Preferences help
enabled [disable] Abstract
Number of results
2008 | 55 | 2 | 329-337
Article title

Induction of the multixenobiotic/multidrug resistance system in various cell lines in response to perfluorinated carboxylic acids

Title variants
Languages of publication
The multixenobiotic resistance (closely related to multidrug resistance) system controls transport across the plasma membrane as a defense against toxic molecules. Multixenobiotic resistance system consists of an efflux pump, ABCB1 (also named P-glycoprotein, P-gp), and/or a molecule of the ABCC family (also named multiple resistance associated protein, MRP). ABCB1 is able to increase efflux of many low-molecular foreign molecules. Measuring system induction may be used as a biomarker of cell/organism exposure to foreign substances. Various established cell lines were tested for constitutive and induced multixenobiotic resistance proteins by Western blotting immunodetection. The pumping function was indirectly assayed with Rhodamine B by visualization of cell fluorescence in the presence of verapamil. Changes in ABC proteins were measured by flow cytometry after exposition to various perfluorinated carboxylic acids. MCF7 and HeLa cells were found to contain the highest constitutive level of both ABCB1 and ABCC1. HEK293 exhibited much less ABCB1 and no activity of pumping out Rhodamine B. The pumping activity was found to be related to the amount of the cell-type specific 170 kDa ABCB1 protein. An 8-day exposure to 10-4 M perfluorononanoic acid resulted in about 2-2.5-fold increase of ABCB1 level. That was confirmed also for short times by flow cytometry of cells exposed to perfluorinated acids and its natural congeners. Both ABCB1- and ABCC1-related fluorescence increased along with the carbon chain in acids from C6 up to C9 and decreased for C10. Measuring of multixenobiotic resistance changes in vitro induced by chemicals may be a convenient test for screening for their potential toxicity.
Physical description
  • Department of Molecular Enzymology, Intercollegiate Faculty of Biotechnology UG-MUG, Medical University of Gdańsk, Gdańsk, Poland
  • Department of Molecular Enzymology, Intercollegiate Faculty of Biotechnology UG-MUG, Medical University of Gdańsk, Gdańsk, Poland
  • Achard M, Baudrimont M, Boudou A, Bourdineaud JP (2004) Induction of a multixenobiotic resistance protein (MXR) in the Asiatic clam Corbicula fluminea after heavy metals exposure. Aquat Toxicol 67: 347-357.
  • Brooke D, Footitt A, Nwaogu TA (2004) Environmental Risk Evaluation Report: Perfluorooctanesulphonate (PFOS), Environment Agency, UK.
  • Chaudhary PM, Roninson IB (1993) Induction of multidrug resistance in human cells by transient exposure to different chemotherapeutic drugs. J Natl Cancer Inst 85: 632-639.
  • Chin KV, Tanaka S, Darlington G, Pastan I, Gottesman MM (1990) Heat shock and arsenite increase expression of the multidrug resistance (MDR1) gene in human renal carcinoma cells. J Biol Chem 265: 221-226.
  • Cornwall R, Toomey BH, Bard S, Bacon C, Jarman WM, Epel D (1995) Characterization of multixenobiotic/multidrug transport in the gills of the mussel Mytilus californianus and identification of environmental substrates. Aquat Toxicol 31: 277-296.
  • Endicott JA, Ling V (1989) The biochemistry of P-glycoprotein-mediated multidrug resistance. Annu Rev Biochem 58: 137-171.
  • Epel D (1998) Use of multidrug transporters as first lines of defense against toxins in aquatic organisms. Comp Biochem Physiol A 120: 23-28.
  • Eufemia NA, Epel D (1998) The multixenobiotic defense mechanism in mussels is induced by substrates and non-substrates: implications for a general stress response. Mar Environ Res 46: 401-405.
  • Eufemia NA, Epel D (2000) Induction of the multixenobiotic defense mechanism (MXR), P-glycoprotein, in the mussel Mytilus californianus as a general cellular response to environmental stresses. Aquat Toxicol 49: 89-100.
  • Ferte J (2000) Analysis of the tangled relationships between P-glycoprotein-mediated multidrug resistance and the lipid phase of the cell membrane. Eur J Biochem 267: 277-294.
  • Galgani F, Cornwall R, Toomey BH, Epel D (1996) Interaction of environmental xenobiotics with a multixenobiotic defense mechanism in the bay mussel Mytilus galloprovincialis from the coast of California. Environ Toxicol Chem 15: 325-331.
  • Gottesman MM, Pastan I (1993) Biochemistry of multidrug resistance mediated by multidrug transporter. Annu Rev Biochem 62: 385-427.
  • Guruge KS, Yeung LW, Yamanaka N, Miyazaki S, Lam PK, Giesy JP, Jones PD, Yamashita N (2006) Gene expression profiles in rat liver treated with perfluorooctanoic acid (PFOA). Toxicol Sci 89: 93-107.
