600731225] [PMID: 6527251]
[7]
Qian, Y.; Chen, G.; Wang, J.; Ren, L. Preparation and evaluation of probucol-phospholipid complex with enhanced bioavailability and no food effect. AAPS PharmSciTech, 2018, 19(8), 3599-3608.
[http://dx.doi.org/10.1208/s12249-018-1157-2] [PMID: 30238303]
[8]
Kim, K.; Kim, B.H.; Lim, K.S.; Kim, T.E.; Shin, S.G.; Jang, I.J.; Yu, K.S. Potential interactions between cilostazol and probucol: A two-part, single-dose, open-label study in healthy Korean male volunteers. Clin. Ther., 2009, 31(10), 2098-2106.
[http://dx.doi.org/10.1016/j.clinthera.2009.10.005] [PMID: 19922880]
[9]
Li, J.; Yang, Y.; Zhao, M.; Xu, H.; Ma, J.; Wang, S. Improved oral bioavailability of probucol by dry media-milling. Mater. Sci. Eng. C, 2017, 78, 780-786.
[http://dx.doi.org/10.1016/j.msec.2017.04.141] [PMID: 28576049]
[10]
Mamo, J.C.L.; Lam, V.; Al-Salami, H.; Brook, E.; Mooranian, A.; Nesbit, M.; Graneri, L.; D’Alonzo, Z.; Fimognari, N.; Stephenson, A.; Takechi, R. Sodium alginate capsulation increased brain delivery of probucol and suppressed neuroinflammation and neurodegeneration. Ther. Deliv., 2018, 9(10), 703-709.
[http://dx.doi.org/10.4155/tde-2018-0033] [PMID: 30277134]
[11]
Sha, X.; Wu, J.; Chen, Y.; Fang, X. Self-microemulsifying drug-delivery system for improved oral bioavailability of probucol: preparation and evaluation. Int. J. Nanomedicine, 2012, 7, 705-712.
[PMID: 22359449]
[12]
Li, J.F.; Chen, S.; Feng, J.D.; Zhang, M.Y.; Liu, X.X. RETRACTED: Probucol via inhibition of NHE1 attenuates LPS-accelerated atherosclerosis and promotes plaque stability in vivo. Exp. Mol. Pathol., 2014, 96(2), 250-256.
[http://dx.doi.org/10.1016/j.yexmp.2014.02.010] [PMID: 24594116]
[13]
Li, S.; Liang, J.; Niimi, M.; Bilal Waqar, A.; Kang, D.; Koike, T.; Wang, Y.; Shiomi, M.; Fan, J. Probucol suppresses macrophage infiltration and MMP expression in atherosclerotic plaques of WHHL rabbits. J. Atheroscler. Thromb., 2014, 21(7), 648-658.
[http://dx.doi.org/10.5551/jat.21600] [PMID: 24584175]
[14]
Zhong, J.K.; Guo, Z.G.; Li, C.; Wang, Z.K.; Lai, W.Y.; Tu, Y. Probucol alleviates atherosclerosis and improves high density lipoprotein function. Lipids Health Dis., 2011, 10(1), 210.
[http://dx.doi.org/10.1186/1476-511X-10-210] [PMID: 22078494]
[15]
Zhu, H.; Jin, X.; Zhao, J.; Dong, Z.; Ma, X.; Xu, F.; Huang, W.; Liu, G.; Zou, Y.; Wang, K.; Hu, K.; Sun, A.; Ge, J. Probucol protects against atherosclerosis through lipid-lowering and suppressing immune maturation of CD11C+ dendritic cells in STZ-induced diabetic LDLR−/−. Mice. J. Cardiovasc. Pharmacol., 2015, 65(6), 620-627.
[http://dx.doi.org/10.1097/FJC.0000000000000234] [PMID: 25714599]
[16]
Wang, N.; Wei, R.; Li, Q.; Yang, X.; Li, P.; Huang, M.; Wang, R.; Cai, G.; Chen, X. Renal protective effect of probucol in rats with contrast-induced nephropathy and its underlying mechanism. Med. Sci. Monit., 2015, 21, 2886-2892.
