Tissue Distribution, Excretion, and Hepatic Biotransformation of Microcystin-LR in Mice

Robinson, Nancy; Pace, J.; Matson, Charles F.; Miura, George A.; Lawrence, Wade B.

doi:10.21236/ada232418

Cited by 81 publications

(89 citation statements)

References 9 publications

(12 reference statements)

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“…In mice given a sublethal dose of microcystin LR (35 Ag/kg), the peak plasma concentration achieved was 428 nmol/L (21) compared with the IC 50 values of 5 and 39 nmol/L for microcystin LR in OATP1B1-and OATP1B3-transfected HeLa cells, respectively (Table 2). In addition, microcystin rapidly accumulates in the liver, with 70% of the total dose accumulating by 30 min after the injection (21). We have shown that the cytotoxic activity of microcystin LR is rapid, and although maximal activity was not seen until 6 h, a 1-h exposure showed significant levels of activity (Fig.…”

Section: Discussionmentioning

confidence: 74%

Potent cytotoxicity of the phosphatase inhibitor microcystin LR and microcystin analogues in OATP1B1- and OATP1B3-expressing HeLa cells

Liu

et al. 2007

Molecular Cancer Therapeutics

147

126

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Microcystins are a family of cyclic peptides that are potent inhibitors of the protein phosphatase families PP1 and PP2A. Only three human proteins are thought to be able to mediate the hepatic uptake of microcystins (the organic anion-transporting polypeptides OATP1B1, OATP1B3, and OATP1A2), and the predominant hepatic expression of these transporters accounts for the liver-specific toxicity of microcystins. A significant obstacle in the study of microcystins as anticancer drugs is the requirement of specific transport proteins for cellular uptake. We report that OATP1B3 mRNA is up-regulated in non -small cell lung cancer tumors in comparison with normal control tissues. This finding led to the exploration of microcystins as potential anticancer agents. We have developed a HeLa cell model with functional OATP1B1 and OATP1B3 activity. Transiently transfected HeLa cells are over 1,000-fold more sensitive to microcystin LR than the vector-transfected control cells, showing that transporter expression imparts marked selectivity for microcystin cytotoxicity. In addition, microcystin analogues showed variable cytotoxicities in the OATP1B1-and OATP1B3-transfected cells, including two analogues with IC 50 values <1 nmol/L. Cytotoxicity of microcystin analogues seems to correlate to the inhibition of PP2A in these cells and induces rapid cell death as seen by chromatin condensation and cell fragmentation. These studies show that microcystin-induced phosphatase inhibition results in potent cytotoxicity when microcystin compounds can gain intracellular access and are a potent novel class of therapeutic agents for tumors expressing these uptake proteins. [Mol Cancer Ther 2007;6(2):587 -98]

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Section: Discussionmentioning

confidence: 74%

Potent cytotoxicity of the phosphatase inhibitor microcystin LR and microcystin analogues in OATP1B1- and OATP1B3-expressing HeLa cells

Liu

et al. 2007

Molecular Cancer Therapeutics

147

126

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“…On the contrary, low level of binding in fish plasma would increase the availability of MCs, while reduce metabolism half-life through transformation and excretion. It is generally acknowledged that liver is the primary target organ of MCs (Dawson 1998;Robinson et al 1991). Acute toxicity test using tritium-labeled MCs proved that the combination of mammals' liver to MCs were more effective than that of fish (Brooks and Codd 1987), while clearances of MCs in either fish liver or whole body were proved to be much faster than mammal (Williams et al 1995;Robinson 1990;Robinson et al 1989).…”

Section: Discussionmentioning

confidence: 99%

Why mammals more susceptible to the hepatotoxic microcystins than fish: evidences from plasma and albumin protein binding through equilibrium dialysis

Zhang

Gao

et al. 2013

Ecotoxicology

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To elucidate the interspecies variation of susceptibility to microcystins (MCs), fresh plasma and purified albumin from six kinds of mammals and fish were used in toxins-substances binding test. Protein contents in the test plasma were analyzed and the binding characteristics to MCs were compared. Two kinds of widely observed MCs, microcystin-LR (MC-LR) and microcystin-RR (MC-RR) were tested and data were collected through the method of equilibrium dialysis. It was found that total plasma protein and albumin content in mammals were nearly two times and four times higher than that in fish, respectively. In the test range of 0-100 lg/mL, binding rates of fish plasma to MCs were considered significant lower (p \ 0.01) than that of mammals. And human plasma demonstrated the highest binding rate in mammals. In all the test species, plasma protein binding rates of MC-RR were significantly higher than MC-LR (p \ 0.01). Besides, binding profiles of albumin were acquired under the protein content of 0.67 mg/mL. Human serum albumin demonstrated the highest affinity to MCs throughout the six species and differences among the other five species were considered not significant (p [ 0.05). From the view of protein binding, it is concluded that both the variation of plasma protein composition and albumin binding characteristic could influence the existing form of MCs in circulation, change MCs utilization, alter MCs half-life and further contribute to the difference of susceptibility between mammals and fish.

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“…Although the main target organ of MCLR is the liver and despite most of the toxin being excreted via biliar route, a small (9%) percentage of the toxin (free or conjugated with GSH and Cys) is also eliminated through the urine (Robinson et al, 1990;Ito et al, 2002). It should be noted that although MCLR metabolites are less toxic than non-metabolized toxin, they still maintain the inhibitory activity of protein phosphatases PP1 and PP2A (Ito et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Microcystin-LR activates the ERK1/2 kinases and stimulates the proliferation of the monkey kidney-derived cell line Vero-E6

Dias

Matos

Pereira

et al. 2010

Toxicology in Vitro

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a b s t r a c tMicrocystin-LR (MCLR) is a peptide produced by freshwater cyanobacteria that induces severe hepatotoxicity in humans and animals. MCLR is also a potent tumour promoter and it has been proposed that this activity is mediated by the inhibition of protein phosphatases PP1/PP2A, possibly through the activation of proto-oncogenes c-jun, c-fos and c-myc. However, the mechanisms underlying MCLR-induced tumour promotion are still largely unknown, particularly in non-liver cells. In previous studies we have demonstrated that micromolar concentrations of MCLR induce cytotoxic effects in the kidney Vero-E6 cell line. The purpose of the present work was to evaluate whether the exposure to subcytotoxic concentrations of MCLR was sufficient to induce the proliferation of Vero-E6 cells. Through BrdU incorporation assay we show that at nanomolar concentrations MCLR stimulates cell cycle progression in Vero-E6 kidney cell line. Moreover, the analysis of mitogen-activated protein kinases p38, JNK and ERK1/2 activity revealed that the proliferative effect of MCLR is associated with the activation of the pro-proliferative ERK1/2 pathway. These results emphasise the importance to confirm in vivo the impact of MCLR on tumour promotion at kidney level.

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Tissue Distribution, Excretion, and Hepatic Biotransformation of Microcystin-LR in Mice

Cited by 81 publications

References 9 publications

Potent cytotoxicity of the phosphatase inhibitor microcystin LR and microcystin analogues in OATP1B1- and OATP1B3-expressing HeLa cells

Potent cytotoxicity of the phosphatase inhibitor microcystin LR and microcystin analogues in OATP1B1- and OATP1B3-expressing HeLa cells

Why mammals more susceptible to the hepatotoxic microcystins than fish: evidences from plasma and albumin protein binding through equilibrium dialysis

Microcystin-LR activates the ERK1/2 kinases and stimulates the proliferation of the monkey kidney-derived cell line Vero-E6

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