The role of organic anion transporting polypeptides (OATPs/SLCOs) in the toxicity of different microcystin congeners in vitro: A comparison of primary human hepatocytes and OATP-transfected HEK293 cells

Journal Article · Sat May 15 04:00:00 EDT 2010 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2010.02.006· OSTI ID:21344943

Fischer, A; Hoeger, S J; Stemmer, K; Feurstein, D J ^[1]; Knobeloch, D ^[2]; Nussler, A ^[3]

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1. Human and Environmental Toxicology, University of Konstanz, Konstanz (Germany)
2. Department of General, Visceral, and Transplant Surgery, Charite Campus Virchow, Berlin (Germany)
3. Technical University Munich, Department of Traumatology, Munich (Germany)

Cellular uptake of microcystins (MCs), a family of cyclic cyanobacterial heptapeptide toxins, occurs via specific organic anion transporting polypeptides (OATPs), where MCs inhibit serine/threonine-specific protein phosphatase (PP). Despite comparable PP-inhibitory capacity, MCs differ greatly in their acute toxicity, thus raising the question whether this discrepancy results from MC-specific toxikokinetic rather than toxicodynamic differences. OATP-mediated uptake of MC congeners MCLR, -RR, -LW and -LF was compared in primary human hepatocytes and HEK293 cells stably expressing recombinant human OATP1B1/SLCO1B1 and OATP1B3/SLCO1B3 in the presence/absence of OATP substrates taurocholate (TC) and bromosulfophthalein (BSP) and measuring PP-inhibition and cytotoxicity. Control vector expressing HEK293 were resistant to MC cytotoxicity, while TC and BSP competition experiments reduced MC cytotoxicity in HEK293-OATP transfectants, thus confirming the requirement of OATPs for trans-membrane transport. Despite comparable PP-inhibiting capabilities, MCLW and -LF elicited cytotoxic effects at lower equimolar concentrations than MCLR and MCRR, hence suggesting congener selective transport into HEK293-OATP transfectants and primary human hepatocytes. Primary human hepatocytes appeared one order of magnitude more sensitive to MC congeners than the corresponding HEK293 -OATP transfectants. Although the latter maybe due to a much lower level of PPs in primary human hepatocytes, the presence of OATPs other than 1B1 or 1B3 may have added to an increased uptake of MCs. In view of the high sensitivity of human hepatocytes and currently MCLR-only based risk calculations, the actual risk of human MC-intoxication and ensuing liver damage could be underestimated in freshwater cyanobacterial blooms where MCLW and-LF predominate.

• OSTI ID: 21344943
• Journal Information: Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Journal Issue: 1 Vol. 245; ISSN TXAPA9; ISSN 0041-008X
• Country of Publication: United States
• Language: English

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60 APPLIED LIFE SCIENCES
AMINO ACIDS
ANIMAL CELLS
ANIMALS
ANIONS
ANTIGENS
AROMATICS
BODY
BROMOSULFOPHTHALEIN
CARBOXYLIC ACID ESTERS
CARBOXYLIC ACIDS
CHARGED PARTICLES
DIGESTIVE SYSTEM
ENZYME INHIBITORS
ESTERS
FRESH WATER
GLANDS
HAZARDOUS MATERIALS
HAZARDS
HYDROGEN COMPOUNDS
HYDROXY ACIDS
HYDROXY COMPOUNDS
IN VITRO
INDICATORS
IONS
LIVER
LIVER CELLS
MALES
MAMMALS
MAN
MATERIALS
MEMBRANE TRANSPORT
MEN
ORGANIC ACIDS
ORGANIC BROMINE COMPOUNDS
ORGANIC COMPOUNDS
ORGANIC HALOGEN COMPOUNDS
ORGANIC SULFUR COMPOUNDS
ORGANS
OXYGEN COMPOUNDS
PEPTIDES
PHENOLS
POLYPEPTIDES
POLYPHENOLS
PRIMATES
PROTEINS
REAGENTS
SENSITIVITY
SERINE
SOMATIC CELLS
SULFONIC ACIDS
THREONINE
TOXIC MATERIALS
TOXICITY
TOXINS
VERTEBRATES
WATER