The role of inhibition of gap junctional intercellular communication in rodent liver tumor induction by phthalates: review of data on selected phthalates and the potential relevance to man.
Inhibition of gap junctional intercellular communication (GJIC) has been postulated as a nongenotoxic carcinogenic mechanism, probably related to tumor promotion. Recent studies assessed the role of GJIC in the induction of rodent liver tumors by high levels of phthalate esters. Studies with di(2-ethylhexyl) (DEHP) and diisononyl (DINP) phthalates demonstrated that inhibition of GJIC in rats and mice was well correlated with induction of both liver tumors and markers for peroxisomal proliferation. However, GJIC was unaffected in hamsters and primates, species in which phthalate treatment does not induce peroxisomal proliferation. In vitro studies which extended the database to include human liver cells mirrored the in vivo situation; GJIC was inhibited in rat and mouse cells but not in cells from unresponsive species including humans. Peroxisomal proliferation has been characterized as a species-specific process essential for phthalate-induced rodent liver tumor induction. That GJIC was not inhibited in primate liver or human liver cells provides evidence for a second species-specific carcinogenic process. Thus the GJIC data along with those from studies of peroxisomal proliferation support the view that the carcinogenic effects of DEHP and DINP in rodents are not relevant to humans.
McKee
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Exxon Biomedical Sciences, Inc., 1545 Route 22 East, Annandale, New Jersey 08801-0971, USA.
D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D002450:Cell Communication / Q000187:drug effects*; D006224:Cricetinae; D004051:Diethylhexyl Phthalate / Q000633:toxicity; D017629:Gap Junctions / Q000187:drug effects*; D006801:Humans; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000378:metabolism; D051379:Mice; D020025:Peroxisome Proliferators / Q000633:toxicity*; D010795:Phthalic Acids / Q000633:toxicity*; D051381:Rats; D011916:Rats, Inbred F344; D013045:Species Specificity
D002273:Carcinogens; D020025:Peroxisome Proliferators; D010795:Phthalic Acids; C012125:diisononyl phthalate; D004051:Diethylhexyl Phthalate