Effects of N-nitrosomorpholine and phenobarbital on UDPglucuronyltransferase in putative preneoplastic foci of rat liver

Effects of initiators and promoters of hepatocarcinogenesison UDP-glucuronyltransferase and arylhydrocarbon hydroxylasewere investigated in foci of altered hepatocytes. A single admhktrationof N-nitmmorpholine (75 mg/kg, 24 h after partial hepatectomy)was used for initiation and chronic administration of phenobarbital(0.1% in tap water) for promotion. Histological evidence indicatedthat ATPase-negative, y-glutamyltranspeptidase-positive, andUDP-glucuronyltransferase-positive foci were highly correlated.Based on this evidence ATPase-negative foci were used as a guideto monitor early lesions and to microdissect lyophilized fociand extrafocal tissue. It was found that treatment with N-nitrosomorpholineled to a permanent increase of UDP-glucuronyltransferase activityin foci tissue (3- to 5-fold, detected 180 and 330 days afterinitiation). In contrast, arylhydrocarbon hydroxylase activitywas decreased by 50%. Administration of phenobarbital furtherincreased UDP-glucuronyltransferase activity in focal tissue(up to 9-fold, compared with control liver). However, this furtherincrease of enzyme activity by phenobarbital was reversible.The results suggest that (i) initiation by chemical carcinogensleads to permanent alterations of drug metabolizing enzymes,consistent with increased toxin-resistance of initiated hepatocytes,and (ii) chronic administration of phenobarbital markedly enhancesgene expression of UDP-glucuronyltransferase in initiated hepatocytes.