Rodent Responses To Peroxisome Proliferators — A Receptor-Mediated Phenomenon?
The phenomenon of rodent peroxisome proliferation was first observed some years ago when the hypolipidaemic drug clofibrate was administered to rats. Since then, a wide variety of structurally diverse and industrially important compounds have been shown to have similar effects; these compounds include other hypolipidaemic drugs, leukotriene antagonists, herbicides and plasticisers (for review, see Reddy & Lalwani, 1982). In addition to increases in size and number of hepatic peroxisomes, peroxisome proliferators (PPs) in susceptible species also bring about induction of hepatic peroxisomal enzymes, and cause increases in Sphase and ultimately carcinogenesis of the liver (Reddy et al, 1980), although the potency of these compounds differs considerably in terms of their carcinogenicity. This rodent hepatocarcinogenesis is important in the context of human risk assessment, since humans are exposed to many PPs both environmentally and otherwise. PPs are termed non-genotoxic carcinogens since they are almost exclusively negative in routine genotoxicity assays. This raises the question as to the mechanism of carcinogenicity of these compounds. It has been proposed that the generation of hydrogen peroxide through increase in peroxisomal fatty acid poxidation causes DNA damage indirectly through oxidative stress. Perhaps more likely, however is the suggestion that PPs, by inducing DNA replication, are able to ‘fix’ spontaneous and environmentally-induced mutations which eventually give rise to tumours (Cattley et al, 1989).
KeywordsHydrogen Peroxide DMSO Glucocorticoid Cytosol Osteosarcoma
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