Oatp-associated uptake and toxicity of microcystins in primary murine whole brain cells

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2009
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Holst, K.
Fischer, Andreas
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Toxicology and Applied Pharmacology. 2009, 234(2), pp. 247-255. ISSN 0041-008X. eISSN 1096-0333. Available under: doi: 10.1016/j.taap.2008.10.011
Zusammenfassung

Microcystins (MCs) are naturally occurring cyclic heptapeptides that exhibit hepato-, nephro- and possibly neurotoxic effects in mammals. Organic anion transporting polypeptides (rodent Oatp/human OATP) appear to be specifically required for active uptake of MCs into hepatocytes and kidney epithelial cells. Based on symptoms of neurotoxicity in MC-intoxicated patients and the presence of Oatp/OATP at the blood-brainbarrier (BBB) and blood-cerebrospinal-f1uid-barrier (BCFB) it is hypothesized that MCs can be transported across the BBB/BCFB in an Oatp/OATP-dependent manner and can induce toxicity in brain cells via inhibition of protein phosphatase (PP). To test these hypotheses. the presence of murine Oatp (rnOatp) in primary murine whole brain cells (mWBC) was invt'stigated at the mRNA and protein level. MC transport was tested by exposing mWBCs to three different MC-congeners (MC-LR, -LW, -LFJ with/without co-incubation with the OATP/Oatp-substrates taurocholate (TC) and bromosulfophthalein (BSP). Uptake of MCs and cytotoxicity was demonstrated via MC-Western blot analysis, immunocytochemistry, cell viability and PP inhibition assays. All MC congeners bound covalently and inhibited mWBC PP. MC-LF was the most cytotoxic congener followed by -LW and -LR. The lowest toxin concentration significantly reducing mWBC viability after 48 h exposure was 400 nM (MC-LF). Uptake of MCs into mWBCs was inhibited via co-incubation with excess TC (50 and 500 pM) and BSP (50 pM). MC-Western blot analys is demonstrated a concentration-dependent accumulation of MCs. In conclusion, the in vieTO data support the assumed MC-congener-dependent uptake in a mOatp-associated manner and cytotoxicity of MCs in primary murine whole brain cells.

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Fachgebiet (DDC)
570 Biowissenschaften, Biologie
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Cyanobacteria, Toxin, Microcystin, Protein phosphatase, Oatp/OATP, Neurotoxicity, Primary whole brain cells
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ISO 690FEURSTEIN, Daniel, K. HOLST, Andreas FISCHER, Daniel R. DIETRICH, 2009. Oatp-associated uptake and toxicity of microcystins in primary murine whole brain cells. In: Toxicology and Applied Pharmacology. 2009, 234(2), pp. 247-255. ISSN 0041-008X. eISSN 1096-0333. Available under: doi: 10.1016/j.taap.2008.10.011
BibTex
@article{Feurstein2009Oatpa-7219,
  year={2009},
  doi={10.1016/j.taap.2008.10.011},
  title={Oatp-associated uptake and toxicity of microcystins in primary murine whole brain cells},
  number={2},
  volume={234},
  issn={0041-008X},
  journal={Toxicology and Applied Pharmacology},
  pages={247--255},
  author={Feurstein, Daniel and Holst, K. and Fischer, Andreas and Dietrich, Daniel R.}
}
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    <dcterms:abstract xml:lang="eng">Microcystins (MCs) are naturally occurring cyclic heptapeptides that exhibit hepato-, nephro- and possibly neurotoxic effects in mammals. Organic anion transporting polypeptides (rodent Oatp/human OATP) appear to be specifically required for active uptake of MCs into hepatocytes and kidney epithelial cells. Based on symptoms of neurotoxicity in MC-intoxicated patients and the presence of Oatp/OATP at the blood-brainbarrier (BBB) and blood-cerebrospinal-f1uid-barrier (BCFB) it is hypothesized that MCs can be transported across the BBB/BCFB in an Oatp/OATP-dependent manner and can induce toxicity in brain cells via inhibition of protein phosphatase (PP). To test these hypotheses. the presence of murine Oatp (rnOatp) in primary murine whole brain cells (mWBC) was invt'stigated at the mRNA and protein level. MC transport was tested by exposing mWBCs to three different MC-congeners (MC-LR, -LW, -LFJ with/without co-incubation with the OATP/Oatp-substrates taurocholate (TC) and bromosulfophthalein (BSP). Uptake of MCs and cytotoxicity was demonstrated via MC-Western blot analysis, immunocytochemistry, cell viability and PP inhibition assays. All MC congeners bound covalently and inhibited mWBC PP. MC-LF was the most cytotoxic congener followed by -LW and -LR. The lowest toxin concentration significantly reducing mWBC viability after 48 h exposure was 400 nM (MC-LF). Uptake of MCs into mWBCs was inhibited via co-incubation with excess TC (50 and 500 pM) and BSP (50 pM). MC-Western blot analys is demonstrated a concentration-dependent accumulation of MCs. In conclusion, the in vieTO data support the assumed MC-congener-dependent uptake in a mOatp-associated manner and cytotoxicity of MCs in primary murine whole brain cells.</dcterms:abstract>
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