Abstract
Benzo[a]pyrene (B[a]P) is one of the polycyclic aromatic hydrocarbons which is formed due to smoking of foods, incomplete combustion of woods, vehicle exhausts, and cigarettes smokes. B[a]P gets entry into human and animal bodies mainly through their diets. Metabolic activation of B[a]P is required to induce mutagenesis and carcinogenesis in animal and human studies. Carotenoids and retinoids are phytochemicals that if ingested have multiple physiological interferences in the human and animal bodies. In this study, we firstly investigated the protective effects of β-carotene, β-apo-8-carotenal, retinol, and retinoic acid against B[a]P-induced mutagenicity and oxidative stress in human HepG2 cells. Secondly, we tested the hypothesis of modulating xenobiotic metabolizing enzymes (XMEs) by carotenoids and retinoids as a possible mechanism of protection by these micronutrients against B[a]P adverse effects. The obtained results declared that β-carotene and retinol significantly reduced B[a]P-induced mutagenicity and oxidative stress. Tested carotenoids and retinoids reduced B[a]P-induced phase I XMEs and induced B[a]P reduced phase II and III XMEs. Thus, the protective effects of these micronutrients are probably due to their ability of induction of phase II and III enzymes and interference with the induction of phase I enzymes by the promutagen, B[a]P. It is highly recommended to consume foods rich in these micronutrients in the areas of high PAH pollution.
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References
Agency for Toxic Substances and Disease Registry (ATSDR) (1995) Toxicological profile for polycyclic aromatic hydrocarbons (PAHs). Atlanta, GA, U.S.: Department of Health and Human Services, Public HealthService. PB/95/264370. http://www.atsdr.cdc.gov/toxprofiles/tp69.pdf. Accessed 10 May 2017
Alsharif NZ, Hassoun EA (2004) Protective effects of vitamin A and vitamin E succinate against 2,3,7,8-tetrachlorodibenzo-pdioxin (TCDD)-induced body wasting, hepatomegaly, thymic atrophy, production of reactive oxygen species and DNA damage in C57BL/6J mice. Basic Clin Pharmacol Toxicol 95(3):131–138. https://doi.org/10.1111/j.1742-7843.2004.950305.x
Amara IE, Anwar-Mohamed A, El-Kadi AO (2010) Mercury modulates the CYP1A1 at transcriptional and posttranslational levels in human hepatoma HepG2 cells. Toxicol Lett 199(3):225–233. https://doi.org/10.1016/j.toxlet.2010.09.003
Ames BN, Gold LS (1990) Chemical carcinogenesis: too many rodent carcinogens. Proc Natl Acad Sci U S A 87(19):7772–7776. https://doi.org/10.1073/pnas
Armentano MF, Bisaccia F, Miglionico R, Russo D, Nolfi N, Carmosino M, Andrade PB, Valentão P, Diop MS, Milella L (2015) Antioxidant and proapoptotic activities of Sclerocarya birrea [(A. Rich.) Hochst.] methanolic root extract on the hepatocellular carcinoma cell line HepG2. Biomed Res Int 2015:561589. https://doi.org/10.1155/2015/561589
Bhagavathy S, Sumathi P (2012) Evaluation of antigenotoxic effects of carotenoids from green algae Chlorococcum humicola using human lymphocytes. Asian Pac J Trop Biomed 2(2):109–117. https://doi.org/10.1016/S2221-1691(11)60203-7
Bhuvaneswari V, Velmurugan B, Nagini S (2002) Induction of glutathione-dependent hepatic biotransformation enzymes by lycopene in the hamster cheek pouch carcinogenesis model. J Biochem Mol Biol Biophys 6(4):257–260. https://doi.org/10.1080/10258140290030843
Chen W, Su H, Xu Y, Bao T, Zheng X (2016) Protective effect of wild raspberry (Rubus hirsutus Thunb.) extract against acrylamide-induced oxidative damage is potentiated after simulated gastrointestinal digestion. Food Chem 196:943–952. https://doi.org/10.1016/j.foodchem.2015.10.024
Darwish WS, Ikenaka Y, Eldaly E, Ishizuka M (2010a) Mutagenic activation and detoxification of benzo[a]pyrene in vitro by hepatic cytochrome P4501A1 and phase II enzymes in three meat-producing animals. Food Chem Toxicol 48(8):2526–2531. https://doi.org/10.1016/j.fct.2010.06.026
Darwish WS, Ikenaka Y, Ohno M, Eldaly E, Ishizuka M (2010b) Carotenoids as regulators for inter-species difference in cytochrome P450 1A expression and activity in food producing animals and rats. Food Chem Toxicol 48(11):3201–3208. https://doi.org/10.1016/j.fct.2010.08.022
