Polycyclic aromatic hydrocarbons such as benzo[a]pyrene (BaP) can induce cytochrome P450 1A1 (CYP1A1) via a p53-dependent mechanism. The effect of different p53-activating chemotherapeutic drugs on CYP1A1 expression, and the resultant effect on BaP metabolism, was investigated in a panel of isogenic human colorectal HCT116 cells with differing TP53 status. Cells that were TP53(+/+), TP53(+/-) or TP53(-/-) were treated for up to 48 h with 60 μM cisplatin, 50 μM etoposide or 5 μM ellipticine, each of which caused high p53 induction at moderate cytotoxicity (60-80% cell viability). We found that etoposide and ellipticine induced CYP1A1 in TP53(+/+) cells but not in TP53(-/-) cells, demonstrating that the mechanism of CYP1A1 induction is p53-dependent; cisplatin had no such effect. Co-incubation experiments with the drugs and 2.5 μM BaP showed that: (i) etoposide increased CYP1A1 expression in TP53(+/+) cells, and to a lesser extent in TP53(-/-) cells, compared to cells treated with BaP alone; (ii) ellipticine decreased CYP1A1 expression in TP53(+/+) cells in BaP co-incubations; and (iii) cisplatin did not affect BaP-mediated CYP1A1 expression. Further, whereas cisplatin and etoposide had virtually no influence on CYP1A1-catalysed BaP metabolism, ellipticine treatment strongly inhibited BaP bioactivation. Our results indicate that the underlying mechanisms whereby etoposide and ellipticine regulate CYP1A1 expression must be different and may not be linked to p53 activation alone. These results could be relevant for smokers, who are exposed to increased levels of BaP, when prescribing chemotherapeutic drugs. Beside gene-environment interactions, more considerations should be given to potential drug-environment interactions during chemotherapy.

Department of Analytical Environmental and Forensic Sciences MRC PHE Centre for Environment and Health King's College London 150 Stamford Street London SE1 9NH United Kingdom

Department of Analytical Environmental and Forensic Sciences MRC PHE Centre for Environment and Health King's College London 150 Stamford Street London SE1 9NH United Kingdom; NIHR Health Protection Research Unit in Health Impact of Environmental Hazards at King's College London in partnership with Public Health England London 150 Stamford Street London SE1 9NH United Kingdom

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

Zobrazit více v PubMed

Aimova D., Poljakova J., Kotrbova V., Moserova M., Frei E., Arlt V.M., Stiborova M. Ellipticine and benzo(a)pyrene increase their own metabolic activation via modulation of expression and enzymatic activity of cytochromes P450 1A1 and 1A2. Interdiscip. Toxicol. 2008;1:160–168. PubMed PMC

Alexandrov L.B., Ju Y.S., Haase K., Van Loo P., Martincorena I., Nik-Zainal S., Totoki Y., Fujimoto A., Nakagawa H., Shibata T., Campbell P.J., Vineis P., Phillips D.H., Stratton M.R. Mutational signatures associated with tobacco smoking in human cancer. Science. 2016;354:618–622. PubMed PMC

Arlt V.M., Stiborova M., Henderson C.J., Thiemann M., Frei E., Aimova D., Singh R., Gamboa da Costa G., Schmitz O.J., Farmer P.B., Wolf C.R., Phillips D.H. Metabolic activation of benzo[a]pyrene in vitro by hepatic cytochrome P450 contrasts with detoxification in vivo: experiments with hepatic cytochrome P450 reductase null mice. Carcinogenesis. 2008;29:656–665. PubMed

Arlt V.M., Krais A.M., Godschalk R.W., Riffo-Vasquez Y., Mrizova I., Roufosse C.A., Corbin C., Shi Q., Frei E., Stiborova M., van Schooten F.J., Phillips D.H., Spina D. Pulmonary inflammation impacts on CYP1A1-mediated respiratory tract DNA damage induced by the carcinogenic air pollutant benzo[a]pyrene. Toxicol. Sci. 2015;146:213–225. PubMed PMC

