Selective loss of nucleoside carrier expression in rat hepatocarcinomas

Evidence that hepatoma cell lines show differential expression of concentra tive nucleoside transporters (CNT1 and CNT2) prompted us to study the trans porter proteins in 2 models of hepatocarcinogenesis, the chemically induced Solt and Farber model and the albumin-SV40 large T antigen (Alb-SV40) tran sgenic rat. CNT1 expression was lower in tumor biopsy specimens from Alb-SV 40 rat livers than in normal tissue. Immunocytochemistry revealed that the CNT1 protein was indeed absent in the tumor lesions. CNT1 was also absent i n a cell line, L25, derived from the Alb-SV40 transgenic rat liver tumors, whereas another cell line, L37, derived from the normal-appearing parenchym a, retained the expression of both carrier isoforms, The protein expression correlated with the nucleoside transport properties of these cell lines. M oreover, although CNT2 expression was highly dependent on the growth charac teristics of the 2 cell lines, as was CNT1 (albeit to a lower extent) in L3 7 cells, it was not expressed in L25 cells at any stage of cell growth. In contrast to the transgenic model of hepatocarcinogenesis, in the chemically induced tumors the expression of CNT2 was lower, although still detectable . In summary, these data indicate that hepatocarcinogenesis leads to a sele ctive loss or diminished expression of nucleoside carrier isoforms, a featu re that may be relevant to our understanding of the molecular basis of the bioavailability of those drugs that are nucleoside derivatives and may be s ubstrates of these carriers. The transport properties and isoform-expressio n profile of the L25 and L37 cell lines make them suitable hepatocyte cultu re models with which to study nucleoside transport processes and drug sensi tivity.