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Peroxisome proliferators and carcinogenesis: editorial perspectives
Mutation Research 448 Ž2000. 117–119 www.elsevier.comrlocatermolmut Community address: www.elsevier.comrlocatermutres
Editorial to Special Issue on peroxisome proliferators
Peroxisome proliferators and carcinogenesis: editorial perspectives
Peroxisome proliferation is a fascinating and much studied response of the rodent liver to a diverse class of natural and synthetic chemicals known as peroxisome proliferators. In the 1960s, the response was initially described by Hess et al. as an unusual form of hepatomegaly, characterized by an increase in hepatocellular peroxisomes, following administration of the drug, clofibrate wNature 208 Ž1965. 856–858x. By 1980, several hypolipidemic drugs were established as peroxisome proliferators, and the link between peroxisome proliferation and an increased incidence of rodent liver cancer was noted by Reddy et al. wNature 283 Ž1980. 397–398x. As these drugs apparently lacked the ability to cause DNA damage in available test systems, a search was on to identify the mechanism of carcinogenesis. In addition, it was increasingly evident that in addition to the modification of hepatocellular ultrastructure, peroxisome proliferation included selective enzyme induction and hyperplasia in hepatocytes. The inability to completely dissect these different aspects of the response to peroxisome proliferators in an in vivo model of carcinogenesis continues to result in some uncertainty concerning the role of each in carcinogenesis. Many of the responses clearly display commonality with subsequent tumorigenesis but causality is harder to define. In the 1980s, peroxisome proliferation received a greater interest on the part of public agencies, as it became apparent that some important nonpharmaceutical chemicals in commerce were both peroxisome proliferators and rodent liver carcino-
gens following oral administration in rodents. Among these, di-Ž2-ethylhexyl. phthalate ŽDEHP., a widely used plasticizer, attracted considerable attention following the US National Toxicology Program’s carcinogenesis bioassay. In that study, DEHP was carcinogenic, resulting in increased incidence of hepatocellular neoplasms in both rats and mice. DEHP is widely used in various plastics, both in consumer products and medical devices. When peroxisome proliferators only included drugs, it was sufficient to evaluate the possibility of an increased cancer risk in selected patient populations, where its relationship to positive health benefits such as altered lipid profiles and lowered risk of coronary heart disease could also be considered. However, the observation of these same carcinogenic responses to various plasticizers as well as other non-pharmaceutical chemicals Žfor example, diphenyl ether herbicides. raised the possibility of inadvertent risk to a much larger segment of the public. At the same time, the experience with peroxisome proliferators in bioassays continued to accumulate and some general features were becoming apparent. First was the observation that any chemical that caused a somewhat more than trivial hepatic level of peroxisome proliferation in short-term studies was likely to increase the risk of cancer in rodents. This appeared to be true for both rats and mice, although differences in external dose and pharmacokinetics sometimes could result in selectivity for one of these rodent species. Furthermore, other than species differences, differences in study design and conduct
0027-5107r00r$ - see front matter q 2000 Elsevier Science B.V. All rights reserved. PII: S 0 0 2 7 - 5 1 0 7 Ž 9 9 . 0 0 2 3 0 - 4
118
Editorial to Special Issue on peroxisome proliferators
made it difficult to establish any minimum response Žcompared to background. that would predict the risk of cancer in a precise manner. However, the relationship between peroxisome proliferation and rodent liver cancer appeared secure, at least in a qualitative or semi-quantitative sense. ŽIncidentally, this relationship also led to suggestions that any extrapolation of cancer risk across a range of doses might utilize a threshold model.. Second, the chemical entities that caused peroxisome proliferation and cancer, as well as their metabolites, were lacking in the ability to damage DNA directly. While it was and still is acknowledged that some chemicals may, in fact, be both genotoxic carcinogens and peroxisome proliferators, experience suggests that this combination of mechanisms is, at most, exceptionally rare. Third, the carcinogenic response associated with peroxisome proliferators was by and large limited to hepatocytes. This remains the case for mice. In rats, occasional studies have demonstrated an increase in incidence of neoplasia in one or more additional