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Current Molecular Pharmacology

Editor-in-Chief

ISSN (Print): 1874-4672
ISSN (Online): 1874-4702

Systematic Review Article

Toxicity, Genotoxicity, and Carcinogenicity of Isotretinoin

Author(s): Serkan Yilmaz*

Volume 16, Issue 1, 2023

Published on: 22 July, 2022

Article ID: e200522205086 Pages: 8

DOI: 10.2174/1874467215666220520143124

Price: $65

Abstract

Background: Acne is a chronic inflammatory disease mainly observed in adolescence, but it can also be seen during the neonatal, infantile, pre-pubertal, and adult periods. Isotretinoin (13-cis-retinoic acid) is a first-generation retinoid and is the most effective treatment for acne vulgaris.

Objective: The present study has been systematically designed to figure out the toxic, genotoxic, and carcinogenic activities of isotretinoin.

Methods: In this study, a systematic approach was followed by focusing on the possible links between these topics. The search of the databases was carried out author in accordance with the guidelines of the Centre for Reviews and Dissemination (2009) developed by York University National Institute of Health Research. The search was concentrated on the Web of Science, PubMed, Science Direct, Scopus, EBSCO Host, and Google Scholar databases.

Results: Isotretinoin was found as a toxic agent in all studies. All researchers proposed that apoptosis is the only pathway of adverse effects of isotretinoin. However, genotoxicity, teratogenicity, and carcinogenicity information of isotretinoin is very limited and controversial.

Conclusion: More detailed studies need to clarify the genotoxic and carcinogenic potential of isotretinoin. Patients should be informed correctly, the risks of treatment should be explained, and awareness should be raised.

Keywords: Isotretinoin, acne, toxicity, genotoxicity, carcinogenicity, chronic in flammation disease.

