Abstract
During the last couple of decades, efforts have been made to study the toxic effects of individual aryl hydrocarbon receptors (AhR) ligands such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or heavy metals typified by arsenic As(III). However, little is known about the combined toxic effects of TCDD and As(III) in vivo. Previous reports from our laboratory and others have demonstrated that As(III), by itself or in the presence of AhR ligands, such as TCDD, is capable of differentially altering the expression of various phase I and phase II AhR-regulated genes in in vitro systems. Thus, the objective of the current study was to investigate whether or not similar effects would occur at the in vivo level. Therefore, we examined the effect of exposure to As(III) (12.5 mg/kg) in the absence and presence of TCDD (15 μg/kg) on the AhR-regulated genes using C57Bl/6 mice. Our results demonstrated that As(III) alone inhibited Cyp1a1 and Cyp1a2 in the kidney, while it induced their levels in the lung and did not affect their mRNA levels in the heart. As(III) also induced Nqo1 and Gsta1 in all tested tissues. Upon co-exposure to As(III) and TCDD, As(III) inhibited the TCDD-mediated induction of Cyp1a1 in the kidney and heart, Cyp1a2 in the kidney and heart, while it potentiated TCDD-mediated induction of Cyp1a1 in the lung, and Nqo1 and Gsta1 in the kidney and lung. In conclusion, the present study demonstrates for the first time that As(III) modulates constitutive and TCDD-induced AhR-regulated genes in a time-, tissue-, and AhR-regulated enzyme-specific manner.
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Abbreviations
- AhR:
-
Aryl hydrocarbon receptor
- As(III):
-
Arsenite
- Cyp450s:
-
Cytochrome P450s
- Gsta1:
-
Glutathione-S-transferase A1
- HO-1:
-
Heme oxygenase-1
- Nqo1:
-
NADP(H): quinone oxidoreductase
- TCDD:
-
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)
- XRE:
-
Xenobiotic responsive element
References
Anwar-Mohamed A, El-Kadi AO (2010) Arsenite down-regulates cytochrome P450 1A1 at the transcriptional and posttranslational levels in human HepG2 cells. Free Radic Biol Med 48(10):1399–1409. doi:10.1016/j.freeradbiomed.2010.02.027
Anwar-Mohamed A, Elbekai RH, El-Kadi AO (2009) Regulation of CYP1A1 by heavy metals and consequences for drug metabolism. Expert Opin Drug Metab Toxicol 5(5):501–521. doi:10.1517/17425250902918302
ATSDR (2011) Priority list of hazardous substances. The agency for toxic substances and diseases registry. http://www.atsdr.cdc.gov/SPL/index.html. Accessed 25 Oct 2011
Barakat MM, El-Kadi AO, du Souich P (2001) L-NAME prevents in vivo the inactivation but not the down-regulation of hepatic cytochrome P450 caused by an acute inflammatory reaction. Life Sci 69(13):1559–1571. doi:10.1016/S0024-3205(01)01241-3
Birnbaum LS (1986) Distribution and excretion of 2,3,7,8-tetrachlorodibenzo-p-dioxin in congenic strains of mice which differ at the Ah locus. Drug Metab Dispos 14(1):34–40. doi:10.1016/0272-0590(90)90175-J
CEPA (2012) Toxic substances list—schedule 1. Canadian Environmental Protection Act. http://ec.gc.ca/lcpe-cepa/default.asp?lang=En&n=0DA2924D-1&wsdoc=4ABEFFC8-5BEC-B57A-F4BF-11069545E434. Accessed 28 Mar 2012
Cui X, Kobayashi Y, Akashi M, Okayasu R (2008) Metabolism and the paradoxical effects of arsenic: carcinogenesis and anticancer. Curr Med Chem 15(22):2293–2304. doi:10.2174/092986708785747526
Denison MS, Nagy SR (2003) Activation of the aryl hydrocarbon receptor by structurally diverse exogenous and endogenous chemicals. Annu Rev Pharmacol Toxicol 43:309–334. doi:10.1146/annurev.pharmtox.43.100901.135828