[http://dx.doi.org/10.12659/MSM.895543] [PMID: 26408630]
[17]
Ma, X.; Jiao, Z.; Liu, Y.; Chen, J.; Li, G.; Liu, T.; Tse, G.; Yuan, R. Probucol protects against contrast-induced acute kidney injury via the extracellular signal-regulated kinases 1 and 2 (ERK1/2)/JNK-caspase 3 pathway in diabetic rats. Med. Sci. Monit., 2019, 25, 1038-1045.
[http://dx.doi.org/10.12659/MSM.913106] [PMID: 30728344]
[18]
Yang, S.; Zhao, L.; Han, Y.; Liu, Y.; Chen, C.; Zhan, M.; Xiong, X.; Zhu, X.; Xiao, L.; Hu, C.; Liu, F.; Zhou, Z.; Kanwar, Y.S.; Sun, L. Probucol ameliorates renal injury in diabetic nephropathy by inhibiting the expression of the redox enzyme p66Shc. Redox Biol., 2017, 13, 482-497.
[http://dx.doi.org/10.1016/j.redox.2017.07.002] [PMID: 28728079]
[19]
Liu, G.; Ji, W.; Huang, J.; Liu, L.; Wang, Y. 4-HNE expression in diabetic rat kidneys and the protective effects of probucol. J. Endocrinol. Invest., 2016, 39(8), 865-873.
[http://dx.doi.org/10.1007/s40618-015-0428-y] [PMID: 26830905]
[20]
Liu, H.W.; Luo, Y.; Zhou, Y.F.; Chen, Z.P. Probucol prevents diabetes-induced retinal neuronal degeneration through upregulating Nrf2. BioMed Res. Int., 2020, 2020, 1-8.
[http://dx.doi.org/10.1155/2020/3862509] [PMID: 32149102]
[21]
Higashi, K.; Mori, A.; Sakamoto, K.; Ishii, K.; Nakahara, T. Probucol slows the progression of cataracts in streptozotocin-induced hyperglycemic rats. Pharmacology, 2019, 103(3-4), 212-219.
[http://dx.doi.org/10.1159/000496055] [PMID: 30721902]
[22]
Liu, H.; Cai, M. Effect of probucol on hemodynamics, rheology and blood lipid of diabetic retinopathy. Exp. Ther. Med., 2018, 15(4), 3809-3814.
[http://dx.doi.org/10.3892/etm.2018.5917] [PMID: 29581738]
[23]
Kawaguchi, T.; Yanagihara, T.; Yokoyama, T.; Suetsugu-Ogata, S.; Hamada, N.; Harada-Ikeda, C.; Suzuki, K.; Maeyama, T.; Kuwano, K.; Nakanishi, Y. Probucol attenuates hyperoxia-induced lung injury in mice. PLoS One, 2017, 12(4), e0175129.
[http://dx.doi.org/10.1371/journal.pone.0175129] [PMID: 28384256]
[24]
Zhang, H.X.; Li, Y.N.; Wang, X.L.; Ye, C.L.; Zhu, X.Y.; Li, H.P.; Yang, T.; Liu, Y.J. Probucol ameliorates EMT and lung fibrosis through restoration of SIRT3 expression. Pulm. Pharmacol. Ther., 2019, 57, 101803.
[http://dx.doi.org/10.1016/j.pupt.2019.101803] [PMID: 31085231]
[25]
Huang, J.L.; Yu, C.; Su, M.; Yang, S.M.; Zhang, F.; Chen, Y.Y.; Liu, J.Y.; Jiang, Y.F.; Zhong, Z.G.; Wu, D.P. Probucol, a “non-statin” cholesterol-lowering drug, ameliorates D-galactose induced cognitive deficits by alleviating oxidative stress via Keap1/Nrf2 signaling pathway in mice. Aging, 2019, 11(19), 8542-8555.
[http://dx.doi.org/10.18632/aging.102337] [PMID: 31590160]
[26]
Santos, D.B.; Colle, D.; Moreira, E.L.G.; Peres, K.C.; Ribeiro, R.P.; dos Santos, A.A.; de Oliveira, J.; Hort, M.A.; de Bem, A.F.; Farina, M. Probucol mitigates streptozotocin-induced cognitive and biochemical changes in mice. Neuroscience, 2015, 284, 590-600.