Graphical Abstract

[1]
Raza, K.; Singh, B.; Singal, P.; Wadhwa, S.; Katare, O.P. Sys-tematically optimized biocompatible isotretinoin-loaded solid lipid nanoparticles (SLNs) for topical treatment of acne. Colloids Surf. B Biointerfaces, 2013, 105, 67-74.
[http://dx.doi.org/10.1016/j.colsurfb.2012.12.043] [PMID: 23357735]
[2]
Ertam, İ.; Alper, S.; Ceylan, C. Akne vulgaris’de isotretinoin tedavisi ile alınan sonuçlar. Ege Tıp Dergisi, 2000, 39, 177-179.
[3]
Saylan, T. Skin and venereal diseases for physicians. Hand-book in 1st Level Health Services, 2nd Edition; War Press, 1991.
[4]
Meigel, W.N. How safe is oral isotretinoin? Dermatology, 1997, 195(Suppl. 1), 22-28.
[http://dx.doi.org/10.1159/000246016] [PMID: 9310742]
[5]
Ortonne, J.P. Oral isotretinoin treatment policy. Do we all agree? Dermatology, 1997, 195(Suppl. 1), 34-37.
[http://dx.doi.org/10.1159/000246018] [PMID: 9310744]
[6]
Saurat, J.H. Systemic retinoids. What’s new? Dermatol. Clin., 1998, 16(2), 331-340.
[http://dx.doi.org/10.1016/S0733-8635(05)70016-4] [PMID: 9589207]
[7]
Sykes, N.L., Jr; Webster, G.F. Acne. A review of optimum treatment. Drugs, 1994, 48(1), 59-70.
[http://dx.doi.org/10.2165/00003495-199448010-00006 ] [PMID: 7525195]
[8]
Layton, A.M.; Cunliffe, W.J. Guidelines for optimal use of isotretinoin in acne. J. Am. Acad. Dermatol., 1992, 27(6 Pt 2)(Suppl.), S2-S7.
[http://dx.doi.org/10.1016/S0190-9622(08)80252-6] [PMID: 1460120]
[9]
Jr, W.W. Tunnessen, Acne: An approach to therapy for the pediatrician. Curr. Probl. Pediatr., 1984, 14, 1-36.
[10]
Goldsmith, L.A.; Bolognia, J.L.; Callen, J.P.; Chen, S.C.; Feld-man, S.R.; Lim, H.W.; Lucky, A.W.; Reed, B.R.; Siegfried, E.C.; Thiboutot, D.M.; Wheeland, R.G. American academy of dermatology. American academy of dermatology consensus conference on the safe and optimal use of isotretinoin: Sum-mary and recommendations. J. Am. Acad. Dermatol., 2004, 50(6), 900-906.
[http://dx.doi.org/10.1016/j.jaad.2004.02.012] [PMID: 15153892]
[11]
Rigopoulos, D.; Larios, G.; Katsambas, A.D. The role of isotretinoin in acne therapy: Why not as first-line therapy? facts and controversies. Clin. Dermatol., 2010, 28(1), 24-30.
[http://dx.doi.org/10.1016/j.clindermatol.2009.03.005 ] [PMID: 20082946]
[12]
Strauss, J.S.; Stranieri, A.M.; Farrell, L.N.; Downing, D.T. The effect of marked inhibition of sebum production with 13cis-retinoic acid on skin surface lipid composition. J. Invest. Dermatol., 1980, 74(2), 66-67.
[http://dx.doi.org/10.1111/1523-1747.ep12519851] [PMID: 6444323]
[13]
Nelson, A.M.; Gilliland, K.L.; Cong, Z.; Thiboutot, D.M. 13-cis Retinoic acid induces apoptosis and cell cycle arrest in hu-man SEB-1 sebocytes. J. Invest. Dermatol., 2006, 126(10), 2178-2189.
[http://dx.doi.org/10.1038/sj.jid.5700289] [PMID: 16575387]
[14]
Zane, L.T.; Leyden, W.A.; Marqueling, A.L.; Manos, M.M. A population-based analysis of laboratory abnormalities during isotretinoin therapy for Acne vulgaris. Arch. Dermatol., 2006, 142(8), 1016-1022.
[http://dx.doi.org/10.1001/archderm.142.8.1016] [PMID: 16924051]
[15]
