Protection of HepG2 Cells Against Acrolein Toxicity by 2-cyano-3,12-dioxooleana-1,9-dien-28-imidazolide Via Glutathione-mediated Mechanism

Overview

Journal Exp Biol Med (Maywood)

Specialty Biology

Date 2014 Dec 16

PMID 25504014

Citations 6

Authors

Halley Shah

Adam M Speen

Christina Saunders

Elizabeth A S Brooke

Palanisamy Nallasamy

Hong Zhu

Y Robert Li

Zhenquan Jia

Affiliations

Soon will be listed here.

Abstract

Acrolein is an environmental toxicant, mainly found in smoke released from incomplete combustion of organic matter. Several studies showed that exposure to acrolein can lead to liver damage. The mechanisms involved in acrolein-induced hepatocellular toxicity, however, are not completely understood. This study examined the cytotoxic mechanisms of acrolein on HepG2 cells. Acrolein at pathophysiological concentrations was shown to cause apoptotic cell death and an increase in levels of protein carbonyl and thiobarbituric acid reactive acid substances. Acrolein also rapidly depleted intracellular glutathione (GSH), GSH-linked glutathione-S-transferases, and aldose reductase, three critical cellular defenses that detoxify reactive aldehydes. Results further showed that depletion of cellular GSH by acrolein preceded the loss of cell viability. To further determine the role of cellular GSH in acrolein-mediated cytotoxicity, buthionine sulfoximine (BSO) was used to inhibit cellular GSH biosynthesis. It was observed that depletion of cellular GSH by BSO led to a marked potentiation of acrolein-mediated cytotoxicity in HepG2 cells. To further assess the contribution of these events to acrolein-induced cytotoxicity, triterpenoid compound 2-cyano-3,12-dioxooleana-1,9-dien-28-imidazolide (CDDO-Im) was used for induction of GSH. Induction of GSH by CDDO-Im afforded cytoprotection against acrolein toxicity in HepG2 cells. Furthermore, BSO significantly inhibited CDDO-Im-mediated induction in cellular GSH levels and also reversed cytoprotective effects of CDDO-Im in HepG2 cells. These results suggest that GSH is a predominant mechanism underlying acrolein-induced cytotoxicity as well as CDDO-Im-mediated cytoprotection. This study may provide understanding on the molecular action of acrolein which may be important to develop novel strategies for the prevention of acrolein-mediated toxicity.

Citing Articles

Enzymatic Acrolein Production System and Its Impact on Human Cells.

Hurley K, Folz J, Zgraggen J, Cruz T, Diedrich S, Sturla S Chem Res Toxicol. 2024; 37(8):1374-1381.

PMID: 39155646 PMC: 11337209. DOI: 10.1021/acs.chemrestox.4c00119.

Hydrogen sulfide protects against toxicant acrolein-induced ferroptotic cell death in Sertoli cells.

Mao Z, Ji Q, Chen P, Zhong K, Zeng X Front Pharmacol. 2024; 15:1440147.

PMID: 39148534 PMC: 11324607. DOI: 10.3389/fphar.2024.1440147.

Acrolein Induces Changes in Cell Membrane and Cytosol Proteins of Erythrocytes.

Kopera M, Gwozdzinski K, Pieniazek A Molecules. 2024; 29(11).

PMID: 38893395 PMC: 11173626. DOI: 10.3390/molecules29112519.

Diet as a Source of Acrolein: Molecular Basis of Aldehyde Biological Activity in Diabetes and Digestive System Diseases.

Hikisz P, Jacenik D Int J Mol Sci. 2023; 24(7).

PMID: 37047550 PMC: 10095194. DOI: 10.3390/ijms24076579.

Comparative study of oral versus parenteral crocin in mitigating acrolein-induced lung injury in albino rats.

Rashad W, Sakr S, Domouky A Sci Rep. 2022; 12(1):10233.

PMID: 35715565 PMC: 9205959. DOI: 10.1038/s41598-022-14252-4.

References

Decker T, Lohmann-Matthes M . A quick and simple method for the quantitation of lactate dehydrogenase release in measurements of cellular cytotoxicity and tumor necrosis factor (TNF) activity. J Immunol Methods. 1988; 115(1):61-9. DOI: 10.1016/0022-1759(88)90310-9. View

Hayes J, McLellan L . Glutathione and glutathione-dependent enzymes represent a co-ordinately regulated defence against oxidative stress. Free Radic Res. 1999; 31(4):273-300. DOI: 10.1080/10715769900300851. View

Mohammad M, Avila D, Zhang J, Barve S, Arteel G, McClain C . Acrolein cytotoxicity in hepatocytes involves endoplasmic reticulum stress, mitochondrial dysfunction and oxidative stress. Toxicol Appl Pharmacol. 2012; 265(1):73-82. PMC: 3501104. DOI: 10.1016/j.taap.2012.09.021. View

