The peroxisome proliferators

In the rodent, the evidence for liver tumors in response to PPs is clear and unequivocal. In addition to this hepatocarcinogenesis, 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 acyl CoA oxidase, ACO. Levels of ACO are increased dramatically in the livers of rodents treated with PPs but there is no increase in this enzyme in humans. Because of the close association between peroxisome proliferation and ACO, this enzyme is used as a marker or indicator of the rodent response to PPs. The hnk between peroxisome proliferation and hepatocarcinogenesis remains to be elucidated. However, evidence suggests a commonality and there is consensus that peroxisome proliferation is necessary but not srrfficient per 

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The thiazolidinediones have also been reported to act as inhibitors of the respiratory chain at high concentrations, and this appears to account for their ability to activate AMGPK in cultured cells. However, the primary target of the thiazolidinediones appears to be the peroxisome proliferator-activated receptor-y ( PPAR-y), a member of the nuclear receptor superfamily expressed in adipocytes. One of the major effects of stimulation of PPAR-y in adipocytes is the release ofthe... 

Thiazolidinediones (PPARy-agonists) Thiazolidine-diones ( pioglitazone, rosiglitazone) lower blood glucose levels in animal models of insulin resistance and also in insulin resistant patients. They are agonists of the peroxisome proliferator-activated receptor y (PPARy). Because they enhance the effect of insulin and reduce serum insulin levels in insulin resistant patients, thiazolidinediones are usually referred to as insulin sensitizers . 

Di- and mono-esters of phthalic acid, an ortho-dicarboxylic acid derivative of benzene. These compounds are widely used as industrial plasticizers to coat polyvinylchloride surfaces of plastics used in food packaging and medical devices (iv drip bags, blood storage bags, etc.) and are common environmental contaminants. Several phthalate mono-esters are peroxisome proliferator chemicals and can activate the peroxisome proliferator-activated receptor PPAR. 

Chevalier S et al. Proteomic analysis of differential protein expression in primary hepatocytes induced by EG F, tumour necrosis factor alpha or the peroxisome proliferator nafenopin. Eur J Biochem 2000 267 4624-4634. 

Takagi A, Sai K, Umemura T, et al. 1990. Significant increase of 8-hydroxyguanosine in liver DNA of rats following short-term exposure to the peroxisome proliferators di(2-ethylhexyl)phthalate and di(2-ethylhexyljadipate. Jpn J Cancer Res 81 213-215. 

Both MOZ and MORF have also been linked to control of transcription. In initial analyses, these MYST HATs were found to contain potent trans-activation domains in their C-termini (Champagne et al, 1999 2001). Follow-up studies demonstrated that the two proteins can indeed function as transcriptional co-activators for two Runt-domain transcription factors - Runxl and 2 (also referred to as AMLl 3) (Kitabayashi et al., 2001a Pelletier et al., 2002). Furthermore, MORF has been found in the co-activator complex associated with the peroxisome proliferator-activated receptor alpha in rat liver (Surapureddi et al., 2002). 

The farnesoid X receptor is a member of the class of nuclear hormone receptors, which have key roles in development and homeostasis, as well as in many diseases like obesity, diabetes and cancer. The farnesoid X receptor shows structural similarity to the estrogen receptor (ER ), which mediates a broad spectrum of physiological functions such as regulation of reproduction, modulation of bone density, cholesterol transport and breast cancer. The farnesoid X receptor also shows similarity with the peroxisome proliferation-activated receptor y (PPARy), which is involved in fat metabolism, inflammatory and immune responses. The estrogen receptor (ER ), the peroxisome proliferation-activated receptor y (PPARy) and the farnesoid X receptor (FXR) can be clustered in a... 

Rats fed diets containing 30 or 300ppm ammonium perfluorooctanoate for 2 years had increased liver weights with occasional necrosis and an apparent dose-dependent increase in Leydig cell adenomas, but there was no evidence of an increased incidence of hepatocellular carcinoma. In a follow-up study in male mice, 300ppm in the diet for 2 years caused increases in liver, Leydig cell, and pancreatic acinar cell tumors that may have been associated with the peroxisome-proliferating capabilities of the compound. Ammonium perfluorooctanoate also produced sustained increases in serum estradiol concentrations. ... 

The 3,4-dihydro-22/-l,3-benzoxazin-4-one derivative DRF-2519 587, bearing a 2,4-thiazolidinedione moiety in the side chain attached to the nitrogen atom, proved to be an activator of the a- and y-types of the peroxisome proliferator-activated receptors (PPAR-a and -7), which endowed it with antidiabetic and hypolipidemic potential. Compound 587 demonstrated significant plasma glucose-, insulin-, and lipid-lowering activity in mice and improvement in lipid parameters in fat-fed rats <2006BMC584>. 

