ABSTRACT: The microsomal protein cytochrome b5 , which is located in the membrane of the endoplasmic reticulum, has been shown to modulate many reactions catalyzed by cytochrome P450 (CYP) enzymes. We investigated the influence of exposure to the anticancer drug ellipticine and to two environmental carcinogens, benzo[a]pyrene (BaP) and 1-phenylazo-2-naphthol (Sudan I), on the expression of cytochrome b5 in livers of rats, both at the mRNA and protein levels. We also studied the effects of these compounds on their own metabolism and the formation of DNA adducts generated by their activation metabolite(s) in vitro. The relative amounts of cytochrome b5 mRNA, measured by real-time polymerase chain reaction analysis, were induced by the test compounds up to 11.7-fold in rat livers. Western blotting using antibodies raised against cytochrome b5 showed that protein expression was induced by up to sevenfold in livers of treated rats. Microsomes isolated from livers of exposed rats catalyzed the oxidation of ellipticine, BaP, and Sudan I and the formation of DNA adducts generated by their reactive metabolite(s) more effectively than hepatic microsomes isolated from control rats. All test compounds are known to induce CYP1A1. This induction is one of the reasons responsible for increased oxidation of these xenobiotics by microsomes. However, induction of cytochrome b5 can also contribute to their enhanced metabolism.

Analytical and Environmental Sciences Division MRC PHE Centre for Environment and Health King's College London London SE1 9NH UK

Department of Biochemistry Faculty of Science Charles University Albertov 2030 128 40 Prague 2 Czech Republic

Department of Chemistry and Biochemistry Faculty of Agronomy Mendel University in Brno 613 00 Brno Czech Republic

Department of Oncology 2nd Faculty of Medicine Charles University and University Hospital Motol 5 Uvalu 84 150 06 Prague 5 Czech Republic

Division of Radiopharmaceutical Chemistry German Cancer Research Center Im Neuenheimer Feld 280 69120 Heidelberg Germany

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Velick SF, Strittmatter P. J Biol Chem. 1956;221:265. PubMed

Vergeres G, Ramsden J, Waskell L. J Biol Chem. 1995;270:3414. doi: 10.1074/jbc.270.7.3414. PubMed DOI

Vergeres G, Waskell L. Biochimie. 1995;77:604. doi: 10.1016/0300-9084(96)88176-4. PubMed DOI

Porter TD. J Biochem Mol Toxicol. 2002;16:311. doi: 10.1002/jbt.10052. PubMed DOI

Durr UH, Waskell L, Ramamoorthy A. Biochim Biophys Acta. 2007;1768:3235. doi: 10.1016/j.bbamem.2007.08.007. PubMed DOI

Durr UH, Yamamoto K, Im SC, Waskell L, Ramamoorthy A. J Am Chem Soc. 2007;129:6670. doi: 10.1021/ja069028m. PubMed DOI PMC

Schenkman JB, Jansson I. Pharmacol Ther. 2003;97:139. doi: 10.1016/S0163-7258(02)00327-3. PubMed DOI

Sobrado P, Goren MA, James D, Amundson CK, Fox BG. Protein Expr Purif. 2008;58:229. doi: 10.1016/j.pep.2007.11.018. PubMed DOI PMC

Clarke TA, Im SC, Bidwai A, Waskell L. J Biol Chem. 2004;279:36809. doi: 10.1074/jbc.M406055200. PubMed DOI

Guengerich F. Arch Biochem Biophys. 2005;440:204. doi: 10.1016/j.abb.2005.06.019. PubMed DOI

Schenkman JB, Jansson I. Drug Metab Rev. 1999;31:351. doi: 10.1081/DMR-100101923. PubMed DOI

Kotrbova V, Aimova D, Ingr M, Borek-Dohalska L, Martinek V, Stiborova M. Protein Expr Purif. 2009;66:203. doi: 10.1016/j.pep.2009.03.011. PubMed DOI