Darwish WS, Ikenaka Y, Nakayama S, Ishizuka M (2014) The effect of copper on the mRNA expression profile of xenobiotic-metabolizing enzymes in cultured rat H4-II-E cells. Biol Trace Elem Res 158(2):243–248. https://doi.org/10.1007/s12011-014-9915-9
Darwish WS, Ikenaka Y, Nakayama SM, Mizukawa H, Ishizuka M (2016) Constitutive effects of lead on aryl hydrocarbon receptor gene battery and protection by β-carotene and ascorbic acid in human HepG2 cells. J Food Sci 81(1):T275–T281. https://doi.org/10.1111/1750-3841.13162
De Luca LM, Ross SA (1996) Beta-carotene increases lung cancer incidence in cigarette smokers. Nutr Rev 54(6):178–180. https://doi.org/10.1111/j.1753-4887.1996.tb03926.x
Duarte-Salles T, Mendez MA, Morales E, Bustamante M, Rodríguez-Vicente A, Kogevinas M, Sunyer J (2012) Dietary benzo(a)pyrene and fetal growth: effect modification by vitamin C intake and glutathione S-transferase P1 polymorphism. Environ Int 45:1–8. https://doi.org/10.1016/j.envint.2012.04.002
Fuhrman B, Volkova N, Rosenblat M, Aviram M (2000) Lycopene synergistically inhibits LDL oxidation in combination with vitamin E, glabridin, rosmarinic acid, carnosic acid, or garlic. Antioxid Redox Signal 2(3):491–506. https://doi.org/10.1089/15230860050192279
Hildebrandt AG, Bergs C, Heinemeyer G, Schlede E, Roots I, Abbas AB, Schmoldt A (1981) Studies on the mechanism of stimulation of microsomal H2O2formation and benzo(a)pyrene hydroxylation by substrates and flavone. Adv Exp Med Biol 136(Pt A):179–198. https://doi.org/10.1007/978-1-4757-0674-1_11
Huang D, Ohnishi T, Jian H, Furukawa A, Ichikawa Y (1999) Inhibition by retinoids of benzo(a)pyrene metabolism catalyzed by 3-methylcholanthreneinduced rat cytochrome P-450 1A1. Metabolism 48(6):689–692. https://doi.org/10.1016/S0026-0495(99)90166-X
International Agency for Research on Cancer (IARC) (2010) Some non-heterocyclic polycyclic aromatic hydrocarbons and some related exposures. IARC Monogr Eval Carcinog Risks Hum 92:1–853
Joseph P, Jaiswal AK (1998) NAD(P)H:quinone oxidoreductase 1 reduces the mutagenicity of DNA caused by NADPH:P450 reductase-activated metabolites of benzo(a)pyrene quinones. Br J Cancer 77(5):709–719. https://doi.org/10.1038/bjc.1998.117
Kasperczyk S, Dobrakowski M, Kasperczyk J, Ostalowska A, Zalejska-Fiolka J, Birkner E (2014) Beta-carotene reduces oxidative stress, improves glutathione metabolism and modifies antioxidant defense systems in lead-exposed workers. Toxicol Appl Pharmacol 280(1):36–41. https://doi.org/10.1016/j.taap.2014.07.006
Kim KB, Lee BM (1997) Oxidative stress to DNA, protein, and antioxidant enzymes (superoxide dismutase and catalase) in rats treated with benzo(a)pyrene. Cancer Lett 113(1-2):205–212. https://doi.org/10.1016/S0304-3835(97)04610-7
Korashy H, El-Kadi A (2012) Transcriptional and posttranslational mechanisms modulating the expression of the cytochrome P450 1A1 gene by lead in HepG2 cells: a role of heme oxygenase. Toxicology 291(1-3):113–121. https://doi.org/10.1016/j.tox.2011.11.006
Lampen A, Ebert B, Stumkat L, Jacob J, Seidel A (2004) Induction of gene expression of xenobiotic metabolism enzymes and ABC-transport proteins by PAH and a reconstituted PAH mixture in human Caco-2 cells. Biochem Biophys Acta 1681(1):38–46. https://doi.org/10.1016/j.bbaexp.2004.09.010
Larsson SC, Bergkvist L, Näslund I, Rutegård J, Wolk A (2007) Vitamin A, retinol, and carotenoids and the risk of gastric cancer: a prospective cohort study. Am J Clin Nutr 85(2):497–503
Mureithi D, Darwish WS, Ikenaka Y, Kanja L, Ishizuka M (2012) Cytochrome P450 3A mRNA expression along goat and rat gastrointestinal tracts. Jpn J Vet Res 60(4):205–210. https://doi.org/10.14943/jjvr.60.4.205
Nebert DW, Roe AL, Dieter MZ, Solis WA, Yang Y, Dalton TP (2000) Role of the aromatic hydrocarbon receptor and [Ah] gene battery in the oxidative stress response, cell cycle control, and apoptosis. Biochem Pharmacol 59(1):65–85. https://doi.org/10.1016/S0006-2952(99)00310-X
Nishino H, Murakoshi M, Tokuda H, Satomi Y (2009) Cancer prevention by carotenoids. Arch Biochem Biophys 483(2):165–168. https://doi.org/10.1016/j.abb.2008.09.011
Ohno S, Nakajin S (2009) Determination of mRNA expression of human UDP-glucuronosyltransferases and application for localization in various human tissues by real-time reverse transcriptase-polymerase chain reaction. Drug Metab Dispos 37(1):32–40. https://doi.org/10.1124/dmd.108.023598