Jia Z, Misra B, Zhu H, Li Y, Misra H . Upregulation of cellular glutathione by 3H-1,2-dithiole-3-thione as a possible treatment strategy for protecting against acrolein-induced neurocytotoxicity. Neurotoxicology. 2008; 30(1):1-9. DOI: 10.1016/j.neuro.2008.11.007. View

LoPachin R, Gavin T, Petersen D, Barber D . Molecular mechanisms of 4-hydroxy-2-nonenal and acrolein toxicity: nucleophilic targets and adduct formation. Chem Res Toxicol. 2009; 22(9):1499-508. PMC: 4452948. DOI: 10.1021/tx900147g. View

Smeyne M, Boyd J, Raviie Shepherd K, Jiao Y, Pond B, Hatler M . GSTpi expression mediates dopaminergic neuron sensitivity in experimental parkinsonism. Proc Natl Acad Sci U S A. 2007; 104(6):1977-82. PMC: 1785361. DOI: 10.1073/pnas.0610978104. View

Ismahil M, Hamid T, Haberzettl P, Gu Y, Chandrasekar B, Srivastava S . Chronic oral exposure to the aldehyde pollutant acrolein induces dilated cardiomyopathy. Am J Physiol Heart Circ Physiol. 2011; 301(5):H2050-60. PMC: 3213964. DOI: 10.1152/ajpheart.00120.2011. View

Cao Z, Hardej D, Trombetta L, Trush M, Li Y . Induction of cellular glutathione and glutathione S-transferase by 3H-1,2-dithiole-3-thione in rat aortic smooth muscle A10 cells: protection against acrolein-induced toxicity. Atherosclerosis. 2003; 166(2):291-301. DOI: 10.1016/s0021-9150(02)00331-3. View

Bein K, Leikauf G . Acrolein - a pulmonary hazard. Mol Nutr Food Res. 2011; 55(9):1342-60. DOI: 10.1002/mnfr.201100279. View

10.

Horvath J, Witmer C, Witz G . Nephrotoxicity of the 1:1 acrolein-glutathione adduct in the rat. Toxicol Appl Pharmacol. 1992; 117(2):200-7. DOI: 10.1016/0041-008x(92)90238-n. View

11.

Suh N, Wang Y, Honda T, Gribble G, Dmitrovsky E, Hickey W . A novel synthetic oleanane triterpenoid, 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid, with potent differentiating, antiproliferative, and anti-inflammatory activity. Cancer Res. 1999; 59(2):336-41. View

12.

Seo H, Nishinaka T, Yabe-Nishimura C . Nitric oxide up-regulates aldose reductase expression in rat vascular smooth muscle cells: a potential role for aldose reductase in vascular remodeling. Mol Pharmacol. 2000; 57(4):709-17. DOI: 10.1124/mol.57.4.709. View

13.

Esterbauer H, Schaur R, Zollner H . Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes. Free Radic Biol Med. 1991; 11(1):81-128. DOI: 10.1016/0891-5849(91)90192-6. View

14.

Vindis C, Escargueil-Blanc I, Uchida K, Elbaz M, Salvayre R, Negre-Salvayre A . Lipid oxidation products and oxidized low-density lipoproteins impair platelet-derived growth factor receptor activity in smooth muscle cells: implication in atherosclerosis. Redox Rep. 2007; 12(1):96-100. DOI: 10.1179/135100007X162248. View

15.

Pessione F, Ramond M, Njapoum C, Duchatelle V, Degott C, Erlinger S . Cigarette smoking and hepatic lesions in patients with chronic hepatitis C. Hepatology. 2001; 34(1):121-5. DOI: 10.1053/jhep.2001.25385. View

16.

Wilkening S, Stahl F, Bader A . Comparison of primary human hepatocytes and hepatoma cell line Hepg2 with regard to their biotransformation properties. Drug Metab Dispos. 2003; 31(8):1035-42. DOI: 10.1124/dmd.31.8.1035. View

17.

Park Y, Kim J, Misonou Y, Takamiya R, Takahashi M, Freeman M . Acrolein induces cyclooxygenase-2 and prostaglandin production in human umbilical vein endothelial cells: roles of p38 MAP kinase. Arterioscler Thromb Vasc Biol. 2007; 27(6):1319-25. DOI: 10.1161/ATVBAHA.106.132837. View

18.

Li L, Holian A . Acrolein: a respiratory toxin that suppresses pulmonary host defense. Rev Environ Health. 1998; 13(1-2):99-108. View

19.

Zhu H, Zhang L, Itoh K, Yamamoto M, Ross D, Trush M . Nrf2 controls bone marrow stromal cell susceptibility to oxidative and electrophilic stress. Free Radic Biol Med. 2006; 41(1):132-43. DOI: 10.1016/j.freeradbiomed.2006.03.020. View

20.

Zhu H, Jia Z, Misra B, Zhang L, Cao Z, Yamamoto M . Nuclear factor E2-related factor 2-dependent myocardiac cytoprotection against oxidative and electrophilic stress. Cardiovasc Toxicol. 2008; 8(2):71-85. DOI: 10.1007/s12012-008-9016-0. View