Research progress in safety of PPAR agonists

doi:10.19803/j.1672-8629.20230001

Abstract

Abstract: Peroxisome proliferator-activated receptors (PPAR) are important nuclear receptors that regulate the expression of genes responsible for energy metabolism, inflammatory response, cellular development and differentiation. Their agonists have been developed for the treatment of metabolic diseases such as diabetes, dyslipidemia and atherosclerosis. However, the adverse effects of PPAR agonists limit their use in clinical practice. This paper summarizes the types of toxicity and toxicity mechanisms associated with isotype-specific PPAR agonists and presents reports of adverse reactions to dual PPAR agonists and pan-PPAR agonists in clinical trials in order to better understand the toxic effects of PPAR agonists and provide references for the design of safer PPAR agonists.

Key words: peroxisome proliferator-activated receptors(PPAR), agonist, hepatotoxicity, cardiotoxicity, myotoxicity, carcinogenicity

CLC Number:

R977
R994.11

ZHANG Qin, ZHANG Luyong, JIANG Zhenzhou. Research progress in safety of PPAR agonists[J]. Chinese Journal of Pharmacovigilance, 2023, 20(8): 950-955.

References

[1] BOUGARNE N, WEYERS B, DESMET S J, et al.Molecular actions of PPARα in lipid metabolism and inflammation[J]. Endocr Rev, 2018, 39(5): 760-802.
[2] GIGLIO RV, PAPANAS N, RIZVI AA, et al.An update on the current and emerging use of thiazolidinediones for type 2 diabetes[J]. Medicina (Kaunas), 2022, 58(10): 1475.
[3] CHENG HS, TAN WR, LOW ZS, et al.Exploration and development of PPAR modulators in health and disease: an update of clinical evidence[J]. International Journal of Molecular Sciences, 2019, 20(20): 5055.
[4] DIXIT G, PRABHU A.The pleiotropic peroxisome proliferator activated receptors: regulation and therapeutics[J]. Exp Mol Pathol, 2022, 124: 104723.
[5] SINGH G, CORREA R.Fibrate Medications[M]. StatPearls: Treasure Island (FL), 2022.
[6] YIN L, WANG L, SHI Z, et al.The role of peroxisome proliferator-activated receptor gamma and atherosclerosis: post-translational modification and selective modulators[J]. Front Physiol, 2022, 13: 826811.
[7] BABAI S, AUCLERT L, LE-LOUëT H. Safety data and withdrawal of hepatotoxic drugs[J]. Therapie, 2021, 76(6): 715-723.
[8] KALLIORA C, DROSATOS K.The glitazars paradox: cardiotoxicity of the metabolically beneficial dual PPARα and PPARγ activation[J]. J Cardiovasc Pharmacol, 2020, 76(5): 514-526.
[9] Pharnexcloud. Hyperlipidaemia treatment agents: palmodia tablets 0.1 mg[DB/OL].[2023-04-26]. https://data.pharnexcloud.com/7/table/61?q=pemafibrate.
[10] The Internet Drug Index for prescription drug. Side Effects Drug Center: Fibricor (Fenofibric Acid) Drug[EB/OL].(2023-04-12)[2023-04-26]. https://www.rxlist.com/fibricor-drug.htm.
[11] The Internet Drug Index for prescription drug. Side Effects Drug Center: Vascepa (Icosapent Ethyl Capsules) Drug[EB/OL].(2022-07-29)[2023-04-26]. https://www.rxlist.com/vascepa-drug.htm.
[12] Pharnexcloud. Drug instructions: aluminium clofibrate tablets[DB/OL].(2001-12-20)[2023-04-26]. https://data.pharnexcloud.com/6/table/159?q=aluminii%20clofibras.
