Elsevier

Toxicology Letters

Volumes 112–113, 15 March 2000, Pages 49-57
Toxicology Letters

Apoptosis and proliferation in nongenotoxic carcinogenesis: species differences and role of PPARα

https://doi.org/10.1016/S0378-4274(99)00243-XGet rights and content

Abstract

Peroxisome proliferators (PPs) are nongenotoxic rodent hepatocarcinogens that cause liver enlargement and hepatocarcinogenesis associated with peroxisome proliferation, induction of hepatocyte DNA synthesis and suppression of apoptosis. Acyl CoA oxidase (ACO) is a key enzyme of peroxisomal β-oxidation and its transcriptional activation by PPs is often used as marker for the rodent response. PPs activate the peroxisome proliferator activated receptor-alpha, PPARα. Recent data suggest a role for tumour necrosis factor α (TNFα). This cytokine appears to be permissive for a PPARα-dependent growth response to PPs. Humans and guinea pigs appear to be nonresponsive to the adverse effects of PPs noted in rodents. These species differences can be attributed to reduced quantity of full length functional PPARα in human liver and evidence supports the presence of a truncated form of PPARα, hPPARα8/14 in human liver. In addition, species differences could be attributed to qualitative differences in the PPARα-mediated response because the promoter for human ACO differs in sequence and activity from the rat equivalent. These data contribute to our understanding of how chemicals may cause tumours in rodents and how this response may differ in humans.

Introduction

It is important to determine if chemicals have the potential to cause cancer. For chemicals that damage DNA, this is easily determined using a range of in vitro assays. However for nongenotoxic chemicals, detection depends principally upon 2 year rodent bioassays. For those chemicals found to be positive, hepatocarcinogenesis in the mouse and sometimes the rat is the commonest observation. On the strength of this carcinogenicity in one or two rodent species, chemicals are often classified as probable human carcinogens. However, experimental and epidemiological evidence suggests marked species differences. An understanding of how such chemicals cause rodent carcinogenesis will allow the development of markers that can be used to identify at an early stage those chemicals with the potential to induce rodent tumours. In addition, such knowledge provides the opportunity to assess relevance of these mechanisms to humans.

Section snippets

The peroxisome proliferator class of rodent nongenotoxic hepatocarcinogens

Peroxisome proliferators (PPs) constitute a large and chemically diverse family of nongenotoxic rodent hepatocarcinogens (reviewed in Moody et al., 1991, Ashby et al., 1994). This family includes fibrate hypolipidaemic drugs such as bezafibrate and gemfibrozil, given to patients at risk of heart disease to lower blood cholesterol and restore lipid balance (Tucker and Orton, 1992). Also, the PP class includes chemicals of environmental and industrial significance such as the plasticizer

Rodent response to peroxisome proliferators: role of PPARα

In 1990, a receptor that mediates the effects of PPs, the peroxisome proliferator activated receptor alpha (PPARα) was identified in mouse liver (Issemann and Green, 1990) The isolation of human PPARα and other isoforms of PPAR (β and γ) both from rodents and humans followed on rapidly (reviewed in Tugwood et al., 1996). In rats and mice, PPARα is highly expressed in the liver, whereas other forms such as PPARγ are expressed predominantly in fatty adipose tissue and in the immune system. This

TNF-α: role in nongenotoxic hepatocarcinogenesis

TNFα-is a proinflammatory mediator proximally associated with necrotic injury (reviewed in Roberts and Kimber, 1999). However, others have suggested that TNF-α may have a role as a positive mediator of hepatocyte growth. To determine if TNF-α may play a role in the response to PPs, we analysed the response of primary mouse and rat hepatocyte cultures to exogenous TNF-α. TNFα was able to induce S-phase and suppress apoptosis, much like PPs such as nafenopin. Furthermore, blocking antibodies

Species differences in response to PPs

In the rodent, PPs induce peroxisome proliferation associated with the increased expression of enzymes found in the peroxisome that are responsible for metabolism of fatty acids. One of the key enzymes in this pathway is ACO. Levels of ACO are increased dramatically in the livers of rodents treated with PPs (Fig. 2) and this enzyme is used as a marker of the rodent response to PPs (Fig. 2). Evidence suggests that peroxisome proliferation is necessary but not sufficient per se for the observed

Species differences in quantity and activity of PPARα

When PPARα was cloned from mouse and shown to mediate the response to PPs, it was suggested that perhaps nonresponsive species such as humans and guinea pigs would lack a functional receptor. This was rapidly disproved because full-length, functional PPARα have been cloned from both human (reviewed in Tugwood et al., 1996) and guinea pig (Bell et al., 1998, Tugwood et al., 1998). These receptors have comparable intrinsic activity in reporter gene assays (Tugwood et al., 1998). However, the

Species differences in quality of the PPARα-mediated response

A second hypothesis to explain lack of human response is based on quality of the PPARα-mediated response (Chevalier and Roberts, 1998). Thus, even in the presence of sufficient human PPARα, genes associated with rodent peroxisome proliferation and cancer would not be switched on. Evidence in support of this hypothesis arises from recent observations of species difference in the sequence of the ACO gene promoter (Woodyatt et al., 1999), a marker for rodent peroxisome proliferation (Fig. 4). The

Acknowledgements

We would like to thank Mike Cunningham, (NIEHS, USA) for providing the human liver samples used to screen for hPPARα-8114.

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