Crockett, S.D.; Porter, C.Q.; Martin, C.F.; Sandler, R.S.; Kap-pelman, M.D. Isotretinoin use and the risk of inflammatory bowel disease: A case-control study. Am. J. Gastroenterol., 2010, 105(9), 1986-1993.
[http://dx.doi.org/10.1038/ajg.2010.124] [PMID: 20354506]
[16]
Singer, S.; Tkachenko, E.; Sharma, P.; Barbieri, J.S.; Mostagh-imi, A. Psychiatric adverse events in patients taking isotret-inoin as reported in a food and drug administration database from 1997 to 2017. JAMA Dermatol., 2019, 155(10), 1162-1166.
[http://dx.doi.org/10.1001/jamadermatol.2019.1416 ] [PMID: 31268488]
[17]
Bigby, M.; Stern, R.S. Adverse reactions to isotretinoin. A report from the adverse drug reaction reporting system. J. Am. Acad. Dermatol., 1988, 18(3), 543-552.
[http://dx.doi.org/10.1016/S0190-9622(88)70078-X] [PMID: 3280622]
[18]
Huang, Y.C.; Cheng, Y.C. Isotretinoin treatment for acne and risk of depression: A systematic review and meta-analysis. J. Am. Acad. Dermatol., 2017, 76(6), 1068-1076.e9.
[http://dx.doi.org/10.1016/j.jaad.2016.12.028] [PMID: 28291553]
[19]
Layton, A. The use of isotretinoin in acne. Dermatoendocrinol, 2009, 1(3), 162-169.
[http://dx.doi.org/10.4161/derm.1.3.9364] [PMID: 20436884]
[20]
Erturan, İ Naziroğlu, M.; Akkaya, V.B. Isotretinoin treatment induces oxidative toxicity in blood of patients with Acne vul-garis: A clinical pilot study. Cell Biochem. Funct., 2012, 30(7), 552-557.
[http://dx.doi.org/10.1002/cbf.2830] [PMID: 22517509]
[21]
Ferguson, S.A.; Cisneros, F.J.; Gough, B.J.; Ali, S.F. Four weeks of oral isotretinoin treatment causes few signs of gen-eral toxicity in male and female Sprague-Dawley rats. Food Chem. Toxicol., 2005, 43(8), 1289-1296.
[http://dx.doi.org/10.1016/j.fct.2005.02.016] [PMID: 15950819]
[22]
Abali, R.; Yuksel, M.A.; Aktas, C.; Celik, C.; Guzel, S.; Erfan, G.; Sahin, O. Decreased ovarian reserve in female Sprague-Dawley rats induced by isotretinoin (retinoic acid) exposure. Reprod. Biomed. Online, 2013, 27(2), 184-191.
[http://dx.doi.org/10.1016/j.rbmo.2013.04.010] [PMID: 23768617]
[23]
Beytemür, O.; Yüksel, S.; Tetikkurt, Ü.S.; Genç, E.; Olcay, E.; Güleç, A. Isotretinoin induced achilles tendinopathy: Histo-pathological and biomechanical evaluation on rats. Acta Orthop. Traumatol. Turc., 2018, 52(5), 387-391.
[http://dx.doi.org/10.1016/j.aott.2018.06.006] [PMID: 30017488]
[24]
Ibrahim Al-Othman, S.; Nasser Bin-Jumah, M. Abdullah Alk-osome, R. Deleterious effects of perinatal exposure to isotret-inoin drug on the offspring of pregnant mice. Int. J. Pharmacol., 2019, 15(6), 706-715.
[http://dx.doi.org/10.3923/ijp.2019.706.715]
[25]
Kim, S.K.; Shin, S.J.; Yoo, Y.; Kim, N.H.; Kim, D.S.; Zhang, D.; Park, J.A.; Yi, H.; Kim, J.S.; Shin, H.C. Oral toxicity of isotretinoin, misoprostol, methotrexate, mifepristone and levonorgestrel as pregnancy category X medications in female mice. Exp. Ther. Med., 2015, 9(3), 853-859.
[http://dx.doi.org/10.3892/etm.2015.2203] [PMID: 25667641]
[26]
Kumaş M.; Eşrefoğlu, M.; Güler, E.M. Protective effects of silymarin against isotretinoin induced liver and kidney injury in mice. Indian J. Exp. Biol., 2018, 56, 158-163.
[27]
