Induction of poly(ADP-ribosyl)ation in the kidney after in vivo application of renal carcinogens.

Dichlorovinylcysteine, the key metabolite thought to be responsible for the nephrocarcinogenicity of trichloroethene and dichloroacetylene, induces DNA double-strand breaks followed by increased poly(ADP-ribosyl)ation of nuclear proteins in cultured renal cells (Vamvakas et al., 1992, Biochem. Pharmacol. 44, 1131-1138). Poly(ADP-ribosyl)ation represents a post-translational modification of nuclear proteins involved in DNA repair, DNA replication, and modulation of gene expression. The present study investigates the induction of DNA double-strand breaks and poly(ADP-ribosyl)ation in the renal cortex after in vivo administration of several renal carcinogens to male Wistar rats, and the temporal relationship between these two processes. Dichlorovinylcysteine caused a time-dependent increase in the amount of poly(ADP-ribosyl)conjugates in the kidney cortex, which was preceded by increased formation of DNA double-strand breaks. Potassium bromate and ferric nitrilotriacetate, whose nephrocarcinogenicity is thought to result from increased formation of reactive oxygen species, both induced poly(ADP-ribosyl)ation with the concomitant formation of DNA double-strand breaks. Dimethylnitrosamine, an indirect acting methylating agent, and trimethylpentane, a non-genotoxic renal carcinogen, failed to induce poly(ADP-ribosyl)ation or a significant increase in DNA double-strand breaks in the renal cortex. The results indicate that nephrocarcinogens capable of inducing DNA fragmentation also induce post-translational modification of renal proteins via increased poly(ADP-ribosyl)ation.