Baker S.C., Arlt V.M., Indra R., Joel M., Stiborova M., Eardley I., Ahmad N., Otto W., Burger M., Rubenwolf P., Phillips D.H., Southgate J. Differentiation-associated urothelial cytochrome P450 oxidoreductase predicates the xenobiotic-metabolising activity of luminal muscle-invasive bladder cancers. Mol. Carcinog. 2018 (Epub ahead of print) PubMed PMC

Bragado P., Armesilla A., Silva A., Porras A. Apoptosis by cisplatin requires p53 mediated p38alpha MAPK activation through ROS generation. Apoptosis. 2007;12:1733–1742. PubMed

Dooley T.P., Gadwood R.C., Kilgore K., Thomasco L.M. Development of an in vitro primary screen for skin depigmentation and antimelanoma agents. Skin Pharmacol. 1994;7:188–200. PubMed

Florea A.M., Busselberg D. Cisplatin as an anti-tumor drug: cellular mechanisms of activity, drug resistance and induced side effects. Cancers. 2011;3:1351–1371. PubMed PMC

Freed-Pastor W.A., Prives C. Mutant p53: one name, many proteins. Genes Dev. 2012;26:1268–1286. PubMed PMC

Frei E., Bieler C.A., Arlt V.M., Wiessler M., Stiborova M. Covalent binding of the anticancer drug ellipticine to DNA in V79 cells transfected with human cytochrome P450 enzymes. Biochem. Pharmacol. 2002;64:289–295. PubMed

Goldstein I., Marcel V., Olivier M., Oren M., Rotter V., Hainaut P. Understanding wild-type and mutant p53 activities in human cancer: new landmarks on the way to targeted therapies. Cancer Gene Ther. 2011;18:2–11. PubMed

Goldstein I., Rivlin N., Shoshana O.Y., Ezra O., Madar S., Goldfinger N., Rotter V. Chemotherapeutic agents induce the expression and activity of their clearing enzyme CYP3A4 by activating p53. Carcinogenesis. 2013;34:190–198. PubMed

Hagopian G.S., Mills G.B., Khokhar A.R., Bast R.C., Jr., Siddik Z.H. Expression of p53 in cisplatin-resistant ovarian cancer cell lines: modulation with the novel platinum analogue (1R, 2R-diaminocyclohexane)(trans-diacetato)(dichloro)-platinum(IV) Clin. Cancer Res. 1999;5:655–663. PubMed

Hamouchene H., Arlt V.M., Giddings I., Phillips D.H. Influence of cell cycle on responses of MCF-7 cells to benzo[a]pyrene. BMC Genomics. 2011;12:333. PubMed PMC

Hockley S.L., Arlt V.M., Jahnke G., Hartwig A., Giddings I., Phillips D.H. Identification through microarray gene expression analysis of cellular responses to benzo(a)pyrene and its diol-epoxide that are dependent or independent of p53. Carcinogenesis. 2008;29:202–210. PubMed

IARC Some non-heterocyclic polycyclic aromatic hydrocarbons and some related exposures. IARC Monogr. Eval. Carcinog. Risk. Hum. 2010:92. PubMed PMC

Karpinich N.O., Tafani M., Rothman R.J., Russo M.A., Farber J.L. The course of etoposide-induced apoptosis from damage to DNA and p53 activation to mitochondrial release of cytochrome c. J. Biol. Chem. 2002;277:16547–16552. PubMed

Kotrbova V., Mrazova B., Moserova M., Martinek V., Hodek P., Hudecek J., Frei E., Stiborova M. Cytochrome b(5) shifts oxidation of the anticancer drug ellipticine by cytochromes P450 1A1 and 1A2 from its detoxication to activation, thereby modulating its pharmacological efficacy. Biochem. Pharmacol. 2011;82:669–680. PubMed