cell types including gastric enterochromaffin-like cells, testicular interstitial ŽLeydig. cells, and pancreatic acinar cells. Evidence for the mechanism of carcinogenesis for these nonhepatic cell types is limited but highly suggestive that peroxisome proliferation is not involved. Therefore, the relationship between peroxisome proliferation and carcinogenesis remained focused on hepatocytes. Also during the 1980s, several studies began to suggest that human hepatocytes might be refractory to the effects of peroxisome proliferators. These studies included evaluation of liver biopsy samples from patients on long-term fibrate therapy, as well as studies of human hepatocytes in vitro. Although these studies clearly had and continue to have certain limitations, the differences between humans and rodents with respect to peroxisome proliferation led to a variety of contentions regarding the relevance of rodent liver cancer for human risk assessment of peroxisome proliferators. These contentions were further supported by results of studies and medical experience with patients on long-term fibrate therapy, who had no discernible increased risk of cancer. Efforts to address questions about the mechanism of liver carcinogenesis in rodents and the relevance of the rodent response to humans have been substantially aided by the discovery, by Green et al., of a
nuclear receptor that mediates the response of hepatocytes to peroxisome proliferators wNature 347 Ž1990. 645–650x. This receptor, called the Aperoxisome proliferator-activated receptor alphaB ŽPPARa ., was identified as a member of the steroid and thyroid hormone nuclear receptor superfamily that cooperates with another superfamily member, RXR, to induce transcription of selected genes. Current and ongoing studies are designed to describe the molecular interaction of peroxisome proliferators with PPARa in the initiation of transcription. Attempts to define the role of PPARa in mediating the hepatic effects of peroxisome proliferators have been facilitated by the development of a PPARa gene knockout mouse strain by Gonzalez et al. wMolecular and Cellular Biology 15 Ž1995. 3012–3022x. The utilization of these mice in the delineation of PPARa-mediated effects is continuing to be an active area of investigation. The discovery of PPARa has led to the demonstration that this receptor is necessary in the mechanism of hepatic carcinogenesis by peroxisome proliferators. However, it is less clear whether PPARa is sufficient to account for all aspects of the liver’s response to peroxisome proliferators. Kupffer cell activation is observed upon initiation of treatment of rodents with peroxisome proliferators, as first reported by Thurman et al. wCancer Research 56 Ž1996. 1–4x. There is some evidence that this activation of Kupffer cells and release of cytokines, notably TNFa , might initiate signal transduction pathways that cooperate with PPARa-mediated gene transcription in mediating selected components of the response to peroxisome proliferators, particularly the hyperplasia of hepatocytes. Alternatively, the production of TNFa by some or all types of liver cells may be permissive for a PPARa-dependent response of the hepatocytes to peroxisome proliferators. Additional findings to support or refute a definite role of the cooperative or permissive signaling pathways are likely to emerge as investigations continue. The discovery of PPARa has been important for the characterization of differences between rodent and human sensitivity to the hepatic effects of peroxisome proliferators. Recent and ongoing studies have suggested that, while humans do have functional PPARa , there are likely to be important differences ranging from level of receptor expression to aspects
Editorial to Special Issue on peroxisome proliferators
of receptor function. There is considerable hope that this active area of research will provide a more complete understanding of the species differences in responses, including hepatic carcinogenesis. In conclusion, the story of peroxisome proliferation and its relationship to cancer has developed into an interesting saga for biology and for carcinogen risk assessment, with implications for regulation of certain carcinogens that go beyond the scope of this volume. It is clearly a story where much is known, but where there are notable opportunities to know more. Finally, a note of appreciation is expressed to the reviewers who have greatly assisted in the preparation of this volume.
a
b
)
119
Russell C. Cattley a, ) Amgen Inc., Department of Pathology, MS 15-2-B, 1 Amgen Center DriÕe, Thousand Oaks, CA 19320, USA E-mail address: [email protected]
Ruth A. Roberts b AstraZeneca Central Toxicology Laboratory, Alderley Park, Macclesfield SK10 4TJ, UK
Corresponding author. Tel.: q1-805-447-3983; fax: q1-805447-1939.
