Journal Article

Inhibition of ebselen on aflatoxin B<sub>1</sub>-induced hepatocarcinogenesis in Fischer 344 rats

Cheng-Feng Yang, Jin Liu, Shanthi Wasser, Han-Ming Shen, Carolyn Eng-Looi Tan and Choon-Nam Ong

in Carcinogenesis

Volume 21, issue 12, pages 2237-2243
Published in print December 2000 | ISSN: 0143-3334
Published online December 2000 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/21.12.2237
Inhibition of ebselen on aflatoxin B1-induced hepatocarcinogenesis in Fischer 344 rats

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Aflatoxin B1 (AFB1), a potent hepatocarcinogen, enhances ROS formation and causes oxidative DNA damage, which may play a role in its carcinogenicity. We have demonstrated recently that ebselen, an organic selenium compound, protects against the cytotoxicity of AFB1 through its antioxidant capability. The present study was designed to investigate the effect of ebselen on AFB1-induced hepatocarcinogenesis in an animal model. Fischer 344 rats were first treated with either deionized water or ebselen (5 mg/kg, 5 days/week) via gavage for 4 weeks, then given AFB1 (0.4 mg/kg, gavage, once a week) or AFB1 plus ebselen (5 mg/kg, 5 days/week) for another 24 weeks. The results showed that the hepatocarcinogenicity of AFB1 in rats was significantly reduced by ebselen treatment as indicated by a decrease in: (i) serum γ-glutamyl transpeptidase activity; (ii) expression of mRNAs of liver α-fetoprotein and the placental form of glutathione S-transferase (GST-P); and (iii) the area and mean density of staining of liver GST-P foci. Ebselen treatment significantly reduced the formation of hepatic AFB1–DNA adducts and 8-hydroxydeoxyguanosine caused by AFB1 exposure. These findings suggest that ebselen can inhibit the carcinogenicity of AFB1. In addition to the reduction of AFB1–DNA adduct formation, the protective effect of ebselen against AFB1-induced oxidative DNA damage may also, at least in part, contribute to its anticarcinogenic property.

Keywords: AFB1, aflatoxin B1; AFB1-FAPY, 2,3-dihydro-2-(N5-formyl-2,5,6-triamino-4-oxopyrimidin-N5-yl-)-3-hydroxy-AFB1; AFBO, AFB1-8,9-epoxide; AFP, α-fetoprotein; ALT, alanine aminotransferase; CYP450, cytochrome P450; DAB, diaminobenzidine; dG, deoxyguanosine; DMSO, dimethylsulfoxide; dNTPs, deoxynucleotide triphosphates; GGT, γ-glutamyl transpeptidase; G3PDH, glyceraldehyde-3-phosphate dehydrogenase; GST-P, glutathione S-transferase, placental form; HCC, hepatocellular carcinoma; 8-OHdG, 8-hydroxydeoxyguanosine; ROS, reactive oxygen species; RT–PCR, reverse transcription–polymerase chain reaction.

Journal Article.  5706 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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