Hepatotoxicity of microcystin-LR in fed and fasted rats

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

doi:10.1016/0041-0101(91)90287-2

Cited by 48 publications

(32 citation statements)

References 27 publications

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“…As previously observed in rats (19), mice (9) and fish (15), the present study reports damage to the liver in MCLRtreated rats. γ-GTP = gamma-glutamyl transpeptidase; LDH = lactate dehydrogenase; BUN = blood urea nitrogen; MDA = malondialdehyde.…”

Section: Discussionsupporting

confidence: 89%

“…Furthermore, there are also interspecies differences in the susceptibility to the acute effects of the toxin (16). Previous studies in rats have shown that the LD50 (25 hr, intraperitoneal injection) for MCLR was 122 µg/Kg body weight (19).…”

mentioning

confidence: 96%

“…There are a lot of different analogues of MCs, being microcystin-LR (MCLR), in acute terms, one of the most potent MCs. This microcystin is a potent hepatotoxin that accumulates in the liver, disrupting sinusoidal endothelial cells and causing hemorrhagic shock and rapid death in mice (17), rats (19), and fish (15). In addition, previous studies have showed that exposure to MCLR may cause renal toxic effects, including histopathological changes and modifications in the kidney functional parameters in rats (20) and fish (15).…”

mentioning

confidence: 99%

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Influence of Microcystin-LR on the activity of membrane enzymes in rat intestinal mucosa

Moreno

Mate

Repetto

et al. 2003

J. Physiol. Biochem.

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I. M. MORENO, A. MATE, G. REPETTO, C. M. VÁZQUEZ and A. M. CAMEÁN. Influence of Microcystin-LR on the activity of membrane enzymes in ratintestinal mucosa. J. Physiol. Biochem., 59 (4), [293][294][295][296][297][298][299][300] 2003.The objective of the present study was to evaluate the effects of microcystin-LR (MCLR) on the activity of membrane enzymes from intestinal mucosa. In addition, serum chemistry and peroxidative status of both serum and intestinal homogenate were evaluated after treatment with MCLR. Wistar rats were treated with intraperitoneal injection of either 100 µg pure MCLR/Kg body weight or saline solution. A significant increase in liver weight and altered serum enzyme activities were found in MCLR-treated rats, indicating damage to the liver in these rats, as previously suggested. A higher specific activity of sucrase (1.5-fold) was observed after the administration of MCLR, whereas other intestinal apical membrane enzymes, such as lactase, maltase and alkaline phosphatase were not modified by the treatment. The specific activities of acid phosphatase and succinate dehydrogenase, markers for lysosomal and mitochondrial membranes, respectively, were also increased (32% and 60%, respectively) in treated rats. The analysis of lipid peroxidation showed that the peroxidative status was increased in both serum and intestinal mucosa from MCLRtreated rats, reflecting an excess production of oxygen free radicals induced by this cyanobacterial toxin. In conclusion, this study shows that acute exposure to MCLR affects the intestinal physiology by modifying the intestinal peroxidation status as well as the activity of membrane enzymes.

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Section: Discussionsupporting

confidence: 89%

mentioning

confidence: 96%

mentioning

confidence: 99%

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Influence of Microcystin-LR on the activity of membrane enzymes in rat intestinal mucosa

Moreno

Mate

Repetto

et al. 2003

J. Physiol. Biochem.

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“…For instance, the median lethal dose (LD 50 ) of MC-LR via intraperitoneal (i.p.) injection is approximately 50-60 μg/kg body weight (BW) in mice (Botes et al 1984;Carmichael et al 1988) and 72 and 122 μg/kg BW for fasted and fed rats (Miura et al 1991), respectively, but increases to 300-550 μg/kg BW in common carp (Cyprinus carpio) (Råbergh et al 1991), to 400-500 μg/ kg BW in rainbow trout (Oncorhynchus mykiss) (Tencalla et al 1994;Kotak et al 1996) and even to 1500 μg/kg BW in perch (Pera fluviatilis) (Ibelings et al 2005). Nevertheless, so far, there is no literature on simultaneous quantification of MC-LR and its two main metabolites and the GSH detoxification dynamics of MCs in mammals, and the role of GSH in the detoxification of MCs in mammals remains largely unknown.…”

