Heme Oxygenase-1 and Breast Cancer Resistance Protein Protect Against Hemeinduced Toxicity

Author(s): Frank A.D.T.G. Wagener, Anita C.A. Dankers, Frank van Summeren, Alwin Scharstuhl, Jeroen J.M.W. van den Heuvel, Jan B. Koenderink, Sebastiaan W.C. Pennings, Frans G.M. Russel, Rosalinde Masereeuw

Journal Name: Current Pharmaceutical Design

Volume 19 , Issue 15 , 2013

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Heme is the functional group of diverse hemoproteins and crucial for many cellular processes. However, heme is increasingly recognized as a culprit for a wide variety of pathologies, including sepsis, malaria, and kidney failure. Excess of free heme can be detrimental to tissues by mediating oxidative and inflammatory injury. Protective mechanisms against free heme are therefore pivotal for cellular survival. We postulated that overexpression of Heme Oxygenase-1 (HO-1) and Breast Cancer Resistance Protein (BCRP) would protect against heme-induced cytotoxicity. HO-1 is a heme-degrading enzyme generating carbon monoxide, iron, and biliverdin/bilirubin, while BCRP is a heme efflux transporter. Human embryonic kidney cells were transduced using a baculovirus system as a novel strategy to efficiently overexpress HO-1 and BCRP. Exposing cells to heme resulted in a dose-dependent increase in reactive oxygen species formation, DNA damage and cell death. Heme-induced cell death was significantly attenuated when cells overexpressed HO-1, BCRP, or both. The protective effects of HO-1 overexpression were most pronounced, while co-treatment with the HO-activity inhibitor tin mesoporphyrin reversed these protective effects. Also cells treated with the anti-oxidants N-acetylcysteine or HO-effector molecule bilirubin showed protection against heme insults, which may explain the increased protection by HO-1 compared to BCRP. In conclusion, both HO-1 and BCRP protect against heme-induced toxicity and may thus form novel therapeutic targets for heme-mediated pathologies.

Keywords: Heme-HO system, ABC transporter, ABCG2, BCRP, cytotoxicity, reactive oxygen species, DNA damage, redox balance

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Article Details

Year: 2013
Published on: 21 March, 2013
Page: [2698 - 2707]
Pages: 10
DOI: 10.2174/1381612811319150004
Price: $65

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