Mechanisms of action of oxidant carcinogens.

Oxidants can act at multiple stages of carcinogenesis. While they cause genetic damage and are cytotoxic, they also activate cellular pathways which alter gene expression, growth, and differentiation. Certain pathways used by polypeptide growth factors and hormones are also activated by oxidants. For example, oxidants stimulate the phosphorylation of the ribosomal subunit S6, the phosphotransferase activity of protein kinase C, and induce its translocation to the plasma membrane. On the genomic level, oxidants increase the transcription of the growth-competence-related protooncogenes c-fos and c-myc. In addition to these growth factor-type reactions, oxidants induce pathways which are unique to them. Poly ADP-ribosylation of chromosomal proteins is of particular relevance to oxidant carcinogenesis. It represents an epigenetic consequence of DNA-breakage. Both histones and nonhistone proteins are poly ADP-ribosylated in response to oxidants. Among non-histones, ADPR-transferase, topoisomerase I, and the fos oncoprotein were identified as acceptors. Inhibition of poly ADP-ribosylation suppressed the oxidant-induced transcription of c-fos. Since fos oncoprotein serves as a transcriptional regulator, we speculate that its poly ADP-ribosylation and that of other chromosomal proteins plays a role in the modulation of gene expression in response to oxidative stress.