Inhibition of initiation of simian virus 40 DNA replication in vitro by the ursodeoxycholic acid and its derivatives

In this study, the effects of the ursodeoxycholic acid (UDCA), and its derivatives, on DNA replication were examined using simian virus (SV40) DNA replication in vitro. We found that UDCA and its derivatives inhibited SV40 DNA replication, and predominantly inhibited the initiation stage of DNA replication. UDCA and its derivatives inhibited the DNA cleavage by topoisomerase I (topo I). Among them, HS- 1183 significantly reduced the activity of topo I. UDCA, at 100 μM, significantly reduced polymerase α-primase (pol α-primase) activity, but HS-1030 and HS-1183 showed a weak inhibitory effect. The ssDNA binding activity of replication protein A (RPA) was little affected by UDCA and HS-1030, but was weakly inhibited by HS-1183. Based on their properties, we suggest that UDCA and its derivatives might inhibit some molecules that is required to establish replication forks during the initiation reaction and their cytotoxicity might be related to the inhibitory effect they have on this fundamental cellular process.