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.
McLaren
J
J
Institut für Toxikologie, Universität Würzburg, Germany.
Boulikas
T
T
Vamvakas
S
S
D000114:Acetylene / Q000031:analogs & derivatives* / Q000633:toxicity; D000818:Animals; D001959:Bromates / Q000633:toxicity; D002273:Carcinogens / Q000633:toxicity*; D002467:Cell Nucleus / Q000187:drug effects / Q000201:enzymology; D004249:DNA Damage; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism; D004128:Dimethylnitrosamine / Q000633:toxicity; D005290:Ferric Compounds / Q000633:toxicity; D007672:Kidney Cortex / Q000187:drug effects* / Q000648:ultrastructure; D008297:Male; D008770:Methylnitrosourea / Q000633:toxicity; D009571:Nitrilotriacetic Acid / Q000031:analogs & derivatives / Q000633:toxicity; D011064:Poly Adenosine Diphosphate Ribose / Q000378:metabolism*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D014241:Trichloroethylene / Q000633:toxicity*
D001959:Bromates; D002273:Carcinogens; D005290:Ferric Compounds; C019536:potassium bromate; D011064:Poly Adenosine Diphosphate Ribose; D014241:Trichloroethylene; D008770:Methylnitrosourea; C002978:dichloroacetylene; D011065:Poly(ADP-ribose) Polymerases; D004259:DNA-Directed DNA Polymerase; D009571:Nitrilotriacetic Acid; D004128:Dimethylnitrosamine; D000114:Acetylene; C020326:ferric nitrilotriacetate