Quantitative proteomic analysis of mouse liver response to the peroxisome proliferator diethylhexylphthalate (DEHP)

Citation
N. Macdonald et al., Quantitative proteomic analysis of mouse liver response to the peroxisome proliferator diethylhexylphthalate (DEHP), ARCH TOXIC, 75(7), 2001, pp. 415-424
Citations number
42
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Pharmacology & Toxicology
Journal title
ARCHIVES OF TOXICOLOGY
ISSN journal
0340-5761 → ACNP
Volume
75
Issue
7
Year of publication
2001
Pages
415 - 424
Database
ISI
SICI code
0340-5761(200109)75:7<415:QPAOML>2.0.ZU;2-#
Abstract
Peroxisome proliferators (PPs) are a diverse group of chemicals that cause hepatic proliferation, suppression of apoptosis, peroxisome proliferation a nd liver tumours in rodents. The biochemical response to PPs involves chang es in the expression of peroxisomal beta -oxidation enzymes and fatty acid transport proteins such as acyl-CoA oxidase and liver fatty acid binding pr otein. The response to PPs is mediated by the peroxisome proliferator-activ ated receptor alpha (PPAR alpha) and the livers of PPAR alpha -null transge nic mice do not develop tumours in response to PPs. In order to identify th e molecular pathways underlying the adverse effects of PPs in rodent liver, we carried out two-dimensional differential gel electrophoresis to provide quantitative proteomic analyses of diethylhexylphthalate (DEHP)treated wil d-type or PPAR alpha -null mouse livers. Since tumourigenesis is both PP- a nd PPAR alpha -dependent, analyses were focused on these changes. Fifty-nin e proteins were identified where altered expression was both PPAR alpha- an d PP-dependent. In addition, six proteins regulated by the deletion of PPAR alpha were identified, possibly indicating an adaptive change in response to the loss of this receptor. The proteins that we identified as being regu lated by PPAR alpha are known to be involved in lipid metabolism pathways, but also in amino acid and carbohydrate metabolism, mitochondrial bioenerge tics and in stress responses including several genes not previously reporte d to be regulated by PPAR alpha. These data provide novel insights into the pathways utilised by PPs and may assist in the identification of early mar kers rodent nongenotoxic hepatocarcinogenesis.