ArticlePharmacogenetics and genomics2012
The G671V variant of MRP1/ABCC1 links doxorubicin-induced acute cardiac toxicity to disposition of the glutathione conjugate of 4-hydroxy-2-trans-nonenal.
Article in Pharmacogenetics and genomics, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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8 citing papers in PubMed, 33 citations in OpenAlex.
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- Systems biology approaches to adverse drug effects: the example of cardio-oncology.Nature reviews. Clinical oncology · 2015Review
- Elevated glutathione is not sufficient to protect against doxorubicin-induced nuclear damage in heart in multidrug resistance-associated protein 1 (Mrp1/Abcc1) null mice.The Journal of pharmacology and experimental therapeutics · 2015Article
- Loss of multidrug resistance-associated protein 1 potentiates chronic doxorubicin-induced cardiac dysfunction in mice.The Journal of pharmacology and experimental therapeutics · 2015Article
- FUsed in sarcoma is a novel regulator of manganese superoxide dismutase gene transcription.Antioxidants & redox signaling · 2014Article
- Genomic profiling reveals the potential role of TCL1A and MDR1 deficiency in chemotherapy-induced cardiotoxicity.International journal of biological sciences · 2013Article
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7 authors at 3 institutions in 1 country.
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Abstract
objectiveDoxorubicin-induced acute cardiotoxicity is associated with the Gly671Val (G671V; rs45511401) variant of multidrug resistance-associated protein 1 (MRP1). Doxorubicin redox cycling causes lipid peroxidation and generation of the reactive electrophile, 4-hydroxy-2-trans-nonenal (HNE). Glutathione forms conjugates with HNE, yielding an MRP1 substrate, GS-HNE, whose intracellular accumulation can cause toxicity.
methodsWe established stable HEK293 cell lines overexpressing wild-type MRP1 (HEKMRP1), G671V (HEKG671V), and R433S (HEKR433S), a variant not associated with doxorubicin-induced cardiotoxicity and investigated the sensitivity of HEKG671V cells to doxorubicin and transport capacity of G671V toward GS-HNE.
resultsIn ATP-dependent transport studies using plasma membrane-derived vesicles, the Vmax (pmol/min/mg) for GS-HNE transport was the lowest for G671V (69±4) and the highest for R433S (972±213) compared with wild-type MRP1 (416±22), whereas the Km values were 2.8±0.4, 6.0 or more, and 1.7±0.2 µmol/l, respectively. In cells, the doxorubicin IC50 (48 h) was not different in HEKMRP1 (463 nmol/l) versus HEKR433S (645 nmol/l), but this parameter was significantly lower in HEKG671V (181 nmol/l). HEKG671V retained significantly (approximately 20%) more, whereas HEKR433S retained significantly less intracellular doxorubicin than HEKMRP1. Similarly, HEKG671V cells treated with 1.5 µmol/l of doxorubicin for 24 h retained significantly more GS-HNE. In cells treated with 0.5 µmol/l of doxorubicin for 48 , glutathione and glutathione disulfide levels and the glutathione/glutathione disulfide ratio were significantly decreased in HEKG671V versus HEKMRP1; these values were similar in HEKR433S versus HEKMRP1.
conclusionThese data suggest that decreased MRP1-dependent GS-HNE efflux contributes to increased doxorubicin toxicity in HEKG671V and potentially in individuals carrying the G671V variant.
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