Krais A.M., Speksnijder E.N., Melis J.P., Indra R., Moserova M., Godschalk R.W., van Schooten F.J., Seidel A., Kopka K., Schmeiser H.H., Stiborova M., Phillips D.H., Luijten M., Arlt V.M. The impact of p53 on DNA damage and metabolic activation of the environmental carcinogen benzo[a]pyrene: effects in Trp53(+/ +), Trp53(+/−) and Trp53(-/-) mice. Arch. Toxicol. 2016;90:839–851. PubMed PMC

Krais A.M., Speksnijder E.N., Melis J.P., Singh R., Caldwell A., Gamboa da Costa G., Luijten M., Phillips D.H., Arlt V.M. Metabolic activation of 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine and DNA adduct formation depends on p53: Studies in Trp53(+/+),Trp53(+/−) and Trp53(-/-) mice. Int. J. Cancer. 2016;138:976–982. PubMed PMC

Kucab J.E., Phillips D.H., Arlt V.M. Linking environmental carcinogen exposure to TP53 mutations in human tumours using the human TP53 knock-in (Hupki) mouse model. FEBS J. 2010;277:2567–2583. PubMed

Kucab J.E., Phillips D.H., Arlt V.M. Metabolic activation of diesel exhaust carcinogens in primary and immortalized human TP53 knock-in (Hupki) mouse embryo fibroblasts. Environ. Mol. Mutagen. 2012;53:207–217. PubMed

Kucab J.E., van Steeg H., Luijten M., Schmeiser H.H., White P.A., Phillips D.H., Arlt V.M. TP53 mutations induced by BPDE in Xpa-WT and Xpa-Null human TP53 knock-in (Hupki) mouse embryo fibroblasts. Mutat. Res. 2015;773:48–62. PubMed PMC

Kumagai T., Suzuki H., Sasaki T., Sakaguchi S., Miyairi S., Yamazoe Y., Nagata K. Polycyclic aromatic hydrocarbons activate CYP3A4 gene transcription through human pregnane X receptor. Drug Metab. Pharmacokinet. 2012;27:200–206. PubMed

Labib S., Williams A., Guo C.H., Leingartner K., Arlt V.M., Schmeiser H.H., Yauk C.L., White P.A., Halappanavar S. Comparative transcriptomic analyses to scrutinize the assumption that genotoxic PAHs exert effects via a common mode of action. Arch. Toxicol. 2016;90:2461–2480. PubMed PMC

Long A.S., Lemieux C.L., Arlt V.M., White P.A. Tissue-specific in vivo genetic toxicity of nine polycyclic aromatic hydrocarbons assessed using the MutaMouse transgenic rodent assay. Toxicol. Appl. Pharmacol. 2016;290:31–42. PubMed PMC

Long A.S., Wills J.W., Krolak D., Guo M., Dertinger S.D., Arlt V.M., White P.A. Benchmark dose analyses of multiple genetic toxicity endpoints permit robust, cross-tissue comparisons of MutaMouse responses to orally delivered benzo[a]pyrene. Arch. Toxicol. 2017 (Epub ahead of print) PubMed PMC

Luch A., Baird W.M. Metabolic activation and detoxification of polycyclic aromatic hydrocrabons. In: Luch A., editor. The Carcinogenic Effects of Polycyclic Aromatic Hydrocarbons. Imperial College Press; London: 2015. pp. 19–96.

Montecucco A., Biamonti G. Cellular response to etoposide treatment. Cancer Lett. 2007;252:9–18. PubMed

Nik-Zainal S., Kucab J.E., Morganella S., Glodzik D., Alexandrov L.B., Arlt V.M., Weninger A., Hollstein M., Stratton M.R., Phillips D.H. The genome as a record of environmental exposure. Mutagenesis. 2015;30:763–770. PubMed PMC

Penning T.M. Human aldo-keto reductases and the metabolic activation of polycyclic aromatic hydrocarbons. Chem. Res. Toxicol. 2014;27:1901–1917. PubMed PMC

