Ukr.Biochem.J. 2016; Volume 88, Issue 3, May-Jun, pp. 99-105


Hepatotoxicity of bisphenol A under conditions of differential supplementation with retinoids

I. O. Shmarakov, V. L. Borschovetska, L. P. Ivanishchuk, M. M. Marchenko

Yuriy Fed’kovych Chernivtsi National University, Ukraine;

Classical xenoestrogenic in vivo effects of bisphenol A (2,2-bis(4-hydroxyphenyl)propane, BPA) are well-described in the literature, however the molecular mechanisms of BPA-induced hepatotoxicity are not fully characterized. The work is aimed to assess biochemical markers of BPA induced hepatotoxicity under conditions of differential supplementation with retinoids. We demonstrate that the absence of hepatic retinyl esters as the main form of vitamin A storage provides for a resistance to BPA induced liver damage. Retinoid supplementation increases the hepatotoxic effects of bisphenol A, evidenced in higher indexes of oxidative damage of lipids, proteins and non-protein thiol groups as well as increase of serum alanine  aminotransferase activity and myeloperoxidase activity in liver parenchyma. The absence of hepatotoxicity signs when hepatic retinoid stores are depleted and their presence during normal or excessive retinoid supplementation suggest that hepatic retinoid availability is one of the factors determining the hepatotoxicity of bisphenol A.