Saied, N.M.; Hamza, A.A. Selenium ameliorates isotretinoin-induced liver injury and dyslipidemia via antioxidant effect in rats. Toxicol. Mech. Methods, 2014, 24(6), 433-437.
[http://dx.doi.org/10.3109/15376516.2014.937514] [PMID: 24966012]
[28]
Silva, F.S.G.; Ribeiro, M.P.C.; Santos, M.S.; Rocha-Pereira, P.; Santos-Silva, A.; Custódio, J.B.A. The antiestrogen 4-hydroxytamoxifen protects against isotretinoin-induced per-meability transition and bioenergetic dysfunction of liver mito-chondria: comparison with tamoxifen. J. Bioenerg. Biomembr., 2013, 45(4), 383-396.
[http://dx.doi.org/10.1007/s10863-013-9517-9] [PMID: 23779226]
[29]
Brandt, J.R.; Mick, T.J. Extraspinal enthesopathy caused by isotretinoin therapy. J. Manipulative Physiol. Ther., 1999, 22(6), 417-420.
[http://dx.doi.org/10.1016/S0161-4754(99)70088-6] [PMID: 10478775]
[30]
Graf, S.W.; Whittle, S.L. Isotretinoin-induced skeletal hyperos-tosis. Springerplus, 2014, 3(1), 698-701.
[http://dx.doi.org/10.1186/2193-1801-3-698] [PMID: 26034688]
[31]
DiGiovanna, J.J. Isotretinoin effects on bone. J. Am. Acad. Dermatol., 2001, 45(5), S176-S182.
[http://dx.doi.org/10.1067/mjd.2001.113721] [PMID: 11606950]
[32]
Ozkol, H.U.; Ozkol, H.; Karadag, A.S.; Bilgili, S.G.; Tuluce, Y.; Calka, O. Oral isotretinoin therapy of acne patients decreases serum paraoxonase-1 activity through increasing oxidative stress. Drug Chem. Toxicol., 2015, 38(1), 63-66.
[http://dx.doi.org/10.3109/01480545.2014.905590] [PMID: 24697846]
[33]
Kumar, A.; Kumar, V.K. Toxicity of low-dose intermittent isotretinoin in recalcitrant acne. Med. J. Armed Forces India, 2010, 66(3), 208-212.
[http://dx.doi.org/10.1016/S0377-1237(10)80038-3] [PMID: 27408302]
[34]
Finsterer, J. Enhanced ocular isotretinoin toxicity in mitochon-drial disorder. South. Med. J., 2008, 101(6), 664-665.
[http://dx.doi.org/10.1097/SMJ.0b013e318172f64c] [PMID: 18528226]
[35]
Arce, F.; Gätjens-Boniche, O.; Vargas, E.; Valverde, B.; Díaz, C. Apoptotic events induced by naturally occurring retinoids ATRA and 13-cis retinoic acid on human hepatoma cell lines Hep3B and HepG2. Cancer Lett., 2005, 229(2), 271-281.
[http://dx.doi.org/10.1016/j.canlet.2005.06.047] [PMID: 16135400]
[36]
Nau, H. Teratogenicity of isotretinoin revisited: Species varia-tion and the role of all-trans-retinoic acid. J. Am. Acad. Dermatol., 2001, 45(5), S183-S187.
[http://dx.doi.org/10.1067/mjd.2001.113720] [PMID: 11606951]
[37]
Coberly, S.; Lammer, E.; Alashari, M. Retinoic acid embryopa-thy: Case report and review of literature. Pediatr. Pathol. Lab. Med., 1996, 16(5), 823-836.
[http://dx.doi.org/10.1080/15513819609169308] [PMID: 9025880]
[38]
Shalita, A.R. Mucocutaneous and systemic toxicity of retin-oids: Monitoring and management. Dermatologica, 1987, 175(Suppl. 1), 151-157.
[http://dx.doi.org/10.1159/000248878] [PMID: 3319724]
[39]
Heilgemeir, G.P.; Braun-Falco, O.; Plewig, G.; Sund, M. Effect of 13-cis-retinoic acid on hair growth. Hautarzt, 1982, 33(10), 533-536.
[PMID: 6218145]
[40]
Kmieć M.L.; Pajor, A.; Broniarczyk-Dyła, G. Evaluation of biophysical skin parameters and assessment of hair growth in patients with acne treated with isotretinoin. Postepy Dermatol. Alergol., 2013, 30(6), 343-349.
