Liver tumor promotion by the cyanobacterial cyclic peptide toxin microcystin-LR.
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.
Nishiwaki-Matsushima
R
R
Cancer Prevention Division, National Cancer Center Research Institute, Tokyo, Japan.
Ohta
T
T
Nishiwaki
S
S
Suganuma
M
M
Kohyama
K
K
Ishikawa
T
T
Carmichael
W W
WW
Fujiki
H
H
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D014408:Biomarkers, Tumor / Q000032:analysis; D000458:Cyanobacteria; D004052:Diethylnitrosamine / Q000633:toxicity; D005982:Glutathione Transferase / Q000032:analysis; D008113:Liver Neoplasms / Q000139:chemically induced* / Q000201:enzymology / Q000473:pathology; D008297:Male; D008387:Marine Toxins / Q000633:toxicity*; D052998:Microcystins; D010456:Peptides, Cyclic / Q000633:toxicity*; D010634:Phenobarbital / Q000633:toxicity; D051381:Rats; D011916:Rats, Inbred F344
D014408:Biomarkers, Tumor; D008387:Marine Toxins; D052998:Microcystins; D010456:Peptides, Cyclic; D004052:Diethylnitrosamine; D005982:Glutathione Transferase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; C057862:cyanoginosin LR; D010634:Phenobarbital