Aimová D, Svobodová L, Kotrbová V, Mrázová B, Hodek P, Hudeček J, Václavíková R, Frei E, Stiborová M. Drug Metab Dispos. 2007;35:1926. doi: 10.1124/dmd.107.016048. PubMed DOI

Arlt VM, Stiborova M, Henderson CJ, Thiemann M, Frei E, Aimova D, Singhs R, da Costa GG, Schmitz OJ, Farmer PB, Wolf CR, Philips DH. Carcinogenesis. 2008;29:656. doi: 10.1093/carcin/bgn002. PubMed DOI

Kotrbova V, Mrazova B, Moserova M, Martinek V, Hodek P, Hudecek J, Frei E, Stiborova M. Biochem Pharmacol. 2011;82:669. doi: 10.1016/j.bcp.2011.06.003. PubMed DOI

Stiborova M, Martinek V, Schmeiser HH, Frei E. Neuro Endocrinol Lett. 2006;27(Suppl 2):35. PubMed

Stiborova M, Indra R, Moserova M, Cerna V, Rupertova M, Martinek V, Eckschlager T, Kizek R, Frei E. Chem Res Toxicol. 2012;25:1075. doi: 10.1021/tx3000335. PubMed DOI

Stiborova M, Moserova M, Cerna V, Indra R, Dracinsky M, Šulc M, Henderson CJ, Wolf CR, Schmeiser HH, Phillips DH, Frei E, Arlt VM. Toxicology. 2014;318:1. doi: 10.1016/j.tox.2014.02.002. PubMed DOI

Vranová I, Moserová M, Hodek P, Kizek R, Frei E, Stiborová M. Int J Electrochem Sci. 2013;8:1586.

Stiborova M, Martinek V, Rydlova H, Hodek P, Frei E. Cancer Res. 2002;62:5678. PubMed

Stiborová M, Stiborová-Rupertová M, Bořek-Dohalská L, Wiessler M, Frei E. Chem Res Toxicol. 2003;16:38. doi: 10.1021/tx0200818. PubMed DOI

Stiborová M, Breuer A, Aimová D, Stiborová-Rupertová M, Wiessler M, Frei E. Int J Cancer. 2003;107:885. doi: 10.1002/ijc.11511. PubMed DOI

Stiborova M, Sejbal J, Bořek-Dohalská L, Aimová D, Poljaková J, Forsterová K, Rupertová M, Wiesner J, Hudeček J, Wiessler M, Frei E. Cancer Res. 2004;64:8374. doi: 10.1158/0008-5472.CAN-04-2202. PubMed DOI

Stiborova M, Frei E. Current Med Chem. 2014;21:575. doi: 10.2174/09298673113206660272. PubMed DOI

Indra R, Moserova M, Sulc M, Frei E, Stiborova M. Neuro Endocrinol Lett. 2013;34(Suppl 2):55. PubMed

Hodek P, Koblihova J, Kizek R, Frei E, Arlt VM, Stiborova M. Environ Toxicol Pharmacol. 2013;36:989. doi: 10.1016/j.etap.2013.09.004. PubMed DOI

Stiborová M, Dračínská H, Martínek V, Svášková D, Hodek P, Milichovský J, Hejduková Ž, Brotánek J, Schmeiser HH, Frei E. Chem Res Toxicol. 2013;26:290. doi: 10.1021/tx3004533. PubMed DOI

Stiborová M, Bořek-Dohalská L, Aimová D, Kotrbová V, Kukačková K, Janouchová K, Rupertová M, Ryšlavá H, Hudeček J, Frei E. Gen Physiol Biophys. 2006;25:245. PubMed

Stiborová M, Asfaw B, Frei E, Schmeiser HH, Wiessler M. Chem Res Toxicol. 1995;8:489. doi: 10.1021/tx00046a002. PubMed DOI

Stiborova M, Rupertová M, Aimová D, Ryšlavá H, Frei E. Toxicology. 2007;236:50. doi: 10.1016/j.tox.2007.03.026. PubMed DOI