  • Jette L, Pouliot JF, Murphy GF, Béliveau R (1995) Isoform I (mdr3) is the major form of P-glycoprotein expressed in mouse brain capillaries. Evidence for cross-reactivity of antibody C219 with an unrelated protein. Biochem J 305: 761-766.
  • Juliano RL, Ling V (1976) A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants. Biochim Biophys Acta 455: 152-162.
  • Kleszczynski K, Gardzielewski P, Mulkiewicz E, Stepnowski P, Skladanowski AC (2007) Analysis of structure-cytotoxicity in vitro relationship (SAR) for perfluorinated carboxylic acids. Toxicol in Vitro 21: 1206-1211.
  • Kurelec B (1992) The multixenobiotic resistance mechanism in aquatic organisms. Crit Rev Toxicol 22: 23-43.
  • Kurelec B (1997) A new type of hazardous chemical: the chemosensitizers of multixenobiotic resistance. Environ Health Perspect 105: 855-860.
  • Kurelec B, Pivčevic B (1989) Distinct glutathione-dependent enzyme activities and a verapamil-sensitive binding of xenobiotics in a fresh-water mussel Anodonta cygnea. Biochem Biophys Res Commun 164: 934-940.
  • Kurelec B, Pivčevic B (1991) Evidence for a multixenobiotic resistance mechanism in the mussel Mytilus galloprovincalis. Aquat Toxicol 19: 291-302.
  • Kurelec B, Krča S, Pivčevic B, Ugarkovic D, Bachmann M, Imsiecke G, Müller WE (1992) Expression of P-glycoprotein gene in marine sponges. Identification and characterization of the 125 kDa drug-binding glycoprotein. Carcinogenesis 13: 69-76.
  • Kurelec B, Krča S, Lucic D (1996) Expression of multixenobiotic resistance mechanism in a marine mussel Mytilus galloprovincialis as a biomarker of exposure to polluted environments. Comp Biochem Physiol C 113: 283-289.
  • Kurelec B, Smital T, Pivčevic B, Eufemia N, Epel D (2000) Multixenobiotic resistance, P-glycoprotein and chemosensitizers. Ecotoxicol 9: 307-327.
  • Laemmli UK (1970) Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227: 680-685.
  • Lau C, Thibodeaux JR, Hanson RG, Narotsky MG, Rogers JM, Lindstrom AB, Strynar MJ (2006) Effects of perfluorooctanoic acid exposure during pregnancy in the mouse. Toxicol Sci 90: 510-518.
  • Minier C, Akcha F, Galgani F (1993) P-glycoprotein expression in Crassostrea gigas and Mytilus edulis in polluted seawater. Comp Biochem Physiol B 106: 1029-1036.
  • Minier C, Moore MN (1996) Rhodamine B accumulation and MXR protein expression in mussel blood cells: Effects of exposure to vincristine. Mar Ecol Prog Ser 142: 165-173.
  • Rosenberg MF, Mao Q, Holzenburg A, Ford RC, Deeley RG, Cole SP (2001) The structure of the multidrug resistance protein 1 (MRP1/ABCC1). Crystallization and single-particle analysis. J Biol Chem 276: 16076-16082.
  • Smital T, Kurelec B (1997) Inhibitors of the multixenobiotic resistance mechanism in natural waters: in vivo demonstration of their effects. Environ Toxicol Chem 16: 2164-2170.
  • Toomey BH, Epel D (1993) Multixenobiotic resistance in Urechis caupo embryos: protection from environmental toxins. Biol Bull 185: 355-364.
  • Tsuruo T, Iida H, Tsukagoshi S, Sakurai Y (1981) Overcoming of vincristine resistance in P388 leukemia in vivo and in vitro through enhanced cytotoxicity of vincristine and vinblastine by verapamil. Cancer Res 41: 1967-1972.
  • Uchiumi T, Kohno K, Tanimura H, Matsuo K, Sato S, Uchida Y, Kuwano M (1993) Enhanced expression of the human multidrug resistance 1 gene in response to UV light irradiation. Cell Growth Differ 4: 147-157.
  • Vilaboa NE, Galan A, Troyano A, de Blas E, Aller P (2000) Regulation of multidrug resistance 1 (MDR1)/ P-glycoprotein gene expression and activity by heat-shock transcription factor 1 (HSF1). J Biol Chem 275: 24970-24976.
  • Waldmann P, Pivčevic B, Müller WE, Zahn RK, Kurelec B (1995) Increased genotoxicity of acetylaminofluorene by modulators of multixenobiotic resistance mechanism: studies with the fresh water clam Corbicula fluminea. Mutat Res 342: 113-123.
Document Type
Publication order reference
YADDA identifier
JavaScript is turned off in your web browser. Turn it on to take full advantage of this site, then refresh the page.