nodularin and Cell-Transformation--Neoplastic

Nodularins are an important class of hepatotoxic cyclic pentapeptides that are produced by the cyanobacteria Nodularia spumigena. These peptides have been found worldwide and have been implicated in the deaths of animals as well as a potent cyanotoxin in humans. To date, approximately 10 variants have been discovered, among which nodularin-R is the most abundant. Though the mechanisms of their potential hepatotoxicity and carcinogenicity are not well understood, the most frequently proposed mechanisms are described here. Most importantly, a comprehensive review of nodularins in poisoning is presented, including their bioaccumulation in water, cyanobacterial blooms and aquatic animals, the IC50, LC50 and LD50 values determined in laboratories, and wild, domestic and laboratory animal cases. However, the hazard of these toxins to humans has not been fully elucidated, predominantly due to the lack of exposure data. One of reasons underlying is that most current methods are ill suited for clinical monitoring. Thus, the available assays for the detection and quantification of nodularins are described with an emphasis on the problems encountered with each assay. Our ultimate aim is to demonstrate the urgency of better understanding the toxicity of nodularins, especially in humans, and thus effectively protecting ourselves from their poisoning.

Topics: Algal Proteins; Animals; Biological Assay; Carcinogens; Cell Transformation, Neoplastic; Cytotoxins; Harmful Algal Bloom; Hepatocytes; Humans; Lethal Dose 50; Liver; Nodularia; Oxidative Stress; Peptides, Cyclic; Phosphoprotein Phosphatases

Microcystin-LR and nodularin, along with okadaic acid, are potent inhibitors of protein phosphatases 1 and 2A (PP1 and PP2A). The mechanisms of action of microcystin-LR and nodularin in the liver and that of okadaic acid, a potent tumor promoter on mouse skin, have attracted the attention of the scientists. This paper reviews several topics: new inhibitors of PP1 and PP2A with new chemical structures, structure-function relationships for both receptor binding and inhibition of protein phosphatases, the crystal structure of PP1 or PP2A-toxin complex, induction of gene expression and apoptosis. These subjects were studied by using in vitro and in vivo experimental systems. Two-stage carcinogenesis experiments with microcystin-LR and nodularin for the first time demonstrated that microcystin-LR is a new tumor promoter in rat liver initiated with diethylnitrosamine (DEN), and that nodularin is a potent tumor promoter associated with weak initiating activity in rat liver initiated with DEN. A working group of WHO (IARC) concluded that microcystin-LR is "possibly carcinogenic to humans" and that nodularin is "not classifiable as to carcinogenicity". Our studies revealed that chemical tumor promoters are inducers of TNF-α in the cells of target tissues and that TNF-α is an endogenous tumor promoter. This advance in carcinogenesis made it possible to look for the link between chemical tumor promoters and endogenous tumor promoters, such as TNF-α and IL-1. The carcinogenic features of TNF-α are described in this review, and the TNF-α inducing protein (Tipα) of Helicobacter pylori genome is presented as an example of a tumor promoter of human stomach cancer development.

Topics: Animals; Carcinogens; Cell Transformation, Neoplastic; Humans; Marine Toxins; Microcystins; Neoplasms; Okadaic Acid; Peptides, Cyclic; Protein Tyrosine Phosphatases; Structure-Activity Relationship; Tumor Necrosis Factor-alpha

To assess the combinative role of aflatoxin B1(AFB1), cyanobacterial toxins (cyanotoxins), and hepatitis B virus (HBV) x gene in hepatotumorigenicity.. One-week-old animals carrying HBV x gene and their wild-type littermates were intraperitoneally (ip) injected with either single-dose AFB1 [6 mg/kg body weight (bw)], repeated-dose cyanotoxins (microcystin-LR or nodularin, 10 microg/kg bw once a week for 15 wk), DMSO (vehicle control) alone, or AFB1 followed by cyanotoxins a week later, and were sacrificed at 24 and 52 wk post-treatment.. AFB1 induced liver tumors in 13 of 29 (44.8%) transgenic mice at 52 wk post-treatment, significantly more frequent than in wild-type mice (13.3%). This significant difference was not shown in the 24-wk study. Compared with AFB1 exposure alone, MC-LR and nodularin yielded approximately 3-fold and 6-fold increases in the incidence of AFB(1)-induced liver tumors in wild-type animals at 24 wk, respectively. HBV x gene did not further elevate the risk associated with co-exposure to AFB1 and cyanotoxins. With the exception of an MC-LR-dosed wild-type mouse, no liver tumor was observed in mice treated with cyanotoxins alone at 24 wk. Neither DMSO-treated transgenic mice nor their wild-type littermates had pathologic alterations relevant to hepatotumorigenesis in even up to 52 wk.. HBV x gene and nodularin promote the development of AFB(1)-induced liver tumors. Co-exposure to AFB1 and MC-LR tends to elevate the risk of liver tumors at 24 wk relative to exposure to one of them. The combinative effect of AFB1, cyanotoxins and HBVx on hepatotumorigenesis is weak at 24 wk.

Topics: Aflatoxin B1; Animals; Bacterial Toxins; Carcinoma, Hepatocellular; Cell Transformation, Neoplastic; Cyanobacteria Toxins; Dose-Response Relationship, Drug; Drug Synergism; Liver Neoplasms; Male; Marine Toxins; Mice; Mice, Transgenic; Microcystins; Peptides, Cyclic; Poisons; Polymerase Chain Reaction; Time Factors; Trans-Activators; Viral Regulatory and Accessory Proteins