Stiborova M, Poljaková J, Ryšlavá H, Dračínský M, Eckschlager T, Frei E. Int J Cancer. 2007;120:243. doi: 10.1002/ijc.22247. PubMed DOI

Stiborová M, Rupertová M, Frei E. Biochim Biophys Acta. 2011;1814:175. doi: 10.1016/j.bbapap.2010.05.016. PubMed DOI

Stiborová M, Bieler CA, Wiessler M, Frei E. Biochem Pharmacol. 2001;62:1675. doi: 10.1016/S0006-2952(01)00806-1. PubMed DOI

Krais AM, Speksnijder EN, Melis JP, Indra R, Moserova M, Godschalk RW, van Schooten FJ, Seidel A, Kopka K, Schmeiser HH, Stiborova M, Phillips DH, Luijten M, Arlt VM. Arch Toxicol. 2015 PubMed PMC

Refat NA, Ibrahim ZS, Moustafa GG, Sakamoto KQ, Ishizuka M, Fujita S. J Biochem Mol Toxicol. 2008;22:77. doi: 10.1002/jbt.20220. PubMed DOI

Stiborová M, Asfaw B, Anzenbacher P, Hodek P. Cancer Lett. 1988;40:327. doi: 10.1016/0304-3835(88)90092-4. PubMed DOI

Indra R, Moserova M, Kroftova N, Sulc M, Martinkova M, Adam V, Eckschlager T, Kizek R, Arlt VM, Stiborova M. Neuro Endocrinol Lett. 2014;35(Suppl 2):105. PubMed

Lubet RA, Connolly G, Kouri RE, Nebert DW, Bigelow SW. Biochem Pharmacol. 1983;32:3053. doi: 10.1016/0006-2952(83)90248-4. PubMed DOI

Gasiewicz TA, Kende AS, Rucci G, Whitney B, Willey JJ. Biochem Pharmacol. 1996;52:1787. doi: 10.1016/S0006-2952(96)00600-4. PubMed DOI

Chang CY, Puga A. Mol Cell Biol. 1998;18:525. doi: 10.1128/MCB.18.1.525. PubMed DOI PMC

Nebert DW, Dalton TP, Okey AB, Gonzalez FJ. J Biol Chem. 2004;279:23847. doi: 10.1074/jbc.R400004200. PubMed DOI

Endo K, Uno S, Seki T, Ariga T, Kusumi Y, Mitsumata M, Yamada S, Makishima M. Toxicol Appl Pharmacol. 2008;230:135. doi: 10.1016/j.taap.2008.02.009. PubMed DOI

Wiechelman KJ, Braun RD, Fitzpatrick JD. Anal Biochem. 1988;75:231. doi: 10.1016/0003-2697(88)90383-1. PubMed DOI

Arlt VM, Poirier MC, Sykes SE, Kaarthik J, Moserova M, Stiborova M, Wolf R, Henderson CJ, Phillips DH. Toxicol Lett. 2012;213:160. doi: 10.1016/j.toxlet.2012.06.016. PubMed DOI PMC

Moserova M, Kotrbova V, Aimova D, Sulc M, Frei E, Stiborova M. Interdisc Toxicol. 2009;2:239. doi: 10.2478/v10102-009-0024-0. PubMed DOI PMC

Schmeiser HH, Stiborova M, Arlt VM. Methods Mol Biol. 2013;1044:389. doi: 10.1007/978-1-62703-529-3_21. PubMed DOI

Identification of Human Enzymes Oxidizing the Anti-Thyroid-Cancer Drug Vandetanib and Explanation of the High Efficiency of Cytochrome P450 3A4 in its Oxidation

Application of hepatic cytochrome b5/P450 reductase null (HBRN) mice to study the role of cytochrome b5 in the cytochrome P450-mediated bioactivation of the anticancer drug ellipticine

Cytochrome b5 plays a dual role in the reaction cycle of cytochrome P450 3A4 during oxidation of the anticancer drug ellipticine