Keywords: , , ,


  1. Pandit A, Sachdeva T, Bafna P. Drug-Induced Hepatotoxicity: A Review. JAPS. 2012;2(5):233-243. CrossRef
  2. Maes M, Vinken M, Jaeschke H. Experimental models of hepatotoxicity related to acute liver failure. Toxicol Appl Pharmacol. 2016 Jan 1;290:86-97. PubMed, PubMedCentral, CrossRef
  3. Nahar MS, Liao C, Kannan K, Dolinoy DC. Fetal liver bisphenol A concentrations and biotransformation gene expression reveal variable exposure and altered capacity for metabolism in humans. J Biochem Mol Toxicol. 2013 Feb;27(2):116-23.  PubMed, PubMedCentral, CrossRef
  4. Richter CA, Birnbaum LS, Farabollini F, Newbold RR, Rubin BS, Talsness CE, Vandenbergh JG, Walser-Kuntz DR, vom Saal FS. In vivo effects of bisphenol A in laboratory rodent studies. Reprod Toxicol. 2007 Aug-Sep;24(2):199-224.  PubMed, PubMedCentral, CrossRef
  5. Kundakovic M, Champagne FA. Epigenetic perspective on the developmental effects of bisphenol A. Brain Behav Immun. 2011 Aug;25(6):1084-93.  PubMedPubMedCentral, CrossRef
  6. Wang W, Jiang C, Zhu L, Liang N, Liu X, Jia J, Zhang C, Zhai S, Zhang B. Adsorption of bisphenol A to a carbon nanotube reduced its endocrine disrupting effect in mice male offspring. Int J Mol Sci. 2014 Sep 10;15(9):15981-93.  PubMed, PubMedCentral, CrossRef
  7. Xia W, Jiang Y, Li Y, Wan Y, Liu J, Ma Y, Mao Z, Chang H, Li G, Xu B, Chen X, Xu S. Early-life exposure to bisphenol a induces liver injury in rats involvement of mitochondria-mediated apoptosis. PLoS One. 2014 Feb 28;9(2):e90443. PubMed, PubMedCentral, CrossRef
  8. Shmarakov IO. Retinoid-xenobiotic interactions: the Ying and the Yang. Hepatobiliary Surg Nutr. 2015 Aug;4(4):243-67. PubMed, PubMedCentral
  9. Howell SR, Shirley MA, Ulm EH. Effects of retinoid treatment of rats on hepatic microsomal metabolism and cytochromes P450. Correlation between retinoic acid receptor/retinoid x receptor selectivity and effects on metabolic enzymes. Drug Metab Dispos. 1998 Mar;26(3):234-9. PubMed
  10. Brtko J, Dvorak Z. Role of retinoids, rexinoids and thyroid hormone in the expression of cytochrome p450 enzymes. Curr Drug Metab. 2011 Feb;12(2):71-88. PubMed, CrossRef
  11. Balmer JE, Blomhoff R. Gene expression regulation by retinoic acid. J Lipid Res. 2002 Nov;43(11):1773-808. PubMed, CrossRef
  12. Guide for the care and use of laboratory animals. Washington D. C.: National Academies Press, 2011. 246. р. CrossRef
  13. National Toxicology Program U.S. Department of Health and Human Services. Center For The Evaluation of RisksTo Human Reproduction; NTP-CERHR Monograph on the Potential Human Reproductive and Developmental Effects of Bisphenol A.: NIH Publication, 2008. 599 р.
  14. O’Byrne SM, Wongsiriroj N, Libien J, Vogel S, Goldberg IJ, Baehr W, Palczewski K, Blaner WS. Retinoid absorption and storage is impaired in mice lacking lecithin:retinol acyltransferase (LRAT). J Biol Chem. 2005 Oct 21;280(42):35647-57.  PubMed, PubMedCentral, CrossRef
  15. Wongsiriroj N, Piantedosi R, Palczewski K, Goldberg IJ, Johnston TP, Li E, Blaner WS. The molecular basis of retinoid absorption: a genetic dissection. J Biol Chem. 2008 May 16;283(20):13510-9. PubMedPubMedCentral, CrossRef
  16. Shmarakov IO, Marchyshak TV, Borschovetska VL, Marchenko MM, Tkachuk ZY. Hepatoprotective activity of exogenous RNA. Ukr Biochem J. 2015 Jul-Aug;87(4):37-44. PubMed, CrossRef
  17. Ohkawa H, Ohishi N, Yagi K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem. 1979 Jun;95(2):351-8. PubMed, CrossRef
  18. Levine RL, Garland D, Oliver CN, Amici A, Climent I, Lenz AG, Ahn BW, Shaltiel S, Stadtman ER. Determination of carbonyl content in oxidatively modified proteins. Methods Enzymol. 1990;186:464-78. PubMed, CrossRef
  19. Horyachkovskiy A. Clinical Biochemistry in laboratory diagnostics: A Reference Guide. Odessa: Ecology, 2005. 616 p.
  20. Murphy ME, Kehrer JP. Oxidation state of tissue thiol groups and content of protein carbonyl groups in chickens with inherited muscular dystrophy. Biochem J. 1989 Jun 1;260(2):359-64. PubMed, PubMedCentral, CrossRef
  21. Waterborg JH, Matthews HR. The Lowry method for protein quantitation. Methods Mol Biol. 1994;32:1-4. PubMed, CrossRef
  22. Schmidt J, Kotnik P, Trontelj J, Knez Ž, Mašič LP. Bioactivation of bisphenol A and its analogs (BPF, BPAF, BPZ and DMBPA) in human liver microsomes. Toxicol In Vitro. 2013 Jun;27(4):1267-76. PubMed, CrossRef
  23. Hassan ZK, Elobeid MA, Virk P, Omer SA, ElAmin M, Daghestani MH, AlOlayan EM. Bisphenol A induces hepatotoxicity through oxidative stress in rat model. Oxid Med Cell Longev. 2012;2012:194829.  PubMedPubMedCentral, CrossRef
  24. Shmarakov IO, Borschovetska VL, Marchenko MM, Blaner WS. Retinoids modulate thioacetamide-induced acute hepatotoxicity. Toxicol Sci. 2014 Jun;139(2):284-92.  PubMed, PubMedCentral, CrossRef
  25. Rosengren RJ, Sauer JM, Hooser SB, Sipes IG. The interactions between retinol and five different hepatotoxicants in the Swiss Webster mouse. Fundam Appl Toxicol. 1995 May;25(2):281-92. PubMed, CrossRef
  26. Bray BJ, Goodin MG, Inder RE, Rosengren RJ. The effect of retinol on hepatic and renal drug-metabolising enzymes. Food Chem Toxicol. 2001 Jan;39(1):1-9. PubMed, CrossRef
  27. Bray BJ, Rosengren RJ. Retinol potentiates acetaminophen-induced hepatotoxicity in the mouse: mechanistic studies. Toxicol Appl Pharmacol. 2001 Jun 15;173(3):129-36. PubMed, CrossRef

Creative CommonsThis work is licensed under a Creative Commons Attribution 4.0 International License.