[13] Pharnexcloud. Drug instructions: ciprofibrate tablets[DB/OL].(2005-03-11)[2023-04-26]. https://data.pharnexcloud.com/6/table/159?q=ciprofibrate.
[14] The Internet Drug Index for prescription drug. Side Effects Drug Center: Lopid (Gemfibrozil) Drug[EB/OL].(2021-01-13)[2023-04-26]. https://www.rxlist.com/lopid-drug.htm.
[15] Pharnexcloud. Drug instructions: clofibrate capsules[DB/OL].(2005-03-11)[2023-04-26]. https://data.pharnexcloud.com/6/table/159?q=clofibrate.
[16] Pharnexcloud. Drug instructions: Etofylline Clofibrate Capsules[DB/OL].(2007-06-15)[2023-04-26]. https://data.pharnexcloud.com/6/table/159?q=%E7%9B%8A%E5%A4%9A%E9%85%AF.
[17] Ministry of Food and Drug Safety, MFDS. Search for information on medicines: Lobeglitazone Sulfate[EB/OL].(2013-07-04)[2023-04-26]. https://nedrug.mfds.go.kr/pbp/CCBBB01/getItemDetailCache?cacheSeq=201308005aupdateTs2023-03-14%2015:07:06.424b#none.
[18] The Internet Drug Index for prescription drug. Side Effects Drug Center: Avandia (Rosiglitazone Maleate) Drug[EB/OL].(2022-07-29)[2023-04-26]. https://www.rxlist.com/avandia-drug.htm.
[19] The Internet Drug Index for prescription drug. Side Effects Drug Center: Actos (Pioglitazone Hydrochloride) Drug[EB/OL].(2020-05-19)[2023-04-26]. https://www.rxlist.com/actos-drug.htm.
[20] XI Y, ZHANG Y, ZHU S, et al.PPAR-mediated toxicology and applied pharmacology[J]. Cells, 2020, 9(2):352 .
[21] Pharnexcloud. Drug instructions: Chiglitazar Sodium Tablets[DB/OL].(2021-10-25)[2023-04-26]. https://data.pharnexcloud.com/6/table/159?q=%E8%A5%BF%E6%A0%BC%E5%88%97%E4%BB%96%E9%92%A0.
[22] Pharnexcloud. Drug instructions: bezafibrate tablets[DB/OL].(2010-10-01)[2023-04-26]. https://data.pharnexcloud.com/6/table/159?q=bezafibrate.
[23] ISSEMANN I, GREEN S.Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators[J]. Nature, 1990, 347(6294): 645-650.
[24] YARMOHAMMADI F, HAYES AW, KARIMI G.Targeting PPARs signaling pathways in cardiotoxicity by natural compounds[J]. Cardiovasc Toxicol, 2022, 22(4): 281-291.
[25] SUN C, MAO S, CHEN S, et al.PPARs-orchestrated metabolic homeostasis in the adipose tissue[J]. International Journal of Molecular Sciences, 2021, 22(16): 8974.
[26] GRUNDY S M, STONE N J, BAILEY A L, et al.2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American college of cardiology/American heart association Task force on clinical practice guidelines[J]. Circulation, 2019, 139(25): e1082-e1143.
[27] OKOPIEŃ B, BUŁDAK Ł, BOŁDYS A. Benefits and risks of the treatment with fibrates--a comprehensive summary[J]. Expert Rev Clin Pharmacol, 2018, 11(11): 1099-1112.
[28] LIU A, KRAUSZ KW, FANG ZZ, et al.Gemfibrozil disrupts lysophosphatidylcholine and bile acid homeostasis via PPARα and its relevance to hepatotoxicity[J]. Arch Toxicol, 2014, 88(4): 983-996.
[29] CUNNINGHAM ML, COLLINS BJ, HEJTMANCIK MR, et al.effects of the PPARα agonist and widely used antihyperlipidemic drug gemfibrozil on hepatic toxicity and lipid metabolism[J]. PPAR Research, 2010, 2010: 681963.
[30] HEDRINGTON MS, DAVIS SN.Peroxisome proliferator-activated receptor alpha-mediated drug toxicity in the liver[J]. Expert Opinion On Drug Metabolism & Toxicology, 2018, 14(7): 671-677.
[31] HODEL C.Myopathy and rhabdomyolysis with lipid-lowering drugs[J]. Toxicol Lett, 2002, 128(1-3): 159-168.
