Molecular Aspects of Microcystin-induced Hepatotoxicity and Hepatocarcinogenesis

Abstract

It is known that microcystin (MC) is a cyanotoxin that is a potent environmental inhibitor of eucariotic protein serine/threonine phosphatase 1 and 2A, both in vitro and in vivo. Consequently, these cyanobacterial toxins (MC–IARC group 2B carcinogen, MC extracts–group 3) are potent tumor promoters and there is an indication that they may also act as tumor initiators. The ability of microcystin-LR (MC-LR) to act as a tumor initiator is based on fact that it can induce DNA damage either by direct interaction with DNA or by indirect mechanisms through formation of reactive oxygen species (ROS). Both acute and chronic exposures, to either low or high doses of MC-LR, can activate apoptotic pathways. Chronic exposure to low concentrations of MC-LR contributes to increased risk for cancer development. Epidemiological studies, in certain areas of China, have suggested that MC is one of the risk factors for the high incidence of primary liver cancer (PLC). Recently, we have reported a correlation between PLC and cyanobacterial “blooms” in reservoirs used as a source for drinking water supply in central Serbia. It appears that the combination of acute and chronic exposures to both high and low doses of MC can lead to PLC initiation and promotion. Based on this, we propose that the requirement for the co-factors such as aflatoxin B1 and other mycotoxins, HBV, HCV, alcohol, etc. is not needed for initiation and promotion of PLC by MC-LR as was suggested earlier. The possible mechanisms of the genotoxicity of MC and its role as a hepatocarcinogen are outlined in this review. Furthermore, we show that the exposure of hepatocytes to MC can lead either to malignant proliferation or apoptosis.

Keywords:

• microcystin-LR
• cyanotoxins
• DNA damage
• hepatotoxicity
• apoptosis
• hepatocarcinogenesis
• PLC

ACKNOWLEDGEMENTS

The authors would like to acknowledge the funding of the Ministry of Science and Environmental protection of the Serbian Government (project number: 146021B). We would like to thank Emily Broderick for editing our English.

MC-LR , Microcystin LR; PLC , primary liver cancer; PP-1 , protein phosphatase-1; PP-1c , catalytic subunit of PP-1; PP-2A , protein phosphatase 2A; MAPK , mitogen activated protein kinase; MEK , mitogen activated protein kinase; ERK , extracellular signal-regulated protein kinase; PKC , protein kinase C; DAG , diacyl glycerol; ROS , reactive oxygen species; OA , okadaic acid; OATP , organic anion transporting polypeptide; CDK , cyclin dependent kinase; cyt - c , cytochrome C; JNK , c-jun N-terminal kinase; Bcl-2 , B cell lymphoma 2 gene family (anti-apoptotic member); BID, BAX , pro-apoptotic members of gene family; p53 , tumor supressor gene p53; HBV , Hepatitis Virus B; HCV, Hepatitis Virus C; miRNA , micro RNA; TNF-α , tumor necrosis alpha; IFN-γ , Interferon-γ; IL-1β, -2, -4, -6, -10 , Interleukin-1β, -2, -4, -6, -10; GM-CSF , granulocyte-macrophage colony-stimulating factor.

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