Epigenetic effects of liver tumor promoters and implications for health effects.
During chemical carcinogenesis in the liver, a population of abnormal cells in lesions referred to as altered foci precedes the appearance of neoplasms. Most altered foci do not develop further, but a small fraction progress to formation of neoplasms. Liver tumor promoters increase the fraction that progress. The mechanisms for this action of promoters may involve an effect on the cell membrane. Cells in vivo and in vitro exchange molecules through specialized membrane organelles known as gap junctions. Intercellular transfer of growth and/or differentiation regulating factors could be involved in suppressing the growth of initiated cells in the altered foci. Several liver tumor promoters have been found to inhibit intercellular communication in an in vitro liver culture system. This effect on the cell membrane could, thus, be the basis for the release of cells in foci for further growth into neoplasms. Such an epigenetic action would account for the requirement for high doses and prolonged exposure for certain liver tumor promoters. In addition, it implies a distinct type of health risk analysis for chemicals of this type. Several chemicals, particularly halogenated hydrocarbons, produce primarily or exclusively an increase in liver tumors in rodent strains that are characterized by a substantial background incidence of such tumors. These chemicals have not been demonstrated to have the DNA damaging capability of genotoxic carcinogens and several enhance the hepatocarcinogenicity of previously administered liver carcinogens. Moreover, they exert an inhibition of intercellular communication. Thus, carcinogens of this type may be epigenetic carcinogens functioning as liver tumor promoters. Accordingly, the health risk analysis for these chemicals is different from that for genotoxic carcinogens.
D000818:Animals; D002273:Carcinogens / Q000494:pharmacology; D002450:Cell Communication / Q000187:drug effects; D003043:Cocarcinogenesis; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008113:Liver Neoplasms / Q000139:chemically induced*; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced*; D051381:Rats; D012306:Risk
D002273:Carcinogens