Inhibition of ebselen on aflatoxin B(1)-induced hepatocarcinogenesis in Fischer 344 rats.
Aflatoxin B(1) (AFB(1)), 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 AFB(1) through its antioxidant capability. The present study was designed to investigate the effect of ebselen on AFB(1)-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 AFB(1) (0.4 mg/kg, gavage, once a week) or AFB(1) plus ebselen (5 mg/kg, 5 days/week) for another 24 weeks. The results showed that the hepatocarcinogenicity of AFB(1) in rats was significantly reduced by ebselen treatment as indicated by a decrease in: (i) serum gamma-glutamyl transpeptidase activity; (ii) expression of mRNAs of liver alpha-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 AFB(1)-DNA adducts and 8-hydroxydeoxyguanosine caused by AFB(1) exposure. These findings suggest that ebselen can inhibit the carcinogenicity of AFB(1). In addition to the reduction of AFB(1)-DNA adduct formation, the protective effect of ebselen against AFB(1)-induced oxidative DNA damage may also, at least in part, contribute to its anticarcinogenic property.
Yang
C F
CF
Department of Community, Occupational and Family Medicine, National University of Singapore.
Liu
J
J
Wasser
S
S
Shen
H M
HM
Tan
C E
CE
Ong
C N
CN
D000080242:8-Hydroxy-2'-Deoxyguanosine; D016604:Aflatoxin B1 / Q000032:analysis / Q000633:toxicity*; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology*; D001393:Azoles / Q000494:pharmacology*; D018736:DNA Adducts / Q000032:analysis; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000032:analysis; D005982:Glutathione Transferase / Q000235:genetics; D007527:Isoenzymes / Q000235:genetics; D054833:Isoindoles; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D016566:Organoselenium Compounds / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D011916:Rats, Inbred F344; D017382:Reactive Oxygen Species / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D000509:alpha-Fetoproteins / Q000235:genetics; D005723:gamma-Glutamyltransferase / Q000097:blood
D016588:Anticarcinogenic Agents; D000975:Antioxidants; D001393:Azoles; D018736:DNA Adducts; D007527:Isoenzymes; D054833:Isoindoles; D016566:Organoselenium Compounds; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; C072611:aflatoxin B1-DNA adduct; D000509:alpha-Fetoproteins; C042986:ebselen; D000080242:8-Hydroxy-2'-Deoxyguanosine; D016604:Aflatoxin B1; D005723:gamma-Glutamyltransferase; D005982:Glutathione Transferase; D003849:Deoxyguanosine