Section: Introductionmentioning

confidence: 99%

Quantitatively evaluating detoxification of the hepatotoxic microcystin-LR through the glutathione (GSH) pathway in SD rats

Guo

Chen

et al. 2015

Environ Sci Pollut Res

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Glutathione (GSH) plays crucial roles in antioxidant defense and detoxification metabolism of microcystin-LR (MC-LR). However, the detoxification process of MC-LR in mammals remains largely unknown. This paper, for the first time, quantitatively analyzes MC-LR and its GSH pathway metabolites (MC-LR-GSH and MC-LR-Cys) in the liver of Sprague-Dawley (SD) rat after MC-LR exposure. Rats received intraperitoneal (i.p.) injection of 0.25 and 0.5 lethal dose 50 (LD 50 ) of MC-LR with or without pretreatment of buthionine-(S,R)-sulfoximine (BSO), an inhibitor of GSH synthesis. The contents of MC-LR-GSH were relatively low during the experiment; however, the ratio of MC-LR-Cys to MC-LR reached as high as 6.65 in 0.5 LD 50 group. These results demonstrated that MC-LR-GSH could be converted to MC-LR-Cys efficiently, and this metabolic rule was in agreement with the data of aquatic animals previously reported. MC-LR contents were much higher in BSO+MC-LRtreated groups than in the single MC-LR-treated groups. Moreover, the ratio of MC-LR-Cys to MC-LR decreased significantly after BSO pretreatment, suggesting that the depletion of GSH induced by BSO reduced the detoxification of MCs. Moreover, MC-LR remarkably induced liver damage, and the effects were more pronounced in BSO pretreatment groups. In conclusion, this study verifies the role of GSH in the detoxification of MC-LR and furthers our understanding of the biochemical mechanism for SD rats to counteract toxic cyanobacteria.

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“…Miura et al (1989) have previously demonstrated that liver mitochondria isolated from fasted rats treated with MC-LR showed alterations in appearance which was correlated with a loss of coupled electron transport. Liver mitochondria from toxin treated, fasted rats exhibited complete inhibition of state 3 respiration, while those from toxin-treated, fed rats had ADP/O ratios and respiratory control indices comparable to the control values (Miura et al, 1991).…”

Section: Discussionmentioning

confidence: 66%

Mitochondria a key role in microcystin‐LR kidney intoxication

La-Salete

Oliveira

Palmeira

et al. 2007

J of Applied Toxicology

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Microcystins (MCs) are a group of closely related cyclic heptapeptides produced by a variety of common cyanobacteria. These toxins have been implicated in both human and livestock mortality. Microcystin-LR could affect renal physiology by altering vascular, glomerular and urinary parameters, indicating that MC-LR could act directly on the kidney. The aim of the current work was to examine the effect of MC-LR on mitochondrial oxidative phosphorylation of rat kidney isolated mitochondria.Furthermore, microcystin-LR decreased both state 3 and carbonylcyanide p-trifluoromethoxyphenylhydrazone (FCCP)-uncoupled respiration. The transmembrane potential was strongly depressed by MC-LR in a concentration dependent manner, pointing to an uncoupling effect; however, microcystin-LR did not increase the permeability of the inner mitochondria membrane to protons. Therefore, the transmembrane decrease was a consequence of a strong inhibitory effect on redox complexes. The addition of uncoupling concentrations of MC-LR to Ca 2+ + + + + -loaded mitochondria treated with ruthenium red resulted in mitochondrial permeability transition pore (MPTP) opening, as evidenced by mitochondrial swelling in isosmotic sucrose medium. Mitochondrial swelling in the presence of Ca 2+ + + + + was prevented by cyclosporin A and was drastically inhibited by catalase and dithiothreitol, indicating the participation of mitochondrial generated reactive oxygen species in this process. From this study it can be concluded that the bioenergetic lesion promoted by microcystin-LR seems to be sufficient to explain renal injury.

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Hepatotoxicity of microcystin-LR in fed and fasted rats

Cited by 48 publications

References 27 publications

Influence of Microcystin-LR on the activity of membrane enzymes in rat intestinal mucosa

Influence of Microcystin-LR on the activity of membrane enzymes in rat intestinal mucosa

Quantitatively evaluating detoxification of the hepatotoxic microcystin-LR through the glutathione (GSH) pathway in SD rats

Mitochondria a key role in microcystin‐LR kidney intoxication

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