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 deri vatives, on DNA replication were examined using simian virus (SV40) DNA rep lication in vitro. We found that UDCA and its derivatives inhibited SV40 DN A replication, and predominantly inhibited the initiation stage of DNA repl ication. UDCA and its derivatives inhibited the DNA cleavage by topoisomera se I (topo I). Among them, HS-1183 significantly reduced the activity of to po I. UDCA, at 100 mu M, significantly reduced polymerase alpha-primase (po l alpha-primase) activity, but HS-1030 and HS-1183 showed a weak inhibitory effect. The ssDNA binding activity of replication protein A (RPA) was litt le 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 inhibi t some molecules that is required to establish replication forks during the initiation reaction and their cytotoxicity might be related to the inhibit ory effect they have on this fundamental cellular process. (C) 1999 Elsevie r Science Ireland Ltd. All rights reserved.