Enhancement of biliary excretion of aflatoxin B(1) and suppression of hepatic ornithine decarboxylase activity by 2-(allylthio)pyrazine in rats.
2-(Allylthio)pyrazine (2-AP), a synthetic pyrazine derivative with an allylsulfur moiety, has protective effects against chemically-induced hepatic toxicity. Previous studies have shown that 2-AP significantly reduces the formation of preneoplastic foci in rats exposed to aflatoxin B(1) (AFB(1)). The present study was designed to determine whether 2-AP could increase the biliary excretion of metabolites of AFB(1) in rats treated with this carcinogen and whether the agent could alter the activity of ornithine decarboxylase (ODC), which is considered to be associated with tumor promotion. Rats were pretreated with 2-AP (p.o.) at a daily dose of 50 mg/kg for 5 consecutive days. AFB(1) (5 mg/kg) was administered intraperitoneally 2 h after the last dose of 2-AP. Amounts of principal AFB(1) metabolites, AFB(1)-glutathione and a glucuronide conjugate secreted in bile juice was increased by 56 and 50%, respectively, after the 2-AP treatment. Levels of radiolabelled AFB(1) covalently bound to calf thymus DNA catalyzed by microsomes obtained from 2-AP-treated rats (10 and 50 mg/kg, for 5 days) were reduced by 47 to 66%. ODC activity in AFB(1)-treated rats was determined by the three-step medium-term hepatocarcinogenesis assay. Rats were treated with 2-AP at the daily doses of 10, 25 and 50 mg/kg for 16 consecutive days. During this period, four repeated doses of AFB(1) (1.0 mg/kg) were given to the animals. Rats were then subjected to two-third partial hepatectomy, followed by administration of phenobarbital. 2-AP inhibited AFB(1)-induced ODC activity by 40 to 66%, as determined at the 44th day. Inhibition of AFB(1)-induced ODC activity by 2-AP in conjunction with acceleration of AFB(1) elimination through metabolic conjugation may contribute to its chemopreventive effects against this carcinogen.
Ha
T G
TG
College of Pharmacy, Seoul National University, San 56-1, Shillim-Dong, Kwanak-Gu, Seoul, South Korea.
Mar
W C
WC
Kim
S G
SG
Surh
Y J
YJ
Kim
N D
ND
D016604:Aflatoxin B1 / Q000378:metabolism / Q000493:pharmacokinetics* / Q000633:toxicity*; D000818:Animals; D001646:Bile / Q000378:metabolism; D001659:Biliary Tract / Q000187:drug effects* / Q000378:metabolism*; D002273:Carcinogens / Q000493:pharmacokinetics / Q000633:toxicity; D002851:Chromatography, High Pressure Liquid; D018736:DNA Adducts / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000201:enzymology*; D008297:Male; D065108:Ornithine Decarboxylase Inhibitors; D011719:Pyrazines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
C104935:2-(allylthio)pyrazine; D002273:Carcinogens; D018736:DNA Adducts; D004791:Enzyme Inhibitors; D065108:Ornithine Decarboxylase Inhibitors; D011719:Pyrazines; C072611:aflatoxin B1-DNA adduct; D016604:Aflatoxin B1; D005978:Glutathione