INDUCTION OF POLY(ADP-RIBOSYL)ATION IN THE KIDNEY AFTER IN-VIVO APPLICATION OF RENAL CARCINOGENS

Dichlorovinylcysteine, the key metabolite thought to be responsible fo r the nephrocarcinogenicity of trichloroethene and dichloroacetylene, induces DNA double-strand breaks followed by increased poly(ADP-ribosy l)ation of nuclear proteins in cultured renal cells (Vamvakas et al., 1992, Biochem. Pharmacol. 44, 1131-1138). Poly(ADP-ribosyl)ation repre sents a post-translational modification of nuclear proteins involved i n DNA repair, DNA replication, and modulation of gene expression. The present study investigates the induction of DNA double-strand breaks a nd poly(ADP-ribosyl)ation in the renal cortex after in vivo administra tion of several renal carcinogens to male Wistar rats, and the tempora l relationship between these two processes. Dichlorovinylcysteine caus ed a time-dependent increase in the amount of poly(ADP-ribosyl)conjuga tes in the kidney cortex, which was preceded by increased formation of DNA double-strand breaks. Potassium bromate and ferric nitrilotriacet ate, whose nephrocarcinogenicity is thought to result from increased f ormation of reactive oxygen species, both induced poly(ADP-ribosyl)ati on with the concomitant formation of DNA double-strand breaks. Dimethy lnitrosamine an indirect acting methylating agent, and trimethylpentan e, a non-genotoxic renal carcinogen, failed to induce poly(ADP-ribosyl )ation or a significant increase in DNA double-strand breaks in the re nal cortex. The results indicate that nephrocarcinogens capable of ind ucing DNA fragmentation also induce post-translational modification of renal proteins via increased poly(ADP-ribosyl)ation.