Novel Aspects Related to Biosynthesis and Biological Actions of Hepoxilins: Interrelationship with Phospholipid Hydroperoxide Glutathione Peroxidase (PHGPx)

Abstract

The 12-lipoxygenase (12-LOX) pathway of AA metabolism in platelets and other cells is bifurcated at the level of the oxygenated product 12-hydroperoxyeicosatetranoic acid (12-HPETE) into a reduction route leading to 12-HETE as a primary product and an isomerization route forming hepoxilins (HXA₃ and HXB₃) as major products. Both 12-HETE and hepoxilins are biologically active eicosanoids and possess a myriad of biological actions [1,2 and references therein]. Glutathione peroxidases, which are key players in the defense of tissues and cells against the oxidative damage [3], are also intimately involved in the regulation of AA metabolism [4–7]. This role has been attributed to glutathione peroxidases for following reasons: (a) they reduce the hydroperoxyfatty acids formed by lipoxygenases or cyclooxygenases to corresponding alcohols, (b) they regulate the hydroperoxide tone of the system, which is contributed largely by the hydroperoxyfatty acids. It is known that a low hydroperoxide tone functions as a stimulus for lipoxygenase and cyclooxygenase reactions but a higher hydroperoxide tone causes suicide inactivation of dioxygenases and of substrates for hydroperoxidase reaction [8]. Four different glutathione peroxidases, which are characterized by the selenocysteine group at the active site, are known up until now [3]: cytosolic glutathione peroxidase (GPx-1), PHGPx (GPx4), plasma GPx (pGPx), and gastrointestinal GPx (GIGPx). But, only GPx-1 and PHGPx play a significant role in the intracellular metabolism of eicosanoids. Several studies in the past dealing with the role of glutathione peroxidases in the eicosanoid metabolism of platelets considered predominantly GPX-1 as the sole enzyme. To our knowledge no evidence for the coeval occurrence of PHGPx in platelets has been demonstrated so far. The present study provides an evidence for the presence of PHGPx in platelets. Its pivotal role in the regulation of 12-LOX pathway has been demonstrated by the inactivation of glutathione peroxidases by iodoacetate without any inactivation of 12-LOX [9] as well as in selenium-deficient cells.