Pestell K.E., Hobbs S.M., Titley J.C., Kelland L.R., Walton M.I. Effect of p53 status on sensitivity to platinum complexes in a human ovarian cancer cell line. Mol. Pharmacol. 2000;57:503–511. PubMed

Petros W.P., Younis I.R., Ford J.N., Weed S.A. Effects of tobacco smoking and nicotine on cancer treatment. Pharmacotherapy. 2012;32:920–931. PubMed PMC

Phillips D.H., Arlt V.M. 32P-postlabeling analysis of DNA adducts. Methods Mol. Biol. 2014;1105:127–138. PubMed

Phillips D.H., Venitt S. DNA and protein adducts in human tissues resulting from exposure to tobacco smoke. Int. J. Cancer. 2012;131:2733–2753. PubMed

Phillips D.H. Polycyclic aromatic hydrocarbons in the diet. Mutat. Res. 1999;443:139–147. PubMed

Platt K.L., Oesch F. Efficient synthesis of non-K-region trans-dihydro diols of polycyclic aromatic hydrocarbons from o-quinones and catechols. J. Org. Chem. 1983;48:265–268.

Reed L., Mrizova I., Barta F., Indra R., Moserova M., Kopka K., Schmeiser H.H., Wolf C.R., Henderson C.J., Stiborova M., Phillips D.H., Arlt V.M. Cytochrome b5 impacts on cytochrome P450-mediated metabolism of benzo[a]pyrene and its DNA adduct formation: studies in hepatic cytochrome b5/P450 reductase null (HBRN) mice. Arch. Toxicol. 2018 (Epub ahead of print) PubMed PMC

Siddik Z.H. Cisplatin: mode of cytotoxic action and molecular basis of resistance. Oncogene. 2003;22:7265–7279. PubMed

Simoes M.L., Hockley S.L., Schwerdtle T., Gamboa da Costa G., Schmeiser H.H., Phillips D.H., Arlt V.M. Gene expression profiles modulated by the human carcinogen aristolochic acid I in human cancer cells and their dependence on TP53. Toxicol. Appl. Pharmacol. 2008;232:86–98. PubMed

Stiborova M., Frei E. Ellipticines as DNA-targeted chemotherapeutics. Curr. Med. Chem. 2014;21:575–591. PubMed

Stiborova M., Sejbal J., Borek-Dohalska L., Aimova D., Poljakova J., Forsterova K., Rupertova M., Wiesner J., Hudecek J., Wiessler M., Frei E. The anticancer drug ellipticine forms covalent DNA adducts, mediated by human cytochromes P450, through metabolism to 13-hydroxyellipticine and ellipticine N2-oxide. Cancer Res. 2004;64:8374–8380. PubMed

Stiborova M., Rupertova M., Schmeiser H.H., Frei E. Molecular mechanisms of antineoplastic action of an anticancer drug ellipticine. Biomed. Pap. Med. Fac. Univ. Palacky Olomouc Czech Repub. 2006;150:13–23. PubMed

Stiborova M., Arlt V.M., Henderson C.J., Wolf C.R., Kotrbova V., Moserova M., Hudecek J., Phillips D.H., Frei E. Role of hepatic cytochromes P450 in bioactivation of the anticancer drug ellipticine: studies with the hepatic NADPH:Cytochrome P450 reductase null mouse. Toxicol. Appl. Pharmacol. 2008;226:318–327. PubMed

Stiborova M., Indra R., Moserova M., Cerna V., Rupertova M., Martinek V., Eckschlager T., Kizek R., Frei E. Cytochrome b5 increases cytochrome P450 3A4-mediated activation of anticancer drug ellipticine to 13-hydroxyellipticine whose covalent binding to DNA is elevated by sulfotransferases and N,O-acetyltransferases. Chem. Res. Toxicol. 2012;25:1075–1085. PubMed