Ohno M, Darwish WS, Miki W, Ikenaka Y, Ishizuka M (2011) Astaxanthin can alter CYP1A-dependent activities via two different mechanisms: induction of protein expression and inhibition of NADPH P450 reductase dependent electron transfer. Food Chem Toxicol 49(6):1285–1291. https://doi.org/10.1016/j.fct.2011.03.009
Ohno M, Darwish WS, Ikenaka Y, Miki W, Fujita S, Ishizuka M (2012) Astaxanthin rich crude extract of Haematococcus pluvialis induces cytochrome P450 1A1 mRNA by activating aryl hydrocarbon receptor in rat hepatoma H4IIE cells. Food Chem 130(2):356–361. https://doi.org/10.1016/j.foodchem.2011.07.050
Phillips DH (1999) Polycyclic aromatic hydrocarbons in the diet. Mutat Res 443(1–2):139–147. https://doi.org/10.1016/S1383-5742(99)00016-2
Ranjbar NE, Sadeghi MA, Ghorbani M, Kashaninejad M (2015) Evaluation of antioxidant interactions in combined extracts of green tea (Camellia sinensis), rosemary (Rosmarinus officinalis) and oak fruit (Quercus branti). J Food Sci Technol 52(7):4565–4571. https://doi.org/10.1007/s13197-014-1497-1
Santos-Cervantes ME, Ibarra-Zazueta ME, Loarca-Piña G, Paredes-López O, Delgado-Vargas F (2007) Antioxidant and antimutagenic activities of Randia echinocarpa fruit. Plant Foods Hum Nutr 62(2):71–77. https://doi.org/10.1007/s11130-007-0044-x
Sugimura T, Nagao M, Wakabayashi K (1996) Carcinogenicity of food mutagens. Environ Health Perspect 104(Suppl. 3):429–433. https://doi.org/10.2307/3432798
Tsuji G, Takahara M, Uchi H, Takeuchi S, Mitoma C, Moroi Y, Furue M (2011) An environmental contaminant, benzo(a)pyrene, induces oxidative stress mediated interlukin 8 production in human keratinocytes via the aryl hydrocarbon receptor signaling pathway. J Dermatol Sci 63(1):42–49. https://doi.org/10.1016/j.jdermsci.2010.10.017.
Yamazaki H, Shimada T (1999) Effects of arachidonic acid, prostaglandins, retinol, retinoic acid and cholecalciferol on xenobiotic oxidations catalysed by human cytochrome P450 enzymes. Xenobiotica 29(3):231–241. https://doi.org/10.1080/004982599238632
Yang F, Yang H, Ramesh A, Goodwin JS, Okoro EU, Guo Z (2016) Overexpression of catalase enhances benzo(a)pyrene detoxification in endothelial microsomes. PLoS One 11(9):e0162561. https://doi.org/10.1371/journal.pone.0162561
Acknowledgments
The authors are grateful to Mr. Takahiro Ichise, Ms. Mio Yagihashi, and Ms. Nagisa Hirano for their technical support and great input throughout the research work.
Funding
This work was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan awarded to M. Ishizuka (No. 16H0177906), Y. Ikenaka (No. 26304043, 15H0282505, 15K1221305), S. Nakayama (16K16197), and the foundations of JSPS Core to Core Program (AA Science Platforms) and the Bilateral Joint Research Project (PG36150002 and PG36150003). We also acknowledge the financial support by the Mitsui & Co., Ltd. Environment Fund, the Sumitomo foundation for Environmental Research Projects, the Soroptimist Japan Foundation, the Nakajima Foundation, and the Inui Memorial Trust for Research on Animal Science. The grant number 6509 from Egypt Science and Technology Developing Fund (STDF) awarded to Wageh Sobhy Darwish also supported in part of this study. Wageh Sobhy Darwish is a recipient of Japanese Society for promotion of Science (JSPS) invitation fellowship number L16564.
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W. S. Darwish designed the study, conducted the experiments, drafted the manuscript, and interpreted the results. Y. Ikenaka designed the study and interpreted the results. S. M. Nakayama and L. Thompson drafted the manuscript, interpreted the results, and performed statistical analysis. H. Mizukawa collected the test data. M. Ishizuka designed the study, supervised the work, and interpreted the results.
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Darwish, W.S., Ikenaka, Y., Nakayama, S. et al. β-carotene and retinol reduce benzo[a]pyrene-induced mutagenicity and oxidative stress via transcriptional modulation of xenobiotic metabolizing enzymes in human HepG2 cell line. Environ Sci Pollut Res 25, 6320–6328 (2018). https://doi.org/10.1007/s11356-017-0977-z
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DOI: https://doi.org/10.1007/s11356-017-0977-z