[http://dx.doi.org/10.5114/pdia.2013.39432] [PMID: 24493996]
[41]
Landau, M.; Mesterman, R.; Ophir, J.; Mevorah, B.; Alcalay, J.; Harel, A.; Nevo, Y. Clinical significance of markedly elevat-ed serum creatine kinase levels in patients with acne on isotret-inoin. Acta Derm. Venereol., 2001, 81(5), 350-352.
[http://dx.doi.org/10.1080/000155501317140070] [PMID: 11800143]
[42]
Kaymak, Y. Creatine phosphokinase values during isotretinoin treatment for acne. Int. J. Dermatol., 2008, 47(4), 398-401.
[http://dx.doi.org/10.1111/j.1365-4632.2008.03491.x ] [PMID: 18377609]
[43]
Heudes, A.M.; Laroche, L. Muscular damage during isotret-inoin treatment. Ann. Dermatol. Venereol., 1998, 125(2), 94-97.
[PMID: 9747221]
[44]
Blander, J.M. Death in the intestinal epithelium-basic biology and implications for inflammatory bowel disease. FEBS J., 2016, 283(14), 2720-2730.
[http://dx.doi.org/10.1111/febs.13771] [PMID: 27250564]
[45]
Melnik, B.C. Apoptosis may explain the pharmacological mode of action and adverse effects of isotretinoin, including teratogenicity. Acta Derm. Venereol., 2017, 97(2), 173-181.
[http://dx.doi.org/10.2340/00015555-2535] [PMID: 27671426]
[46]
Silva, F.S.G.; Oliveira, H.; Moreiras, A.; Fernandes, J.C.; Bronze-da-Rocha, E.; Figueiredo, A.; Custódio, J.B.A.; Rocha-Pereira, P.; Santos-Silva, A. The in vitro and in vivo genotoxici-ty of isotretinoin assessed by cytokinesis blocked micronucle-us assay and comet assay. Toxicol. In Vitro, 2013, 27(2), 900-907.
[http://dx.doi.org/10.1016/j.tiv.2013.01.002] [PMID: 23318729]
[47]
Derici Eker, E.; Kocoglu, S.; Sahin, N.O. Investigation of geno-toxicity caused by oral isotretinoin use in acne treatment. Ann. Med. Res., 2019, 26, 1675-1679.
[48]
Bordbar, M.; Zendeh-Boodi, Z.; Saadat, M. The in vivo geno-toxicity of isotretinoin assessed by comet assay. EXCLI J., 2020, 19, 185-186.
[PMID: 32194365]
[49]
Mishra, K.K.; Scholey, J.E.; Daftari, I.K.; Afshar, A.; Tsai, T.; Park, S.; Quivey, J.M.; Char, D.H. Oral isotretinoin and topical retinoid use in a series of young patients with ocular melano-ma. Am. J. Ophthalmol. Case Rep., 2020, 19, 100787.
[http://dx.doi.org/10.1016/j.ajoc.2020.100787] [PMID: 32760850]
[50]
Kaae, J.; Boyd, H.A.; Hansen, A.V.; Wulf, H.C.; Wohlfahrt, J.; Melbye, M. Photosensitizing medication use and risk of skin cancer. Cancer Epidemiol. Biomarkers Prev., 2010, 19(11), 2942-2949.
[http://dx.doi.org/10.1158/1055-9965.EPI-10-0652] [PMID: 20861398]
[51]
Fine, J-D.; Johnson, L.B.; Weiner, M.; Stein, A.; Suchindran, C. Chemoprevention of squamous cell carcinoma in recessive dystrophic epidermolysis bullosa: Results of a phase 1 trial of systemic isotretinoin. J. Am. Acad. Dermatol., 2004, 50(4), 563-571.
[http://dx.doi.org/10.1016/j.jaad.2003.08.008] [PMID: 15034505]
[52]
Lippman, S.M.; Lee, J.J.; Karp, D.D.; Vokes, E.E.; Benner, S.E.; Goodman, G.E.; Khuri, F.R.; Marks, R.; Winn, R.J.; Fry, W.; Graziano, S.L.; Gandara, D.R.; Okawara, G.; Woodhouse, C.L.; Williams, B.; Perez, C.; Kim, H.W.; Lotan, R.; Roth, J.A.; Hong, W.K. Randomized phase III intergroup trial of isotret-inoin to prevent second primary tumors in stage I non-small-cell lung cancer. J. Natl. Cancer Inst., 2001, 93(8), 605-618.