Stiborova M., Poljakova J., Martinkova E., Ulrichova J., Simanek V., Dvorak Z., Frei E. Ellipticine oxidation and DNA adduct formation in human hepatocytes is catalyzed by human cytochromes P450 and enhanced by cytochrome b5. Toxicology. 2012;302:233–241. PubMed

Stiborova M., Cerna V., Moserova M., Mrizova I., Arlt V.M., Frei E. The anticancer drug ellipticine activated with cytochrome P450 mediates DNA damage determining its pharmacological efficiencies: studies with rats, Hepatic Cytochrome P450 Reductase Null (HRN) mice and pure enzymes. Int. J. Mol. Sci. 2014;16:284–306. PubMed PMC

Stiborova M., Moserova M., Cerna V., Indra R., Dracinsky M., Sulc M., Henderson C.J., Wolf C.R., Schmeiser H.H., Phillips D.H., Frei E., Arlt V.M. Cytochrome b and epoxide hydrolase contribute to benzo[a]pyrene-DNA adduct formation catalyzed by cytochrome P450 1A1 under low NADPH:P450 oxidoreductase conditions. Toxicology. 2014;318:1–12. PubMed

Stiborova M., Indra R., Moserova M., Frei E., Schmeiser H.H., Kopka K., Phillips D.H., Arlt V.M. NADH: cytochrome b5 reductase and cytochrome b5 can act as sole electron donors to human cytochrome P450 1A1-mediated oxidation and DNA adduct formation by benzo[a]pyrene. Chem. Res. Toxicol. 2016;29:1325–1334. PubMed PMC

Sulc M., Indra R., Moserova M., Schmeiser H.H., Frei E., Arlt V.M., Stiborova M. The impact of individual cytochrome P450 enzymes on oxidative metabolism of benzo[a]pyrene in human livers. Environ. Mol. Mutagen. 2016;57:229–235. PubMed PMC

Sur S., Pagliarini R., Bunz F., Rago C., Diaz L.A., Jr., Kinzler K.W., Vogelstein B., Papadopoulos N. A panel of isogenic human cancer cells suggests a therapeutic approach for cancers with inactivated p53. Proc. Natl. Acad. Sci. U. S. A. 2009;106:3964–3969. PubMed PMC

Wohak L.E., Krais A.M., Kucab J.E., Stertmann J., Ovrebo S., Seidel A., Phillips D.H., Arlt V.M. Carcinogenic polycyclic aromatic hydrocarbons induce CYP1A1 in human cells via a p53-dependent mechanism. Arch. Toxicol. 2016;90:291–304. PubMed PMC

Yagi H., Thakker D.R., Hernandez O., Koreeda M., Jerina D.M. Synthesis and reactions of the highly mutagenic 7,8-diol 9,10-epoxides of the carcinogen benzo[a]pyrene. J. Am. Chem. Soc. 1977;99:1604–1611. PubMed

Yang J., Bogni A., Schuetz E.G., Ratain M., Dolan M.E., McLeod H., Gong L., Thorn C., Relling M.V., Klein T.E., Altman R.B. Etoposide pathway. Pharmacogenet. Genomics. 2009;19:552–553. PubMed PMC

Zamble D.B., Jacks T., Lippard S.J. p53-Dependent and –independent responses to cisplatin in mouse testicular teratocarcinoma cells. Proc. Natl. Acad. Sci. U. S. A. 1998;95:6163–6168. PubMed PMC

Zhuo X., Zheng N., Felix C.A., Blair I.A. Kinetics and regulation of cytochrome P450-mediated etoposide metabolism. Drug Metab. Dispos. 2004;32:993–1000. PubMed

Zuo J., Brewer D.S., Arlt V.M., Cooper C.S., Phillips D.H. Benzo pyrene-induced DNA adducts and gene expression profiles in target and non-target organs for carcinogenesis in mice. BMC Genomics. 2014;15:880. PubMed PMC

The impact of p53 on aristolochic acid I-induced nephrotoxicity and DNA damage in vivo and in vitro

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