Liver tumor promotion by the cyanobacterial cyclic peptide toxin microcystin-LR

Abstract

Certain waterblooms of toxic cyanobacteria (blue-green algae) are a health threat because of their production of toxic peptides, termed microcystins, which cause liver damage in wild and domesticated animals. The most widely studied microcystin is microcystin-LR, a heptapeptide containing the two L-amino acids, leucine and arginine. The inhibition of protein phosphatase type 1 and type 2A activities by microcystin-LR is similar to that of the known protein phosphatase inhibitor and tumor promoter okadaic acid. We show in this report that microcystin-LR, applied below the acute toxicity level, dose-dependently increases the number and percentage area of positive foci for the placental form of glutathione S-transferase in rat liver, which was initiated with diethylnitrosamine. The result was obtained independently through two animal experiments. This observation indicates that microcystin-LR is a new liver tumor promoter mediated through inhibition of protein phosphatase type 1 and type 2A activities. This provides further evidence that the okadaic acid pathway is a general mechanism of tumor promotion in various organs, such as mouse skin, rat glandular stomach and rat liver.

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

“…To date, more than 90 analogues of MCs have been isolated and identified (Ufelmann et al 2012), among which MC-LR is one of the most common and toxic variants (Gupta et al 2003). MCs are known to be potent hepatotoxins (Dawson 1998) and tumor promoter (Nishiwakimatsushima et al 1992), leading to serious liver damage through inhibition of the serine/threonine protein phosphatases 1 and 2A (PP1 and PP2A) (MacKintosh et al 1990;Fischer et al 2010) and induction of intracellular reactive oxygen species (ROS) production (Ding et al 1998). Consequently, MCs pose potential threats to both aquatic animals (Chen and Xie 2005;Malbrouck and Kestemont 2006) and mammals (Wang et al 2008), as well as to humans (Azevedo et al 2002).…”

Bioaccumulation of microcystins (MCs) in four fish species from Lake Taihu, China: Assessment of risks to humans

“…MCs are potent hepatotoxins (Carmichael, 1992;Dawson, 1998) and promoters of tumour growth (Nishiwakimatsushima et al, 1992). They inhibit eukaryotic protein phosphatase types 1 and 2A, resulting in the excessive phosphorylation of cytoskeletal filaments, which ultimately leads to liver failure, and MCs have also been implicated in the deaths of birds, wild animals, livestock and fish (Carmichael, 1994;Kaebernick and Neilan, 2001).…”

Quantitatively evaluating detoxification of the hepatotoxic microcystins through the glutathione and cysteine pathway in the cyanobacteria-eating bighead carp

“…To date, more than 90 analogues of MCs have been identified (Ufelmann et al, 2012), among which MC-LR (leucine arginine), and RR (arginine arginine) are the most common variants (Gupta et al, 2003). It is well known that MCs are tumor promoter (MacKintosh et al, 1990), due to their abilities of strong inhibition of protein phosphatase 1 and 2A (MacKintosh et al, 1990;Matsushima et al, 1990;Nishiwaki-Matsushima et al, 1992;Yoshizawa et al, 1990). The high incidence of primary liver cancer in eastern China is considered to be related to the presence of MCs in drinking water .…”