@entity5248 ( @entity5248 ), a peroxisome proliferator, has been listed by the International Agency for Research on @entity5 (IARC) and by the National Toxicology Program as a possible or reasonably anticipated @entity1 carcinogen because it induces dose-related @entity96 in both sexes of @entity35 and @entity19 . Recently, the suggestion has been advanced that @entity5248 should be considered unlikely to be a @entity1 carcinogen because it is claimed that the carcinogenic effects of this agent in rodents are due to peroxisome proliferation and that @entity1 are nonresponsive to this process. An IARC working group recently downgraded @entity5248 to "not classifiable as to its carcinogenicity to @entity1 " because they concluded that @entity5248 produces @entity96 in @entity35 and @entity19 by a mechanism involving peroxisome proliferation, which they considered to be not relevant to @entity1 . The literature review presented in this commentary reveals that, although our knowledge of the mechanism of peroxisome proliferation has advanced greatly over the past 10 years, our understanding of the mechanism(s) of carcinogenicty of peroxisome proliferators remains incomplete. Most important is that published studies have not established peroxisome proliferation per se as an obligatory pathway in the carcinogenicity of @entity5248 . No epidemiologic studies have been reported on the potential carcinogenicity of @entity5248 , and @entity5 epidemiologic studies of hypolipidemic fibrate drugs (peroxisome proliferators) are inconclusive. Most of the pleiotropic effects of peroxisome proliferators are mediated by the @entity5601 ( @entity5601 ), a ligand-activated transcription factor that is expressed at lower levels in @entity1 than in @entity35 and @entity19 . In spite of this species difference in @entity5601 expression, hypolipidemic fibrates have been shown to induce @entity31949 in @entity1 and to modulate gene expression (e.g., genes regulating lipid homeostasis) in @entity1 hepatocytes by @entity5601 activation. Thus, @entity1 are responsive to agents that induce peroxisome proliferation in @entity35 and @entity19 . Because peroxisome proliferators can affect multiple signaling pathways by transcriptional activation of @entity5601 -regulated genes, it is likely that alterations in specific regulated pathways (e.g., suppression of apoptosis, protooncogene expression) are involved in @entity5 induction by peroxisome proliferators. In addition, because @entity5248 also induces biological effects that occur independently of peroxisome proliferation (e.g., morphologic cell transformation and decreased levels of gap junction intercellular communication), it is possible that some of these responses also contribute to the carcinogenicity of this chemical. Last, species differences in tissue expression of PPARs indicate that it may not be appropriate to expect exact site correspondence for potential @entity5601 -mediated effects induced by peroxisome proliferators in animals and @entity1 . Because peroxisome proliferation has not been established as an obligatory step in the carcinogenicity of @entity5248 , the contention that @entity5248 poses no carcinogenic risk to @entity1 because of species differences in peroxisome proliferation should be viewed as an unvalidated hypothesis.

Is peroxisome proliferation an obligatory precursor step in the carcinogenicity of @entity5248 ( XXXX )?

@entity1 :: ('9606', 'Species') :: ['humans', 'human'] @entity31949 :: ('MESH:C565732', 'Disease') :: ['hypolipidemia'] @entity96 :: ('MESH:D008113', 'Disease') :: ['liver tumors', 'increases in liver tumors'] @entity5 :: ('MESH:D009369', 'Disease') :: ['tumor', 'cancer', 'Cancer'] @entity19 :: ('10090', 'Species') :: ['mice'] @entity5248 :: ('MESH:D004051', 'Chemical') :: ['DEHP', 'Di(2-ethylhexyl)phthalate'] @entity5601 :: ('5465', 'Gene') :: ['PPAR', 'peroxisome proliferator activated receptor'] @entity35 :: ('10116', 'Species') :: ['rats']
@entity5248 :: (MESH:D004051,Chemical) :: ['DEHP']