[http://dx.doi.org/10.1016/j.neuroscience.2014.10.019] [PMID: 25453776]
[27]
Lam, V.; Clarnette, R.; Francis, R.; Bynevelt, M.; Watts, G.; Flicker, L.; Orr, C.F.; Loh, P.; Lautenschlager, N.; Reid, C.M.; Foster, J.K.; Dhaliwal, S.S.; Robinson, S.; Corti, E.; Vaccarezza, M.; Horgan, B.; Takechi, R.; Mamo, J. Efficacy of probucol on cognitive function in Alzheimer’s disease: Study protocol for a double-blind, placebo-controlled, randomised phase II trial (PIA study). BMJ Open, 2022, 12(2), e058826.
[http://dx.doi.org/10.1136/bmjopen-2021-058826] [PMID: 35190446]
[28]
Santos, D.B.; Peres, K.C.; Ribeiro, R.P.; Colle, D.; Santos, A.A.; Moreira, E.L.G.; Souza, D.O.G.; Figueiredo, C.P.; Farina, M. Probucol, a lipid-lowering drug, prevents cognitive and hippocampal synaptic impairments induced by amyloid β peptide in mice. Exp. Neurol., 2012, 233(2), 767-775.
[http://dx.doi.org/10.1016/j.expneurol.2011.11.036] [PMID: 22173317]
[29]
de Paula Nascimento-Castro, C.; Wink, A.C.; da Fônseca, V.S.; Bianco, C.D.; Winkelmann-Duarte, E.C.; Farina, M.; Rodrigues, A.L.S.; Gil-Mohapel, J.; de Bem, A.F.; Brocardo, P.S. Antidepressant effects of probucol on early-symptomatic yac128 transgenic mice for huntington’s disease. Neural Plast., 2018, 1-17.
[http://dx.doi.org/10.1155/2018/4056383] [PMID: 30186318]
[30]
Ribeiro, R.P.; Moreira, E.L.G.; Santos, D.B.; Colle, D.; dos Santos, A.A.; Peres, K.C.; Figueiredo, C.P.; Farina, M. Probucol affords neuroprotection in a 6-OHDA mouse model of Parkinson’s disease. Neurochem. Res., 2013, 38(3), 660-668.
[http://dx.doi.org/10.1007/s11064-012-0965-0] [PMID: 23334712]
[31]
Kume, A.; Herbas, M.S.; Shichiri, M.; Ishida, N.; Suzuki, H. Effect of anti-hyperlipidemia drugs on the alpha-tocopherol concentration and their potential for murine malaria infection. Parasitol. Res., 2016, 115(1), 69-75.
[http://dx.doi.org/10.1007/s00436-015-4722-6] [PMID: 26358099]
[32]
Shichiri, M.; Ishida, N.; Hagihara, Y.; Yoshida, Y.; Kume, A.; Suzuki, H. Probucol induces the generation of lipid peroxidation products in erythrocytes and plasma of male cynomolgus macaques. J. Clin. Biochem. Nutr., 2019, 64(2), 129-142.
[http://dx.doi.org/10.3164/jcbn.18-7] [PMID: 30936625]
[33]
Kume, A.; Anh, D.T.M.; Shichiri, M.; Ishida, N.; Suzuki, H. Probucol dramatically enhances dihydroartemisinin effect in murine malaria. Malar. J., 2016, 15(1), 472.
[http://dx.doi.org/10.1186/s12936-016-1532-y] [PMID: 27634686]
[34]
Herbas, M.S.; Shichiri, M.; Ishida, N.; Kume, A.; Hagihara, Y.; Yoshida, Y.; Suzuki, H. Probucol-induced α-tocopherol deficiency protects mice against malaria infection. PLoS One, 2015, 10(8), e0136014.
[http://dx.doi.org/10.1371/journal.pone.0136014] [PMID: 26296197]
[35]
Suzuki, H.; Kume, A.; Herbas, M. Potential of vitamin E deficiency, induced by inhibition of α-tocopherol efflux, in murine malaria infection. Int. J. Mol. Sci., 2018, 20(1), 64.
[http://dx.doi.org/10.3390/ijms20010064] [PMID: 30586912]
[36]
Sun, L.; Cai, J.; Gonzalez, F.J. The role of farnesoid X receptor in metabolic diseases, and gastrointestinal and liver cancer. Nat. Rev. Gastroenterol. Hepatol., 2021, 18(5), 335-347.
[http://dx.doi.org/10.1038/s41575-020-00404-2] [PMID: 33568795]
[37]
Fiorucci, S.; Rizzo, G.; Donini, A.; Distrutti, E.; Santucci, L. Targeting farnesoid X receptor for liver and metabolic disorders. Trends Mol. Med., 2007, 13(7), 298-309.
