2-(Allylthio)pyrazine inhibition of aflatoxin B1-induced hepatocarcinogenesis in rats.
2-(Allylthio)pyrazine (2-AP), a synthetic pyrazine derivative with an allylsulfur moiety, has hepatoprotective effects against toxicants. Effect of 2-AP on hepatic tumorigenesis in association with glutathione S-transferase (GST) induction was examined in rats exposed to aflatoxin B1 (AFB1). Both AFB1-DNA adduct formation in the liver and urinary elimination of 8,9-dihydro-8-(N7-guanyl)-9-hydroxy-aflatoxin B1 (AFB1-N7-guanine) adduct were also determined. Male Sprague Dawley rats were treated with 2-AP at the daily oral doses of 10, 25 and 50 mg/kg for 16 consecutive days, during which four repeated doses of AFB1 (1.0 mg/kg) were given to the animals. Rats were then subjected to two-thirds of hepatectomy, followed by administration of phenobarbital (PB). Focal areas of hepatocellular alteration were identified after 44 days and preneoplastic foci expressing the placental form of glutathione S-transferase P (GST-P) were quantified by immunostaining of liver sections. 2-AP reduced the volume of liver occupied by GST-P foci by 65-96%. Under these experimental conditions, 2-AP treatment resulted in significant elevations in GST activity in the liver. Levels of radiolabeled AFB1 covalently bound to hepatic DNA, RNA and proteins were significantly reduced in rats treated with 2-AP for 5 days. 2-AP pretreatment also caused a 45% reduction in the urinary elimination of AFB1-N7-guanine adduct over the 24-h postdosing period. The present findings demonstrated that 2-AP exhibited protective effects against AFB1-induced hepatocarcinogenesis in rats with a marked decrease in the level of AFB1-DNA adduct. Reduction of hepatic DNA adducts might result from elevations of activity of GST, which catalyzes detoxification of the carcinogen.
Ha
T G
TG
College of Pharmacy, Seoul National University, South Korea.
Jang
J J
JJ
Kim
S G
SG
Kim
N D
ND
D016604:Aflatoxin B1 / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D015197:Carcinogenicity Tests; D018736:DNA Adducts / Q000187:drug effects / Q000652:urine; D004273:DNA, Neoplasm / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005982:Glutathione Transferase / Q000378:metabolism; D006498:Hepatectomy; D007124:Immunoenzyme Techniques; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000201:enzymology / Q000517:prevention & control*; D008297:Male; D010634:Phenobarbital / Q000494:pharmacology; D011230:Precancerous Conditions / Q000201:enzymology / Q000473:pathology; D011719:Pyrazines / Q000494:pharmacology*; D012313:RNA / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
C104935:2-(allylthio)pyrazine; D018736:DNA Adducts; D004273:DNA, Neoplasm; D004791:Enzyme Inhibitors; D011719:Pyrazines; D012313:RNA; D016604:Aflatoxin B1; D005982:Glutathione Transferase; D010634:Phenobarbital