Hormesis in Carcinogenicity of Non-genotoxic Carcinogens

Recently the idea of hormesis, a biphasic dose-response relationship in which a chemical exerts opposite effects dependent on the dose, has attracted interest in the field of carcinogenesis. With non-genotoxic agents there is considerable experimental evidence in support of hormesis and the present review highlights current knowledge of doseresponse effects. In particular, several in vivo studies have provided support for the idea that non-genotoxic carcinogens may inhibit hepatocarcinogenesis at low doses. Here, we survey the examples and discuss possible mechanisms of hormesis with cytochrome P450 inducers, such as phenobarbital, 1,1-bis(p-chlorophenyl)-2,2,2-trichloroethane (DDT), α-benzene hexachloride (α-BHC), and other non-genotoxins. Epigenetic processes differentially can be affected by agents that impinge on oxidative stress, DNA repair, cell proliferation, apoptosis, intracellular communication and cell signaling. Non-genotoxic carcinogens may target nuclear receptors, cause aberrant DNA methylation at the genomic level and induce post-translational modifications at the protein level, thereby impacting on the stability or activity of key regulatory proteins, including oncoproteins and tumor suppressor proteins. Via multiple epigenetic lesions, nongenotoxic carcinogens can elicit a variety of changes contributing to cellular carcinogenesis. (J Toxicol Pathol 2006;