Peroxisome proliferator-activated receptor delta is a specific sensor for teratogenic valproic acid derivatives.
The antiepileptic drug valproic acid (2-propylpentanoic acid) is a potent teratogen in both humans and mice. Valproic acid can induce differentiation of F9 teratocarcinoma cells and stimulate peroxisome proliferator-activated receptor (PPAR) activity. In this study, the structure-activity relationship between valproic acid, its teratogenic and non-teratogenic analogues (branched small- and medium chain fatty acids) and the three PPAR subtypes alpha, gamma or delta was investigated. PPAR-alpha and PPAR-gamma were activated by some valproic acid-derivatives; however, no correlation between teratogenicity and receptor activation could be observed. In contrast, only valproic acid and exclusively its teratogenic analogues were able to activate PPAR-delta in different cellular systems. However, valproic acid appears not to be a direct ligand of PPAR-delta, since in contrast to carbaprostacyclin (cPGI), valproic acid showed not to be able to induce complex formation of PPAR-delta-retinoid X receptor (RXR) heterodimers on DNA. In conclusion, in contrast to PPAR-alpha and PPAR-gamma, PPAR-delta shows to be a specific sensor for teratogenic valproic acid-derivatives.
Lampen
A
A
Zentrumsabteilung für Lebensmitteltoxikologie, Tierärztliche Hochschule Hannover, Bischofsholer Damm 15/115, D-30173, Hannover, Germany. Alfonso.Lampen@tiho-hannover.de
Carlberg
C
C
Nau
H
H
D000469:Alkaline Phosphatase / Q000032:analysis; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D016466:CHO Cells; D006224:Cricetinae; D008024:Ligands; D008156:Luciferases / Q000235:genetics; D051379:Mice; D015394:Molecular Structure; D011485:Protein Binding; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D047488:Retinoid X Receptors; D013329:Structure-Activity Relationship; D013723:Teratogens / Q000494:pharmacology; D014157:Transcription Factors / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D014162:Transfection; D014635:Valproic Acid / Q000031:analogs & derivatives / Q000494:pharmacology* / Q000633:toxicity
D000927:Anticonvulsants; D008024:Ligands; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D013723:Teratogens; D014157:Transcription Factors; D014635:Valproic Acid; D008156:Luciferases; D000469:Alkaline Phosphatase