Details

Autor(en) / Beteiligte

• Forsell, Pontus K.A.
• Olsson, Anders O.
• Andersson, Erik
• Nallan, Laxman
• Gelb, Michael H.

Titel

Polychlorinated biphenyls induce arachidonic acid release in human platelets in a tamoxifen sensitive manner via activation of group IVA cytosolic phospholipase A 2-α

Ist Teil von

• Biochemical pharmacology, 2005, Vol.71 (1), p.144-155

Ort / Verlag

Elsevier Inc

Erscheinungsjahr

2005

Quelle

Access via ScienceDirect (Elsevier)

Beschreibungen/Notizen

• Polychlorinated biphenyls (PCBs) are stable compounds commonly found in nature as environmental pollutants. PCBs can affect the endocrine function of hormones such as steroid-hormones. Also, PCBs are known to be inducers of arachidonic acid release in various cells. We report, here, the effects of PCBs on eicosanoid formation, arachidonic acid release and cytosolic phospholipase A 2-α (cPLA 2-α) activation in human platelets. Ortho-substituted PCBs induced a time and dose-dependent release of arachidonic acid and the concomitant formation of 12( S)-hydroxy-5,8- cis-10- trans-14- cis-eicosatetraenoic acid (12-HETE) and 12( S)-hydroxy-5- cis-8,10- trans-heptadecatrienoic acid (12-HHT) in human platelets. The release of arachidonic acid and the formation of 12-HETE was completely blocked by the cPLA 2-α inhibitors AACOCF 3 or pyrrolidine-1. PCB-treatment of platelets demonstrated that the cPLA 2-α protein as well as PLA 2 activity translocated to the membrane fraction, independent of a rise in intracellular Ca 2+. Furthermore, electrophoretic gel mobility shift analysis of cPLA 2-α on SDS-PAGE demonstrated a PCB-dependent phosphorylation of cPLA 2-α. The effects of 17β-estradiol and two structurally unrelated anti-estrogens, nafoxidin and tamoxifen on PCB-induced arachidonic acid release in platelets were also investigated. Both nafoxidin and tamoxifen inhibited PCB-induced arachidonic acid release as well as 12-HETE and 12-HHT formation. Interestingly, platelets incubated with PCBs did not aggregate despite the fact that robust release of arachidonic acid was observed. In summary, these results demonstrate that certain PCBs induce activation of cPLA 2-α independent of a rise in intracellular calcium and a robust release of arachidonic acid release with resulting eicosanoid formation in human platelets.