Elbekai RH, El-Kadi AO (2004) Modulation of aryl hydrocarbon receptor-regulated gene expression by arsenite, cadmium, and chromium. Toxicology 202(3):249–269. doi:10.1016/j.tox.2004.05.009
Elbekai RH, El-Kadi AO (2005) The role of oxidative stress in the modulation of aryl hydrocarbon receptor-regulated genes by As3+, Cd2+, and Cr6+. Free Radic Biol Med 39(11):1499–1511. doi:10.1016/j.freeradbiomed.2005.07.012
Elbekai RH, El-Kadi AO (2007) Transcriptional activation and posttranscriptional modification of Cyp1a1 by arsenite, cadmium, and chromium. Toxicol Lett 172(3):106–119. doi:10.1016/j.toxlet.2007.05.009
Elbekai RH, El-Kadi AO (2008) Arsenite and cadmium, but not chromium, induce NAD(P)H:quinone oxidoreductase 1 through transcriptional mechanisms, in spite of post-transcriptional modifications. Toxicol In Vitro 22(5):1184–1190. doi:10.1016/j.tiv.2008.03.010
Frericks M, Meissner M, Esser C (2007) Microarray analysis of the AHR system: tissue-specific flexibility in signal and target genes. Toxicol Appl Pharmacol 220(3):320–332. doi:10.1016/j.taap.2007.01.014
Habig WH, Pabst MJ, Jakoby WB (1974) Glutathione S-transferases. The first enzymatic step in mercapturic acid formation. J Biol Chem 249(22):7130–7139
He XQ, Chen R, Yang P, Li AP, Zhou JW, Liu QZ (2007) Biphasic effect of arsenite on cell proliferation and apoptosis is associated with the activation of JNK and ERK1/2 in human embryo lung fibroblast cells. Toxicol Appl Pharmacol 220(1):18–24. doi:10.1016/j.taap.2006.12.021
Hu H, Moller G, Abedi-Valugerdi M (1999) Mechanism of mercury-induced autoimmunity: both T helper 1- and T helper 2-type responses are involved. Immunology 96(3):348–357. doi:10.1046/j.1365-2567.1999.00671.x
Hughes MF, Kenyon EM, Edwards BC, Mitchell CT, Thomas DJ (1999) Strain-dependent disposition of inorganic arsenic in the mouse. Toxicology 137(2):95–108. doi:10.1016/S0300-483X(99)00068-2
Jaiswal AK (2000) Regulation of genes encoding NAD(P)H:quinone oxidoreductases. Free Radic Biol Med 29(3–4):254–262. doi:10.1016/S0891-5849(00)00306-3
Klaassen CD (2001) Cassarett and Doull’s toxicology. The basic science of poisons, 6th edn. McGraw-Hill, New York
Klimecki WT, Carter DE (1995) Arsine toxicity: chemical and mechanistic implications. J Toxicol Environ Health 46(4):399–409. doi:10.1080/15287399509532045
Korashy HM, El-Kadi AO (2006) Transcriptional regulation of the NAD(P)H:quinone oxidoreductase 1 and glutathione S-transferase ya genes by mercury, lead, and copper. Drug Metab Dispos 34(1):152–165. doi:10.1124/dmd.105.005397
Lin FH, Stohs SJ, Birnbaum LS, Clark G, Lucier GW, Goldstein JA (1991) The effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on the hepatic estrogen and glucocorticoid receptors in congenic strains of Ah responsive and Ah nonresponsive C57BL/6J mice. Toxicol Appl Pharmacol 108(1):129–139. doi:10.1016/0041-008X(91)90276-K
Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods 25(4):402–408. doi:10.1006/meth.2001.1262
Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193(1):265–275
McMahon M, Itoh K, Yamamoto M, Chanas SA, Henderson CJ, McLellan LI, Wolf CR, Cavin C, Hayes JD (2001) The Cap’n’Collar basic leucine zipper transcription factor Nrf2 (NF-E2 p45-related factor 2) controls both constitutive and inducible expression of intestinal detoxification and glutathione biosynthetic enzymes. Cancer Res 61(8):3299–3307
Mehra M, Kanwar KC (1980) Biochemical changes resulting from the intraperitoneal administration of mercuric chloride and methylmercuric chloride to mice. Toxicol Lett 6(4–5):319–326. doi:10.1016/0378-4274(80)90137-X
Nebert DW, Dalton TP (2006) The role of cytochrome P450 enzymes in endogenous signalling pathways and environmental carcinogenesis. Nat Rev Cancer 6(12):947–960. doi:10.1038/nrc2015
