Organic anion transporting polypeptides expressed in liver and brain mediate uptake of microcystin.
Microcystins are toxins produced by freshwater cyanobacteria. They are cyclic heptapeptides that exhibit hepato- and neurotoxicity. However, the transport systems that mediate uptake of microcystins into hepatocytes and across the blood-brain barrier have not yet been identified. Using the Xenopus laevis oocyte expression system we tested whether members of the organic anion transporting polypeptide superfamily (rodent: Oatps; human: OATPs) are involved in transport of the most common microcystin variant microcystin-LR by measuring uptake of a radiolabeled derivative dihydromicrocystin-LR. Among the tested Oatps/OATPs, rat Oatp1b2, human OATP1B1, human OATP1B3, and human OATP1A2 transported microcystin-LR 2- to 5-fold above water-injected control oocytes. This microcystin-LR transport was inhibited by co-incubation with the known Oatp/OATP substrates taurocholate (TC) and bromosulfophthalein (BSP). Microcystin-LR transport mediated by the human OATPs was further characterized and showed saturability with increasing microcystin-LR concentrations. The apparent K(m) values amounted to 7 +/- 3 microM for OATP1B1, 9 +/- 3 microM for OATP1B3, and 20 +/- 8 microM for OATP1A2. No microcystin-LR transport was observed in oocytes expressing Oatp1a1, Oatp1a4, and OATP2B1. These results may explain some of the observed organ-specific toxicity of microcystin-LR. Oatp1b2, OATP1B1, and OATP1B3 are responsible for microcystin transport into hepatocytes, whereas OATP1A2 mediates microcystin-LR transport across the blood-brain barrier.
Fischer
W J
WJ
Environmental Toxicology, University of Konstanz, D-78457 Konstanz, Germany.
Altheimer
S
S
Cattori
V
V
Meier
P J
PJ
Dietrich
D R
DR
Hagenbuch
B
B
D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000382:microbiology; D005260:Female; D006801:Humans; D008099:Liver / Q000378:metabolism* / Q000382:microbiology; D052998:Microcystins; D027361:Organic Anion Transporters / Q000096:biosynthesis* / Q000502:physiology*; D010456:Peptides, Cyclic / Q000378:metabolism*; D051381:Rats; D014982:Xenopus laevis
D052998:Microcystins; D027361:Organic Anion Transporters; D010456:Peptides, Cyclic; C078588:microcystin