Enhancement of biliary excretion of aflatoxin B 1 and suppression of hepatic ornithine decarboxylase activity by 2-(allylthio)pyrazine in rats

Abstract

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.