dinoprost and pirinixic-acid

In the present study, we investigated the in vitro effects of peroxisome proliferator activated receptor (PPAR) ligands on PGF2α secretion and mRNA expression of prostaglandin F synthase (PGFS) in porcine endometrial explants collected on days 10-12 and 14-16 of the estrous cycle or pregnancy. The explants were incubated for 6h with: PPARα ligands - WY-14643 (agonist) and MK 886 (antagonist); PPARβ ligands - l-165,041 (agonist) and GW 9662 (antagonist); PPARγ ligands - 15d-prostaglandin J2 (PGJ2, agonist), rosiglitazone (agonist) and T0070907 (antagonist). The expression of PGFS mRNA in the endometrium and the concentration of PGF2α in culture media were determined by real time RT-PCR and radioimmunoassay, respectively. During the estrous cycle (days 10-12 and 14-16), the agonists - WY-14643 (PPARα), l-165,041 (PPARβ), PGJ2 and rosiglitazone (PPARγ) - increased PGF2α secretion but did not affect PGFS mRNA abundance. During pregnancy (days 10-12 and 14-16), PPARα and PPARγ ligands did not change PGF2α release, whereas PPARβ agonist augmented PGF2α release on days 14-16 of pregnancy. In addition, WY-14643 and l-165,041 increased PGFS mRNA level in both examined periods of pregnancy. PPARγ agonist (PGJ2) and antagonist (T0070907) enhanced PGFS mRNA abundance in the endometrium on days 10-12 and 14-16 of pregnancy, respectively. The results indicate that PPARs are involved in the production of PGF2α by porcine endometrium, and that the sensitivity of the endometrium to PPAR ligands depends on reproductive status of animals.

Topics: Analysis of Variance; Anilides; Animals; Benzamides; Culture Media; Dinoprost; DNA Primers; Endometrium; Estrous Cycle; Female; Indoles; Peroxisome Proliferator-Activated Receptors; Phenoxyacetates; Pregnancy; Prostaglandin D2; Pyridines; Pyrimidines; Radioimmunoassay; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; Rosiglitazone; Swine; Thiazolidinediones

It has been proposed that nongenotoxic peroxisome proliferators may cause hepatocellular cancer by an oxidative damage-mediated mechanism(s). The argument for this hypothesis is based mainly on the noted ability of peroxisome proliferators to induce significantly H2O2-producing peroxisomal beta-oxidation while causing a minimal induction of H2O2-degrading catalase. The recent discovery, accurate determination, and use of isoprostanes as a sensitive indicator of oxidative damage prompted us to investigate whether induction of hepatic peroxisomal beta-oxidation in male B6C3F1 mice is accompanied by elevated levels of isoprostanes in those livers. The data show that while 7 days of feeding mice a diet containing 100 ppm [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio]acetic acid (WY-14,643) increased peroxisomal beta-oxidation by 16-fold and catalase activity by only 2-fold, hepatic levels of esterified F2-isoprostanes were not altered. These levels were 2.8 +/- 0.5 ng/g liver in control mice and 2.4 +/- 0.1 ng/g liver in mice fed the experimental diet for 7 days. Consequently, it is concluded that oxidative stress does not appear to occur in response to peroxisome proliferation, as evidenced by the lack of increase in hepatic levels of F2-isoprostanes in livers of mice treated with the potent peroxisome proliferator WY-14,643.

Topics: Acyl-CoA Dehydrogenase; Animals; Carcinogens; Diet; Dinoprost; Fatty Acid Desaturases; Liver; Male; Mice; Microbodies; Oxidative Stress; Pyrimidines