Peroxisome PPARa

Peroxisome PPARa RXR(DRI) Fatty acids Peroxisome proliferation... 

Persistent activation of PPARa can induce the development of hepatocellular carcinoma in susceptible rodent species by a nongenotoxic mechanism, i.e., one that does not involve direct DNA damage by peroxisome proliferator chemicals or their metabolites. This hepatocarcinogenic response is abolished in mice deficient in PPARa, underscoring the central role of PPARa, as opposed to that of two other mammalian PPAR forms (PPARy and PPAR5), in peroxisome proliferator chemical-induced hepatocarcinogenesis. Other toxic responses, such as kidney and testicular toxicities caused by exposure to certain phthalate... 

Peroxisome Proliferator-Activated Receptors. Table 1 PPARa target tissues, cellular effects, and physiological effects... 

Peroxisome-proliferator activated receptors (PPARs) are lipid-activated transcription factors exerting several functions in development and metabolism. PPARa is implicated in the regulation of lipid metabolism, lipoprotein synthesis, and inflammatory response in liver and other tissues. 

Another group has evaluated self-organizing maps [63] and shape/ pharmacophore models [64]. They developed a new method termed SQUIRREL to compare molecules in terms of both shape and pharmacophore points. Thus from a commercial library of 199,272 compounds, 1926 were selected based on self-organizing maps trained on peroxisome proliferator-activated receptor a (PPARa) "activity islands." The compounds were further evaluated with SQUIRREL and 7 out of 21 molecules selected were found to be active in PPARa. Furthermore, a new virtual screening technique (PhAST) was developed based on representation of molecules as text strings that describe their pharmacophores [65]. 

In addition to PXR, the expression of UGT1A1 and several other UGT isoforms have also been reported to be regulated by several other nuclear receptors, including constitutive androstane receptor (CAR) [25,27,28] and peroxisome proliferator activated receptor a (PPARa) [29,30],... 

PPARa Peroxisome proliferators-activated receptor type alpha... 

ASBT has a complex regulatory system reflecting the importance of this transporter to bile-acid pool size and bile-acid synthesis rates. Hepatic nuclear factor la (HNF-la) is necessary for expression of ASBT as knockout mice showed no expression and had defective bile-acid transport.Conversely, FXR-null mice showed no difference in expression of ASBT, showing that FXR plays no part in regulation of ASBT. In man, HNF-la controls baseline promoter activity of the ASBT gene as the minimal construct with full promoter activity was found to have 3 HNF-la binding sites. These authors also showed that the promoter construct bound peroxisome proliferator activated receptor a (PPARa)/9 cis retinoic acid receptor heterodimer, demonstrating a link between bile-acid absorption and hepatic lipid metabolism mediated by PPARa. 

Studies of peroxisome proliferator-activated receptor a (PPARa)... 

Studies of PPARa activation in vitro have shown that di(2-ethylhexyl) phthalate metabolites are capable of activating PPARa. A study of PPARa knock-out mice treated with di(2-ethylhexyl) phthalate in vivo demonstrated that the increased liver weights and induction of peroxisomal and microsomal enzymes are absolutely dependent on PPARa (Ward et al, 1998). 

Recent evidence confirms that species differences can involve more than one aspect of PPARa-mediated regulation of gene expression. The insensitivity of human liver to rodent peroxisome proliferators is associated with low levels of expression of PPARa in human liver. Marked species differences in the expression of PPARa mRNA have been demonstrated between rodent and human liver, with the latter expressing 1-10% of the levels found in mouse or rat liver (Palmer et al, 1994 Tugwood et al, 1996 Palmer etal, 1998). Using a sensitive and specific immuno/DNA binding assay. Palmer et al (1998) have shown that active PPARa protein is expressed at variable concentrations in human livers. The study compared 20 different human livers and found that those with the highest levels of PPARa protein expression contained less than 10% of the level in mice. Most of the samples (13/20) contained no detectable PPARa activity, but did... 

Rodent peroxisome proliferators exercise their pleiotropic effects in liver due to activation of PPARa. This process is essential for liver hypertrophy and... 

The absence of a significant response of human liver to induction of peroxisome proliferation and hepatocellular proliferation is explained by several aspects of PPARa-mediated regulation of gene expression. 

Hepatic peroxisome proliferation depends on a nuclear receptor, PPARa, to mediate these responses in mice, based on lack of response to peroxisome proliferators in PPARa-deficient mice. In one study with another peroxisome proliferator, WY-14,643, carcinogenesis was shown to be dependent on the same receptor. Oral administration of di(2-ethylhexyl) phthalate failed to elicit markers of peroxisome proliferation in PPARa-deficient mice, while the same treatment elicited this response in normal mice. Metabolites of di(2-ethylhexyl) phthalate caused activation of PPARa-mediated gene expression in mammalian cell co-transfection assays. Differences between responsive rodents and humans in various aspects of PPARa-mediated regulation of gene expression are consistent with the lack of activity of di(2-ethylhexyl) phthalate metabolites in hepatocyte cultures from 12 people studied to date. 

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... 

Bauer, M.J. Herrmann, R. (1997) Estimation of the environmental contamination by phthalic acid esters leaching from household wastes. Sci. total Environ., 208, 49-57 Bell, A.R., Savoiy, R., Horley, N.J., Choudhuiy, A.I., Dickins, M., Gray, T.J.B, Salter, A M. Bell, D.R. (1998) Molecular basis of non-responsiveness to peroxisome proliferators the guinea-pig PPARa is functional and mediates peroxisome proliferator-induced hypolipidaemia. Biochem. J., 332, 689-693... 

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... 

Tugwood, J.D., Holden, P.R., James, N.H., Prince, R.A. Roberts, R.A. (1998) A peroxisome proliferator-activated receptor-alpha (PPARa) cDNA cloned from guinea-pig liver encodes a protein with similar properties to the mouse PPARa implications for species differences in responses to peroxisome proliferators. Arch. Toxicol., 72, 169-177 Turner, J.H., Petricciani, J.C., Crouch, M.L. Wenger, S. (1974) An evaluation of the effects of diethylhexyl phthalate (DEHP) on mitotically capable cells in blood packs. Transfusion, 14, 560-566... 

Studies of PPARa activation in vitro or in PPARa knock-out mice in vivo have not yet been conducted with di(2-ethylhexyl) adipate however, given that the receptor mediates the same response for a variety of other peroxisome proliferators, it is likely... 

Hepatic peroxisome proliferation has not been evaluated in studies of human subjects or systems treated with di(2-ethylhexyl) adipate. However, interspecies comparisons with other peroxisome proliferators, along with the role of PPARa in this response, indicate that humans can reasonably be predicted to be refractory to induction of peroxisome proliferation and hepatocellular proliferation by di(2-ethylhexyl) adipate. 

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