[http://dx.doi.org/10.1016/j.molmed.2007.06.001] [PMID: 17588816]
[38]
Wang, Y.D.; Chen, W.D.; Wang, M.; Yu, D.; Forman, B.M.; Huang, W. Farnesoid X receptor antagonizes nuclear factor κB in hepatic inflammatory response. Hepatology, 2008, 48(5), 1632-1643.
[http://dx.doi.org/10.1002/hep.22519] [PMID: 18972444]
[39]
Zhu, L.; Baker, R.D.; Zhu, R.; Baker, S.S. Bile acids and the gut microbiome as potential targets for nafld treatment. J. Pediatr. Gastroenterol. Nutr., 2018, 67(1), 3-5.
[http://dx.doi.org/10.1097/MPG.0000000000002010] [PMID: 29697548]
[40]
Bjursell, M.; Wedin, M.; Admyre, T.; Hermansson, M.; Böttcher, G.; Göransson, M.; Lindén, D.; Bamberg, K.; Oscarsson, J.; Bohlooly-Y, M. Ageing Fxr deficient mice develop increased energy expenditure, improved glucose control and liver damage resembling NASH. PLoS One, 2013, 8(5), e64721.
[http://dx.doi.org/10.1371/journal.pone.0064721] [PMID: 23700488]
[41]
Welch, R.D.; Billon, C.; Losby, M.; Bedia-Diaz, G.; Fang, Y.; Avdagic, A.; Elgendy, B.; Burris, T.P.; Griffett, K. Emerging role of nuclear receptors for the treatment of nafld and nASH. Metabolites, 2022, 12(3), 238.
[http://dx.doi.org/10.3390/metabo12030238] [PMID: 35323681]
[42]
Clifford, B.L.; Sedgeman, L.R.; Williams, K.J.; Morand, P.; Cheng, A.; Jarrett, K.E.; Chan, A.P.; Brearley-Sholto, M.C.; Wahlström, A.; Ashby, J.W.; Barshop, W.; Wohlschlegel, J.; Calkin, A.C.; Liu, Y.; Thorell, A.; Meikle, P.J.; Drew, B.G.; Mack, J.J.; Marschall, H.U.; Tarling, E.J.; Edwards, P.A.; de Aguiar Vallim, T.Q. FXR activation protects against NAFLD via bile-acid-dependent reductions in lipid absorption. Cell Metab., 2021, 33(8), 1671-1684.e4.
[http://dx.doi.org/10.1016/j.cmet.2021.06.012] [PMID: 34270928]
[43]
Wu, R.; Wu, X.; Liu, B.; Zhang, W.; Gao, J.; Xiao, X.; Zhang, X. Effect of probucol in improving hepatic steatosis in rats with non-alcoholic steatohepatitis and the mechanism. Nan Fang Yi Ke Da Xue Xue Bao, 2014, 34(5), 731-735.
[PMID: 24849447]
[44]
Yang, R.; Hu, Z.; Zhang, P.; Wu, S.; Song, Z.; Shen, X.; Wei, Z. Probucol ameliorates hepatic stellate cell activation and autophagy is associated with farnesoid X receptor. J. Pharmacol. Sci., 2019, 139(2), 120-128.
[http://dx.doi.org/10.1016/j.jphs.2018.12.005] [PMID: 30638990]
[45]
Lee, J.S.; Mendez, R.; Heng, H.H.; Yang, Z.Q.; Zhang, K. Pharmacological er stress promotes hepatic lipogenesis and lipid droplet formation. Am. J. Transl. Res., 2012, 4(1), 102-113.
[PMID: 22347525]
[46]
Converso, D.P. Taillé, C.; Carreras, M.C.; Jaitovich, A.; Poderoso, J.J.; Boczkowski, J.; Converso, D.P.; Taillé, C.; Carreras, M.C.; Jaitovich, A.; Poderoso, J.J.; Boczkowski, J. HO-1 is located in liver mitochondria and modulates mitochondrial heme content and metabolism. FASEB J., 2006, 20(8), 1236-1238.