Editorial to Special Issue on peroxisome proliferators
Peroxisome proliferators and carcinogenesis: editorial perspectives
Peroxisome proliferation is a fascinating and much studied response of the rodent liver to a diverse class of natural and synthetic chemicals known as peroxisome proliferators. In the 1960s, the response was initially described by Hess et al. as an unusual form of hepatomegaly, characterized by an increase in hepatocellular peroxisomes, following administration of the drug, clofibrate wNature 208 Ž1965. 856–858x. By 1980, several hypolipidemic drugs were established as peroxisome proliferators, and the link between peroxisome proliferation and an increased incidence of rodent liver cancer was noted by Reddy et al. wNature 283 Ž1980. 397–398x. As these drugs apparently lacked the ability to cause DNA damage in available test systems, a search was on to identify the mechanism of carcinogenesis. In addition, it was increasingly evident that in addition to the modification of hepatocellular ultrastructure, peroxisome proliferation included selective enzyme induction and hyperplasia in hepatocytes. The inability to completely dissect these different aspects of the response to peroxisome proliferators in an in vivo model of carcinogenesis continues to result in some uncertainty concerning the role of each in carcinogenesis. Many of the responses clearly display commonality with subsequent tumorigenesis but causality is harder to define. In the 1980s, peroxisome proliferation received a greater interest on the part of public agencies, as it became apparent that some important nonpharmaceutical chemicals in commerce were both peroxisome proliferators and rodent liver carcino-
gens following oral administration in rodents. Among these, di-Ž2-ethylhexyl. phthalate ŽDEHP., a widely used plasticizer, attracted considerable attention following the US National Toxicology Program’s carcinogenesis bioassay. In that study, DEHP was carcinogenic, resulting in increased incidence of hepatocellular neoplasms in both rats and mice. DEHP is widely used in various plastics, both in consumer products and medical devices. When peroxisome proliferators only included drugs, it was sufficient to evaluate the possibility of an increased cancer risk in selected patient populations, where its relationship to positive health benefits such as altered lipid profiles and lowered risk of coronary heart disease could also be considered. However, the observation of these same carcinogenic responses to various plasticizers as well as other non-pharmaceutical chemicals Žfor example, diphenyl ether herbicides. raised the possibility of inadvertent risk to a much larger segment of the public. At the same time, the experience with peroxisome proliferators in bioassays continued to accumulate and some general features were becoming apparent. First was the observation that any chemical that caused a somewhat more than trivial hepatic level of peroxisome proliferation in short-term studies was likely to increase the risk of cancer in rodents. This appeared to be true for both rats and mice, although differences in external dose and pharmacokinetics sometimes could result in selectivity for one of these rodent species. Furthermore, other than species differences, differences in study design and conduct
0027-5107r00r$ - see front matter q 2000 Elsevier Science B.V. All rights reserved. PII: S 0 0 2 7 - 5 1 0 7 Ž 9 9 . 0 0 2 3 0 - 4
118
Editorial to Special Issue on peroxisome proliferators
made it difficult to establish any minimum response Žcompared to background. that would predict the risk of cancer in a precise manner. However, the relationship between peroxisome proliferation and rodent liver cancer appeared secure, at least in a qualitative or semi-quantitative sense. ŽIncidentally, this relationship also led to suggestions that any extrapolation of cancer risk across a range of doses might utilize a threshold model.. Second, the chemical entities that caused peroxisome proliferation and cancer, as well as their metabolites, were lacking in the ability to damage DNA directly. While it was and still is acknowledged that some chemicals may, in fact, be both genotoxic carcinogens and peroxisome proliferators, experience suggests that this combination of mechanisms is, at most, exceptionally rare. Third, the carcinogenic response associated with peroxisome proliferators was by and large limited to hepatocytes. This remains the case for mice. In rats, occasional studies have demonstrated an increase in incidence of neoplasia in one or more additional cell types including gastric enterochromaffin-like cells, testicular interstitial ŽLeydig. cells, and pancreatic acinar