[32] ZHAO Y, OKUYAMA M, HASHIMOTO H, et al.Bezafibrate induces myotoxicity in human rhabdomyosarcoma cells via peroxisome proliferator-activated receptor alpha signaling[J]. Toxicol In Vitro, 2010, 24(1): 154-159.
[33] KADAYAT TM, SHRESTHA A, JEON YH, et al.Targeting peroxisome proliferator-activated receptor delta (PPARδ): a medicinal chemistry perspective[J]. J Med Chem, 2020, 63(18): 10109-10134.
[34] ZHAO L, GANDHI CR, GAO Z-H.Involvement of cytosolic phospholipase A2 alpha signalling pathway in spontaneous and transforming growth factor-beta-induced activation of rat hepatic stellate cells[J]. Liver Int, 2011, 31(10): 1565-1573.
[35] HELLEMANS K, MICHALIK L, DITTIE A, et al.Peroxisome proliferator-activated receptor-beta signaling contributes to enhanced proliferation of hepatic stellate cells[J]. Gastroenterology, 2003, 124(1): 184-201.
[36] RAMANI K, TOMASI M L.Transcriptional regulation of methionine adenosyltransferase 2A by peroxisome proliferator-activated receptors in rat hepatic stellate cells[J]. Hepatology (Baltimore, Md), 2012, 55(6): 1942-1953.
[37] KOSTADINOVA R, MONTAGNER A, GOURANTON E, et al.GW501516-activated PPARβ/δ promotes liver fibrosis via p38-JNK MAPK-induced hepatic stellate cell proliferation[J]. Cell Biosci, 2012, 2(1): 34.
[38] DI-POï N, TAN NS, MICHALIK L, et al.Antiapoptotic role of PPARbeta in keratinocytes via transcriptional control of the Akt1 signaling pathway[J]. Mol Cell, 2002, 10(4): 721-733.
[39] PEDCHENKO TV, GONZALEZ AL, WANG D, et al.Peroxisome proliferator-activated receptor beta/delta expression and activation in lung cancer[J]. Am J Respir Cell Mol Biol, 2008, 39(6): 689-696.
[40] GENINI D, GARCIA-ESCUDERO R, CARBONE GM, et al.Transcriptional and Non-Transcriptional Functions of PPARβ/δ in Non-Small Cell Lung Cancer[J]. PloS One, 2012, 7(9): e46009.
[41] WAGNER KD, DU S, MARTIN L, et al.Vascular PPARβ/δ Promotes Tumor Angiogenesis and Progression[J]. Cells, 2019, 8(12): 1623.
[42] WANG Y, LAN W, XU M, et al.Cancer-associated fibroblast-derived SDF-1 induces epithelial-mesenchymal transition of lung adenocarcinoma via CXCR4/β-catenin/PPARδ signalling[J]. Cell Death & Disease, 2021, 12(2): 214.
[43] TAN M WY, SNG MK, CHENG HS, et al.Deficiency in fibroblast PPARβ/δ reduces nonmelanoma skin cancers in mice[J]. Cell Death and Differentiation, 2020, 27(9): 2668-2680.
[44] GROSS B, PAWLAK M, LEFEBVRE P, et al.PPARs in obesity-induced T2DM, dyslipidaemia and NAFLD[J]. Nature Reviews Endocrinology, 2017, 13(1): 36-49.
[45] BALLAV S, BISWAS B, SAHU VK, et al.PPAR-γ partial agonists in disease-fate decision with special reference to cancer[J]. Cells, 2022, 11(20): 3215.
[46] GRAHAM DJ, DRINKARD CR, SHATIN D.Incidence of idiopathic acute liver failure and hospitalized liver injury in patients treated with troglitazone[J]. Am J Gastroenterol, 2003, 98(1): 175-179.
[47] HU D, WU CQ, LI ZJ, et al.Characterizing the mechanism of thiazolidinedione-induced hepatotoxicity: an in vitro model in mitochondria[J]. Toxicology and Applied Pharmacology, 2015, 284(2): 134-141.
[48] BOELSTERLI UA, BEDOUCHA M.Toxicological consequences of altered peroxisome proliferator-activated receptor gamma (PPARgamma) expression in the liver: insights from models of obesity and type 2 diabetes[J]. Biochemical Pharmacology, 2002, 63(1): 1-10.
