Carcinogenicity, mechanisms peroxisome proliferation

Peters, J.M., Cattley, R.C. Gonzalez, F.J. (1997a) Role of PPAR a in the mechanism of action of the nongenotoxic carcinogen and peroxisome proliferator Wy-14,643. 

Not all of the biochemical events in this complex pathway from PPAR-alpha activation to tumors are completely understood, but much is known. It seems that at least some peroxisome-proliferating chemicals that also produce tumors in rodent livers do so through this pathway. If it can be demonstrated that such a mechanism is at work, then it seems that the risk of tumorigenicity for such compounds would be limited to doses that are sufficient to activate PPAK-alpha sufficiently to initiate the dangerous cascade of events within the cell. Experts have developed a number of experimental criteria that should be met if a compound is to be put in this class of carcinogens. Study of P PAR-alpha activation as a route of carcinogensis is an extremely active area of research. 

Three of the compounds evaluated in this volume (di(2-ethylhexyl) phthalate, di(2-ethylhexyl) adipate and cinnamyl anthranilate) are carcinogenic to the liver in mice and/or rats, and have been proposed to act by a mechanism involving peroxisomal proliferation in hepatocytes in those species. The role of peroxisome proliferation in evaluating carcinogenicity in humans has been discussed (lARC, 1995b). When, for any chemical, the relationship between peroxisome proliferation and liver tumours in rats or mice has been established, this should be considered relevant information in the evaluation of the possible risks for cancer in humans, taking into account the following ... 

In making its overall evaluation of the carcinogenicity to humans of di(2-ethyl-hexyl) phthalate, the Working Group took into consideration that (a) di(2-ethylhexyl) phthalate produces liver tumours in rats and mice by a non-DNA-reactive mechanism involving peroxisome proliferation h) peroxisome proliferation and hepatocellular proliferation have been demonstrated under the conditions of the carcinogenicity studies of di(2-ethylhexyl) phthalate in rats and mice and (c) peroxisome proliferation has not been documented in human hepatocyte cultures exposed to di(2-ethylhexyl) phthalate nor in the liver of exposed non-human primates. Therefore, the mechanism by which di(2-ethylhexyl) phthalate increases the incidence of hepatocellular tumours in rats and mice is not relevant to humans. 

Some general considerations about the role of peroxisome proliferation as a mechanism of carcinogenicity are presented in the General Remarks section of this volume. Studies of this mechanism are reviewed fully in Section 4.5 of the monograph on di(2-ethylhexyl) phthalate in this volume. 

In summary, substantial progress has been made over the past few years in understanding the cytoplasmic organelle peroxisome and factors that alter its normal functions. Peroxisome proliferator-in-duced increase in the liver peroxisomes is associated with an approximately two-fold increase in catalase activity and several-fold increases in the activity of the peroxisomal fatty acid jS-oxidation system. It is also evident from the available literature that hepatic peroxisomal proliferation appears to be a carcinogenic event in rodents, and this may depend on the potency of the inducer. However, there is no single mechanism that is attributed to the peroxisome proliferation or carcinogenesis induced by... 

From the many toxicity studies available it can be concluded that phthalates are not mutagenic, and not carcinogenic even though tumours are induced in rodents via the peroxisome proliferation of liver cells. It has been confirmed that this mechanism is specific for rodents only and thus not relevant for humans. 

In contrast to genotoxic carcinogens, epigenetic carcinogens act by a wide variety of mechanisms. Some of the possible epigenetic mechanisms of chemical carcinogenesis include peroxisome proliferation, inhibition of intercellular communication, microtubule alteration, hormonal imbalance, cytotoxicity, immunomodulation, inhibition of DNA methylation, etc. 

Certain phthalate plasticizers such as di-(2-etltylhexyl) phthalate, DEHP, belong to the peroxisome prohferator, PP, family of rodent liver carcinogens. " Here, the evidence for peroxisome proliferator-mediated rodent carcinogenesis in response to PPs will be considered together with an evaluation of the molecular basis for rodent-human species differences in response. Specifically, this chapter will focus on the role and mechanisms of peroxisome proliferator-induced rodent peroxisomal gene expression and the evidence for lack of relevance of this mechanism to humans. 

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