Significant species differences have been observed in the absorption and disposition of di(2-ethylhexyl) phthalate. The peroxisome-proliferating effect of di(2-ethyl-hexyl) phthalate has been related most specifically in susceptible species to metabolites VI, IX and mono(2-ethylhexyl) phthalate however, analysis of the disposition data does not provide an explanation for the observed species differences in di(2-ethylhexyl) phthalate-induced hepatic peroxisome proliferation. 

Aoyama, T., Peters, J.M., Iritani, N., Nakajima, T., Furihata, K., Hashimoto, T. Gonzalez, F.J. (1998) Altered constitutive expression of fatly acid-metabohzing enzymes in mice lacking the peroxisome proliferator-activated receptor a (PPARa). J. biol. Chem., 213, 5678-5684... 

Hagiwara, A., Tamano, S., Ogiso, T, Asakawa, E. Fukushima, S. (1990) Promoting effect of the peroxisome proliferator, clofibrate, but not di(2-ethylhexyl)phthalate, on urinary bladder carcinogenesis in F344 rats initiated by A-butyl-A-(4-hydroxybutyl)nitrosamine. Jpn. J. Cancer Res., 81,1232-1238... 

Mallette, F.S. von Haam, E. (1952) Studies on the toxicity and skin effects of compounds used in the mbber and plastics indnstiies. II. Plasticizers. Arc/r. ind. Hyg. occup. Med., 6, 231-236 Maloney, E.K. Waxman, D.J. (1999) iran -Activation of PPARa and PPARyby stmcturally diverse enviromnental chemicals. Toxicol, appl. Pharmacol, 161, 209-218 Marsman, D.S., Cattley, R.C., Conway, J.G Popp, J.A. (1988) Relationship of hepatic peroxisome proliferation and replicative DNA synthesis to the hepatocarcinogenicity of the peroxisome proliferators di(2-ethylhexyl)phthalate and [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio]acetic acid (Wy-14,643) in rats. Cancer Res., 48, 6739-6744... 

Marayama, H., Tanaka, T. Williams, GM. (1990) Effects of the peroxisome proliferator di(2-ethylhexyl)phthalate on enzymes in rat liver and on carcinogen-induced liver altered foci in comparison to the promoter phenobarbital Toxicol. Pathol., 18, 257-267 Matsushima, T, Muramatsu, M. Haresaku, M. (1985) Mutation tests on Salmonella typhimurium by the preincubation method. Prog. Mutat. Res., 5, 181-186 Matthews, E.J., DelBalzo, T. Rundell, J.O. (1985) Assays for morphological transformation and mutation to ouabain resistance of Balb/c-3T3 cells in culture. Prog. Mutat. Res., 5, 639-650... 

Miyata, K.S., McCaw, S.E., Patel, H.V., Rachubinski, R.A. Capone, J.P. (1996) The orphan nuclear hormone receptor LXR a interacts with the peroxisome proliferator-activated receptor and inhibits peroxisome proliferator signaling. J. biol. Chem., 271, 9189-9192... 

Popp, J.A., Garvey, L.K., Hamm, T.E., Jr Swenberg, J.A. (1985) Lack of hepatic promotional activity by the peroxisomal proliferating hepatocarcinogen di(2-ethylhexyl)phthalate. Carcinogenesis, 6,141-144 Preston, M.R. Al-Omran, L.A. (1989) Phthalate ester speciation in estuarine water, suspended particulates and sediments. Environ. Pollut., 62, 183-193 Priston, R.A.J. Dean, B.J. (1985) Tests for the induction of chromosome aberrations, polyploidy and sister-chromatic exchanges in rat liver (RL4) cells. Prog. Mutat. Res., 5, 387-395... 

Woodyatt, N.J., Lambe, K.G, Myers, K.A., Tugwood, J.D. Roberts, R.A. (1999) The peroxisome proliferator (PP) response element upstream of the human acyl CoA oxidase gene is inactive among a sample human population significance for species differences in response to PPs. Carcinogenesis, 20, 369-372... 

The receptor protein (52 kDa) is a member of the steroid hormone receptor superfamily, which has a DNA-binding as well as ligand-binding domain. Another receptor, the retinoid X receptor is also involved, and after binding of the peroxisome proliferator, the two receptors form a heterodimer. This binds to a regulatory DNA sequence known as the peroxisome proliferator response element. The end result of the interaction between peroxisome proliferators and this system is that genes are switched on, leading to increases in synthesis (induction) of both microsomal and peroxisomal enzymes and possibly hyperplasia. 

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