Nebert DW, Duffy JJ (1997) How knockout mouse lines will be used to study the role of drug-metabolizing enzymes and their receptors during reproduction and development, and in environmental toxicity, cancer, and oxidative stress. Biochem Pharmacol 53(3):249–254. doi:10.1016/S0006-2952(96)00740-X
Patrick L (2003) Toxic metals and antioxidants: part II. The role of antioxidants in arsenic and cadmium toxicity. Altern Med Rev 8(2):106–128
Preusch PC, Siegel D, Gibson NW, Ross D (1991) A note on the inhibition of DT-diaphorase by dicoumarol. Free Radic Biol Med 11(1):77–80. doi:10.1016/0891-5849(91)90191-5
Rivera SP, Saarikoski ST, Hankinson O (2002) Identification of a novel dioxin-inducible cytochrome P450. Mol Pharmacol 61(2):255–259. doi:10.1124/mol.61.2.255
Seubert JM, Webb CD, Bend JR (2002) Acute sodium arsenite treatment induces Cyp2a5 but not Cyp1a1 in the C57Bl/6 mouse in a tissue (kidney) selective manner. J Biochem Mol Toxicol 16(2):96–106. doi:10.1002/jbt.10023
Shimada T, Sugie A, Shindo M, Nakajima T, Azuma E, Hashimoto M, Inoue K (2003) Tissue-specific induction of cytochromes P450 1A1 and 1B1 by polycyclic aromatic hydrocarbons and polychlorinated biphenyls in engineered C57BL/6 J mice of arylhydrocarbon receptor gene. Toxicol Appl Pharmacol 187(1):1–10
Spink DC, Katz BH, Hussain MM, Spink BC, Wu SJ, Liu N, Pause R, Kaminsky LS (2002) Induction of CYP1A1 and CYP1B1 in T-47D human breast cancer cells by benzo[a]pyrene is diminished by arsenite. Drug Metab Dispos 30(3):262–269. doi:10.1124/dmd.30.3.262
Uno S, Dragin N, Miller ML, Dalton TP, Gonzalez FJ, Nebert DW (2008) Basal and inducible CYP1 mRNA quantitation and protein localization throughout the mouse gastrointestinal tract. Free Radic Biol Med 44(4):570–583. doi:10.1016/j.freeradbiomed.2007.10.044
Vahter M, Concha G (2001) Role of metabolism in arsenic toxicity. Pharmacol Toxicol 89(1):1–5. doi:10.1111/j.1600-0773.2001.890101.x
Whalen R, Boyer TD (1998) Human glutathione S-transferases. Semin Liver Dis 18(4):345–358. doi:10.1055/s-2007-1007169
Wong PS, Vogel CF, Kokosinski K, Matsumura F (2010) Arylhydrocarbon receptor activation in NCI-H441 cells and C57BL/6 mice: possible mechanisms for lung dysfunction. Am J Respir Cell Mol Biol 42(2):210–217. doi:10.1165/rcmb.2008-0228OC
Wu JP, Chang LW, Yao HT, Chang H, Tsai HT, Tsai MH, Yeh TK, Lin P (2009) Involvement of oxidative stress and activation of aryl hydrocarbon receptor in elevation of CYP1A1 expression and activity in lung cells and tissues by arsenic: an in vitro and in vivo study. Toxicol Sci 107(2):385–393. doi:10.1093/toxsci/kfn239
Zordoky BN, Anwar-Mohamed A, Aboutabl ME, El-Kadi AO (2010) Acute doxorubicin cardiotoxicity alters cardiac cytochrome P450 expression and arachidonic acid metabolism in rats. Toxicol Appl Pharmacol 242(1):38–46. doi:10.1016/j.taap.2009.09.012
Acknowledgments
This work was supported by Natural Sciences and Engineering Research Council of Canada (NSERC) Discovery Grant RGPIN 250139-07 to A.O.S. A.A-M. is the recipient of Alberta Ingenuity Graduate Scholarship and Izaak Walton Killam memorial graduate Scholarship. I.E.A is the recipient of Libyan Government Scholarship.
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Anwar-Mohamed, A., Abdelhamid, G., Amara, I.E.A. et al. Differential modulation of aryl hydrocarbon receptor regulated enzymes by arsenite in the kidney, lung, and heart of C57BL/6 mice. Arch Toxicol 86, 897–910 (2012). https://doi.org/10.1007/s00204-012-0855-x
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DOI: https://doi.org/10.1007/s00204-012-0855-x