[http://dx.doi.org/10.1093/jnci/93.8.605] [PMID: 11309437]
[53]
Hong, W.K.; Endicott, J.; Itri, L.M.; Doos, W.; Batsakis, J.G.; Bell, R.; Fofonoff, S.; Byers, R.; Atkinson, E.N.; Vaughan, C.; Toth, B.B.; Kramer, A.; Dimery, I.W.; Skipper, P.; Strong, S. 13-cis-retinoic acid in the treatment of oral leukoplakia. N. Engl. J. Med., 1986, 315(24), 1501-1505.
[http://dx.doi.org/10.1056/NEJM198612113152401] [PMID: 3537787]
[54]
Hong, W.K.; Lippman, S.M.; Itri, L.M.; Karp, D.D.; Lee, J.S.; Byers, R.M.; Schantz, S.P.; Kramer, A.M.; Lotan, R.; Peters, L.J.; Dimery, I.W.; Brown, B.W.; Goepfert, H. Prevention of second primary tumors with isotretinoin in squamous-cell car-cinoma of the head and neck. N. Engl. J. Med., 1990, 323(12), 795-801.
[http://dx.doi.org/10.1056/NEJM199009203231205] [PMID: 2202902]
[55]
Lippman, S.M.; Batsakis, J.G.; Toth, B.B.; Weber, R.S.; Lee, J.J.; Martin, J.W.; Hays, G.L.; Goepfert, H.; Hong, W.K. Com-parison of low-dose isotretinoin with beta carotene to prevent oral carcinogenesis. N. Engl. J. Med., 1993, 328(1), 15-20.
[http://dx.doi.org/10.1056/NEJM199301073280103] [PMID: 8416267]
[56]
Benner, S.E.; Pajak, T.F.; Lippman, S.M.; Earley, C.; Hong, W.K. Prevention of second primary tumors with isotretinoin in patients with squamous cell carcinoma of the head and neck: Long-term follow-up. J. Natl. Cancer Inst., 1994, 86(2), 140-141.
[http://dx.doi.org/10.1093/jnci/86.2.140] [PMID: 8271298]
[57]
Rustin, G.J.S.; Quinnell, T.G.; Johnson, J.; Clarke, H.; Nel-strop, A.E.; Bollag, W. Trial of isotretinoin and calcitriol moni-tored by CA 125 in patients with ovarian cancer. Br. J. Cancer, 1996, 74(9), 1479-1481.
[http://dx.doi.org/10.1038/bjc.1996.568] [PMID: 8912548]
[58]
Boerner, A.R.; Petrich, T.; Weckesser, E.; Fricke, H.; Hof-mann, M.; Otto, D.; Weckesser, M.; Langen, K.J.; Knapp, W.H. Monitoring isotretinoin therapy in thyroid cancer using 18F-FDG PET. Eur. J. Nucl. Med. Mol. Imaging, 2002, 29(2), 231-236.
[http://dx.doi.org/10.1007/s00259-001-0702-4] [PMID: 11926385]
[59]
Skroza, N.; Proietti, I.; Tolino, E.; Bernardini, N.; La Viola, G.; Nicolucci, F.; Pampena, R.; Mancini, M.T.; Balduzzi, V.; Po-tenza, C.; Zuber, S. Isotretinoin for the treatment of squamous cell carcinoma arising on an epidermoid cyst. Dermatol. Ther., 2014, 27(2), 94-96.
[http://dx.doi.org/10.1111/dth.12062] [PMID: 24703265]
[60]
Castleberry, R.P.; Emanuel, P.D.; Zuckerman, K.S.; Cohn, S.; Strauss, L.; Byrd, R.L.; Homans, A.; Chaffee, S.; Nitschke, R.; Gualtieri, R.J. A pilot study of isotretinoin in the treatment of juvenile chronic myelogenous leukemia. N. Engl. J. Med., 1994, 331(25), 1680-1684.
[http://dx.doi.org/10.1056/NEJM199412223312503] [PMID: 7605422]
[61]
Chen, S.E.; Choi, S.S.; Rogers, J.E.; Lei, X.; De Groot, J.F. Isotretinoin maintenance therapy for glioblastoma: A retro-spective review. J. Oncol. Pharm. Pract., 2014, 20(2), 112-119.
[http://dx.doi.org/10.1177/1078155213483348] [PMID: 23676507]

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