[49] LEE SM, MURATALLA J, DIAZ-RUIZ A, et al. Rosiglitazone requires hepatocyte PPARγ expression to promote steatosis in male mice with diet-induced obesity[J]. Endocrinology, 2021, 162(11): bqab175.
[50] LEBOVITZ HE.Thiazolidinediones: the Forgotten Diabetes Medications[J]. Curr Diab Rep, 2019, 19(12): 151.
[51] DUAN SZ, IVASHCHENKO CY, RUSSELL MW, et al.Cardiomyocyte-specific knockout and agonist of peroxisome proliferator-activated receptor-gamma both induce cardiac hypertrophy in mice[J]. Circ Res, 2005, 97(4): 372-379.
[52] HE H, TAO H, XIONG H, et al.Rosiglitazone causes cardiotoxicity via peroxisome proliferator-activated receptor γ-independent mitochondrial oxidative stress in mouse hearts[J]. Toxicol Sci, 2014, 138(2): 468-481.
[53] LIU Y, YAN X, MAO G, et al.Metabonomic profiling revealed an alteration in purine nucleotide metabolism associated with cardiac hypertrophy in rats treated with thiazolidinediones[J]. J Proteome Res, 2013, 12(12): 5634-5641.
[54] CHANG CS, TSAI PJ, SUNG JM, et al.Diuretics prevent thiazolidinedione-induced cardiac hypertrophy without compromising insulin-sensitizing effects in mice[J]. The American Journal of Pathology, 2014, 184(2): 442-453.
[55] GOLDSTEIN BJ, ROSENSTOCK J, ANZALONE D, et al.Effect of tesaglitazar, a dual PPAR alpha/gamma agonist, on glucose and lipid abnormalities in patients with type 2 diabetes: a 12-week dose-ranging trial[J]. Curr Med Res Opin, 2006, 22(12): 2575-2590.
[56] HELLMOLD H, ZHANG H, ANDERSSON U, et al.Tesaglitazar, a PPARalpha/gamma agonist, induces interstitial mesenchymal cell DNA synthesis and fibrosarcomas in subcutaneous tissues in rats[J]. Toxicol Sci, 2007, 98(1): 63-74.
[57] LONG GG, REYNOLDS VL, LOPEZ-MARTINEZ A, et al.Urothelial carcinogenesis in the urinary bladder of rats treated with naveglitazar, a gamma-dominant PPAR alpha/gamma agonist: lack of evidence for urolithiasis as an inciting event[J]. Toxicol Pathol, 2008, 36(2): 218-231.
[58] LINCOFF AM, TARDIF JC, SCHWARTZ GG, et al.Effect of aleglitazar on cardiovascular outcomes after acute coronary syndrome in patients with type 2 diabetes mellitus: the AleCardio randomized clinical trial[J]. JAMA, 2014, 311(15): 1515-1525.
[59] KALLIORA C, KYRIAZIS ID, OKA SI, et al.Dual peroxisome-proliferator-activated-receptor-alpha/gamma activation inhibits SIRT1-PGC1alpha axis and causes cardiac dysfunction[J]. JCI Insight, 2019, 5(17): e129556.
[60] RATZIU V, HARRISON SA, FRANCQUE S, et al. Elafibranor, an agonist of the peroxisome proliferator-activated receptor-α and -δ, induces resolution of nonalcoholic steatohepatitis without fibrosis worsening[J]. Gastroenterology, 2016, 150(5): 1147-1159.e5.
[61] CHAMBERLAIN S, GABRIEL H, STRITTMATTER W, et al.An exploratory phase IIa study of the PPAR delta/gamma agonist T3D-959 assessing metabolic and cognitive function in subjects with mild to moderate Alzheimer’s disease[J]. J Alzheimers Dis, 2020, 73(3): 1085-1103.
[62] FRANCQUE SM, BEDOSSA P, RATZIU V, et al.A Randomized, controlled trial of the Pan-PPAR agonist lanifibranor in NASH[J]. N Engl J Med, 2021, 385(17): 1547-1558.