Journal Article

Enhancement of glutathione <i>S</i>-transferase placental-form positive liver cell foci development by microcystin-LR in aflatoxin B<sub>1</sub>-initiated rats

Masaru Sekijima, Tomoaki Tsutsumi, Toshinori Yoshida, Takanori Harada, Fumio Tashiro, Gang Chen, Shun-Zhang Yu and Yoshio Ueno

in Carcinogenesis

Volume 20, issue 1, pages 161-165
Published in print January 1999 | ISSN: 0143-3334
Published online January 1999 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/20.1.161
Enhancement of glutathione S-transferase placental-form positive liver cell foci development by microcystin-LR in aflatoxin B1-initiated rats

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The objective of this study was to elucidate whether microcystin-LR (MC-LR), a hepatotoxic blue-green algal toxin in drinking water, is carcinogenic or possesses the ability to modulate aflatoxin B1 (AFB1)-induced hepatocarcinogenicity. In a medium-term liver bioassay, male Fischer 344 rats were given a single i.p. injection of diethylnitrosamine (DEN, 200 mg/kg) followed by an i.p. injection of MC-LR for 6 weeks after 2 weeks of DEN treatment. To study the synergism between AFB1 and MC-LR, DEN-treated rats were given an i.p. injection of AFB1 (0.5 mg/kg) dissolved in dimethyl sulfoxide (DMSO) followed by MC-LR at 2 weeks after the treatment. In a separate experiment, the rats were first given AFB1 (0.5 mg/kg) and 2 weeks later an i.p. injection of 1 or 10 μg/kg of MC-LR twice a week for 6 weeks. Most rats were subjected to a two-thirds partial hepatectomy (PH) at week 3 and were killed under anesthesia at week 8. Liver sections were analyzed for glutathione S-transferase placental form (GST-P) expression, and subjected to histopathological examination for phenotypic alteration of hepatocellular foci. In rats that did not receive DEN, MC-LR did not cause a significant increase in the numbers of GST-P-positive foci, whereas AFB1 induced a slight increase in GST-P-positive foci development. In rats given DEN, MC-LR enhanced the expression of GST-P-positive foci, as did AFB1 but no synergism was observed. Histopathological analysis revealed that the area of eosinophilic foci, a biomarker for preneoplastic liver lesion, markedly increased because of MC-LR. In rats given AFB1 as an initiator, treatment with MC-LR resulted in a synergistic increase in the development of GST-P-positive foci. These results suggest that the hepatocarcinogenicities of MC-LR and AFB1 can be predicted in experimental animals with a medium-term bioassay. Furthermore, tumor promoting activity of MC-LR was demonstrated in rats treated with AFB1.

Keywords: ABC, avidin–biotin–peroxidase complex; AFB1 , aflatoxin B1; DEN, diethylnitrosamine; DMSO, dimethyl sulfoxide; ELISA, enzyme-linked immunosorbent assay; GGT, γ-glutamyl transpeptidase; GST-P, glutathione S-transferase placental form; H&E, hematoxylin and eosin; MC-LR, microcystin-LR; PH, partial hepatectomy; PLC, primary liver cancer.

Journal Article.  4141 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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