Pathophysiological mechanisms of active oxygen.
Besides being toxic, oxidants can induce pathophysiological effects in mammalian cells. For example they can stimulate rather than inhibit cell growth. Since oxidants are ubiquitous they may represent 'natural' tumour promoters. Our work with xanthine/xanthine-oxidase as an extracellular source of active oxygen (AO) and promotable (clone 41) and non-promotable (clone 30) mouse epidermal cells JB6 allows insights into the mechanism of action of oxidant promoters. We found that AO stimulated the growth only of promotable clone 41 after an initial period of moderate inhibition while it was strongly cytostatic for non-promotable clone 30. Active oxygen induced larger amounts of DNA-strand breaks and poly ADP-ribosylation of chromosomal proteins in non-promotable cells. In addition, AO was capable of inducing the growth- and differentiation-related proto-oncogenes c-fos and c-myc in promotable and non-promotable JB6 cells. We speculate that these genes can exert their functions only in the promotable clone 41 because the general cytostatic effects of AO are moderate. A possible explanation for the differences between these 2 clones was discovered when we compared the constitutive activities, protein concentrations and mRNA levels for the antioxidant enzymes catalase (CAT), Cu,Zn-superoxide dismutase (SOD) and glutathione-peroxidase (GPx). We found that CAT and SOD (but not GPx) levels were 2-3-fold higher in the promotable clone 41. We propose that promotable cells possess a superior antioxidant defence which protects them from excessive cytostatic effects of AO.
Cerutti
P
P
Department of Carcinogenesis, Swiss Institute for Experimental Cancer Research, Epalinges/Lausanne, Switzerland.
Larsson
R
R
Krupitza
G
G
Muehlematter
D
D
Crawford
D
D
Amstad
P
P
D000818:Animals; D000975:Antioxidants; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002999:Clone Cells; D004249:DNA Damage; D005609:Free Radicals; D010100:Oxygen / Q000633:toxicity*; D010766:Phosphorylation; D011519:Proto-Oncogenes / Q000187:drug effects; D012269:Ribosomal Proteins / Q000235:genetics / Q000378:metabolism
D000975:Antioxidants; D005609:Free Radicals; D012269:Ribosomal Proteins; D010100:Oxygen; D002118:Calcium