[http://dx.doi.org/10.1096/fj.05-4204fje] [PMID: 16672635]
[47]
Li, D.; Zhao, D.; Du, J.; Dong, S.; Aldhamin, Z.; Yuan, X.; Li, W.; Du, H.; Zhao, W.; Cui, L.; Liu, L.; Fu, N.; Nan, Y. Heme oxygenase-1 alleviated non-alcoholic fatty liver disease via suppressing ROS-dependent endoplasmic reticulum stress. Life Sci., 2020, 253, 117678.
[http://dx.doi.org/10.1016/j.lfs.2020.117678] [PMID: 32376267]
[48]
Chen, Y.; Pandiri, I.; Joe, Y.; Kim, H.J.; Kim, S.K.; Park, J.; Ryu, J.; Cho, G.J.; Park, J.W.; Ryter, S.W.; Chung, H.T. Synergistic effects of cilostazol and probucol on er stress-induced hepatic steatosis via heme oxygenase-1-dependent activation of mitochondrial biogenesis. Oxid. Med. Cell. Longev., 2016, 2016, 1-14.
[http://dx.doi.org/10.1155/2016/3949813] [PMID: 27057275]
[49]
Wu, R.; Zhang, W.; Liu, B.; Gao, J.; Xiao, X.; Zhang, F.; Zhou, H.; Wu, X.; Zhang, X. Probucol ameliorates the development of nonalcoholic steatohepatitis in rats fed high-fat diets. Dig. Dis. Sci., 2013, 58(1), 163-171.
[http://dx.doi.org/10.1007/s10620-012-2335-9] [PMID: 22878918]
[50]
Yoshida, T.; Yoshioka, K.; Sakane, N.; Umekawa, T.; Kondo, M. Probucol prevents the progression of fatty liver in MSG obese mice. Exp. Clin. Endocrinol. Diabetes, 1995, 103(2), 119-122.
[http://dx.doi.org/10.1055/s-0029-1211339] [PMID: 7553075]
[51]
Zhang, X.; Li, Z.; Liu, D.; Xu, X.; Shen, W.; Mei, Z. Effects of probucol on hepatic tumor necrosis factor-α, interleukin-6 and adiponectin receptor-2 expression in diabetic rats. J. Gastroenterol. Hepatol., 2009, 24(6), 1058-1063.
[http://dx.doi.org/10.1111/j.1440-1746.2008.05719.x] [PMID: 19220660]
[52]
Zhan, Y.T.; Weng, J.; Li, L.; Xu, Q.; Song, X.; Guo, X.X. Protective effect of probucol on liver injury induced by carbon tetrachloride in rats. Hepatol. Int., 2011, 5(4), 899-905.
[http://dx.doi.org/10.1007/s12072-011-9256-0] [PMID: 21484128]
[53]
Su, X.; Wang, Y.; Zhou, G.; Yang, X.; Yu, R.; Lin, Y.; Zheng, C. Probucol attenuates ethanol-induced liver fibrosis in rats by inhibiting oxidative stress, extracellular matrix protein accumulation and cytokine production. Clin. Exp. Pharmacol. Physiol., 2014, 41(1), 73-80.
[http://dx.doi.org/10.1111/1440-1681.12182] [PMID: 24117782]
[54]
Merat, S.; Malekzadeh, R.; Sohrabi, M.R.; Sotoudeh, M.; Rakhshani, N.; Sohrabpour, A.A.; Naserimoghadam, S. Probucol in the treatment of non-alcoholic steatohepatitis: a double-blind randomized controlled study. J. Hepatol., 2003, 38(4), 414-418.
[http://dx.doi.org/10.1016/S0168-8278(02)00441-5] [PMID: 12663231]
[55]
Ishitobi, T.; Hyogo, H.; Tokumo, H.; Arihiro, K.; Chayama, K. Efficacy of probucol for the treatment of non-alcoholic steatohepatitis with dyslipidemia: An open-label pilot study. Hepatol. Res., 2014, 44(4), 429-435.
[http://dx.doi.org/10.1111/hepr.12135] [PMID: 23607264]
[56]
Merat, S.; Aduli, M.; Kazemi, R.; Sotoudeh, M.; Sedighi, N.; Sohrabi, M.; Malekzadeh, R. Liver histology changes in nonalcoholic steatohepatitis after one year of treatment with probucol. Dig. Dis. Sci., 2008, 53(8), 2246-2250.
[http://dx.doi.org/10.1007/s10620-007-0109-6] [PMID: 18049900]

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