cells. Evidence for the mechanism of carcinogenesis for these nonhepatic cell types is limited but highly suggestive that peroxisome proliferation is not involved. Therefore, the relationship between peroxisome proliferation and carcinogenesis remained focused on hepatocytes. Also during the 1980s, several studies began to suggest that human hepatocytes might be refractory to the effects of peroxisome proliferators. These studies included evaluation of liver biopsy samples from patients on long-term fibrate therapy, as well as studies of human hepatocytes in vitro. Although these studies clearly had and continue to have certain limitations, the differences between humans and rodents with respect to peroxisome proliferation led to a variety of contentions regarding the relevance of rodent liver cancer for human risk assessment of peroxisome proliferators. These contentions were further supported by results of studies and medical experience with patients on long-term fibrate therapy, who had no discernible increased risk of cancer. Efforts to address questions about the mechanism of liver carcinogenesis in rodents and the relevance of the rodent response to humans have been substantially aided by the discovery, by Green et al., of a
nuclear receptor that mediates the response of hepatocytes to peroxisome proliferators wNature 347 Ž1990. 645–650x. This receptor, called the Aperoxisome proliferator-activated receptor alphaB ŽPPARa ., was identified as a member of the steroid and thyroid hormone nuclear receptor superfamily that cooperates with another superfamily member, RXR, to induce transcription of selected genes. Current and ongoing studies are designed to describe the molecular interaction of peroxisome proliferators with PPARa in the initiation of transcription. Attempts to define the role of PPARa in mediating the hepatic effects of peroxisome proliferators have been facilitated by the development of a PPARa gene knockout mouse strain by Gonzalez et al. wMolecular and Cellular Biology 15 Ž1995. 3012–3022x. The utilization of these mice in the delineation of PPARa-mediated effects is continuing to be an active area of investigation. The discovery of PPARa has led to the demonstration that this receptor is necessary in the mechanism of hepatic carcinogenesis by peroxisome proliferators. However, it is less clear whether PPARa is sufficient to account for all aspects of the liver’s response to peroxisome proliferators. Kupffer cell activation is observed upon initiation of treatment of rodents with peroxisome proliferators, as first reported by Thurman et al. wCancer Research 56 Ž1996. 1–4x. There is some evidence that this activation of Kupffer cells and release of cytokines, notably TNFa , might initiate signal transduction pathways that cooperate with PPARa-mediated gene transcription in mediating selected components of the response to peroxisome proliferators, particularly the hyperplasia of hepatocytes. Alternatively, the production of TNFa by some or all types of liver cells may be permissive for a PPARa-dependent response of the hepatocytes to peroxisome proliferators. Additional findings to support or refute a definite role of the cooperative or permissive signaling pathways are likely to emerge as investigations continue. The discovery of PPARa has been important for the characterization of differences between rodent and human sensitivity to the hepatic effects of peroxisome proliferators. Recent and ongoing studies have suggested that, while humans do have functional PPARa , there are likely to be important differences ranging from level of receptor expression to aspects
Editorial to Special Issue on peroxisome proliferators
of receptor function. There is considerable hope that this active area of research will provide a more complete understanding of the species differences in responses, including hepatic carcinogenesis. In conclusion, the story of peroxisome proliferation and its relationship to cancer has developed into an interesting saga for biology and for carcinogen risk assessment, with implications for regulation of certain carcinogens that go beyond the scope of this volume. It is clearly a story where much is known, but where there are notable opportunities to know more. Finally, a note of appreciation is expressed to the reviewers who have greatly assisted in the preparation of this volume.
a
b
)
119
Russell C. Cattley a, ) Amgen Inc., Department of Pathology, MS 15-2-B, 1 Amgen Center DriÕe, Thousand Oaks, CA 19320, USA E-mail address: [email protected]
Ruth A. Roberts b AstraZeneca Central Toxicology Laboratory, Alderley Park, Macclesfield SK10 4TJ, UK
Corresponding author. Tel.: q1-805-447-3983; fax: q1-805447-1939.