Expression of specific UDP‐glucuronosyltransferase isoforms in carcinogen‐induced preneoplastic rat liver nodules

The expression of specific UDP‐glucuronosyltransferase isoforms in 2‐acetylaminofluorane—induced rat liver preneoplastic nodules was studied; livers from pair‐fed littermates were used as controls. For comparison, liver and kidney from 3‐methylcholanthrene—treated or untreated (control) rats were used. Steadystate UDP‐glucuronosyltransferase mRNA levels were determined by Northern blot analysis or in situ hybridization of tissue sections using a 30‐mer oligonucleotide specific for the 3‐methylcholanthrene—inducible UDP‐glucuronosyltransferase (which is active toward 4‐nitrophenol) or a double‐stranded cDNA probe specific for androsterone—UDP‐glucuronosyltransferase. For 3‐methylcholanthrene—inducible UDP‐glucurono‐syltransferase, the mRNA level was very low in control liver; there was a 15‐fold increase after 3‐methylcholanthrene treatment. This mRNA was present at relatively high concentration in the kidney and there was a threefold increase after 3‐methylcholanthrene administration. In livers with preneoplastic nodules 1 mo after cessation of carcinogen administration, this mRNA concentration was approximately 15 times greater than in control liver. Similar changes in the level of the 3‐methylcholanthrene—inducible UDP‐glucuronosyltransferase were also observed by in situ hybridization of tissue sections. Immunocytochemical studies using an antiserum that recognizes the 3‐methylcholanthrene–inducible UDP‐glucuronosyltransferase showed a marked increase in the concentration of this isoform in preneoplastic nodules compared with the adjacent nonnodular liver. Consistent with the changes in mRNA levels, there was a threefold increase in 4‐nitrophenol–UDP‐glucuronosyltransferase activity in 3‐methylcholanthrene–treated rat livers and in livers with preneoplastic nodules. In contrast to the 3‐methyl‐cholanthrene–inducible UDP‐glucuronosyltransferase mRNA, the androsterone–UDP‐glucuronosyltransferase mRNA was abundant in the liver and nearly absent in the kidney; its concentration was not increased after 3‐methylcholanthrene administration or in preneoplastic nodules. Immunocytochemical studies using an antiserum that recognizes androsterone‐ testosterone– and bilirubin–UDP‐glucuronosyltransferase isoforms did not show any increase of the concentration of these antigens in preneoplastic nodules. Similarly, activities for androsterone, testosterone and bilirubin also did not increase after 3‐methylcholanthrene administration or in livers bearing the preneoplastic nodules. (HEPATOLOGY 1991;13:38—46).