5-hydroxy-6-8-11-14-eicosatetraenoic-acid and Psoriasis

A novel series of 2- and 3-substituted 1,8-dihydroxy-9(10H)-anthracenones were synthesized and tested for their inhibitory activity against 5-lipoxygenase (5-LO) in bovine polymorphonuclear leukocytes and the growth of human keratinocytes. Structure-activity relationships are discussed with respect to the following redox properties of the compounds: reactivity against 2,2-diphenyl-1-picrylhydrazyl, generation of hydroxyl radicals as measured by deoxyribose degradation, and inhibition of lipid peroxidation in model membranes. Inhibition of cell proliferation seemed to be related to these properties, whereas 5-LO inhibition was not. Within a class of structural analogs the activity against 5-LO, which was markedly improved as compared to that of the antipsoriatic drug anthralin, correlated well with the overall lipophilicity. Even though a number of compounds in this series enhanced oxidative damage to nonlipid molecules such as deoxyribose, their antioxidant properties predominate in membrane lipids. Among the prooxidant compounds were also the most potent antiproliferative agents (IC50 values in the 10(-7) M range).

Topics: Administration, Topical; Animals; Anthracenes; Anti-Inflammatory Agents; Antioxidants; Cattle; Cell Division; Cells, Cultured; Humans; Hydroxyeicosatetraenoic Acids; Keratinocytes; Leukotriene B4; Lipid Peroxidation; Liposomes; Lipoxygenase Inhibitors; Malondialdehyde; Molecular Structure; Neutrophils; Oxidation-Reduction; Psoriasis; Structure-Activity Relationship

Purified serum samples from asthmatic and psoriatic patients and healthy controls were analysed by high-pressure liquid chromatography (HPLC) and the amounts of leukotrienes were measured from the corresponding HPLC fractions by specific radioimmunoassays. In the serum of healthy controls the amounts of leukotrienes B4, C4 and D4 were very small or negligible. Rather great amount of leukotriene B4 was, however, detected in the serum of many asthmatic and psoriatic patients. The amount of leukotriene B4 was in the serum of asthmatic patients 120 +/- 20 pmol/ml (n = 11, mean +/- SEM) and in that of psoriatic patients 100 +/- 10 pmol/ml (n = 10). The amounts of leukotrienes C4 and D4 were rather small in the serum of most patients. The amount of leukotriene C4 was, however, very high (250 pmol/ml) in the serum of a psoriatic patient. Significant amount of leukotriene D4 was also detected in the serum of this patient. The present study indicated that leukotrienes are formed during blood clotting in the leukocytes of asthmatic and psoriatic patients and that the rate of formation is so high that leukotrienes may have a role in these diseases.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Adolescent; Adult; Aged; Asthma; Chromatography, High Pressure Liquid; Female; Humans; Hydroxyeicosatetraenoic Acids; Leukotriene B4; Male; Middle Aged; Psoriasis; SRS-A

Polymorphonuclear leukocytes (PMN) from ten patients with chronic stable plaque psoriasis, five of whom had more than 40% skin involvement and five with less than 20% involvement, responded in a dose-related fashion to stimulation with the arachidonic acid lipoxygenase products 5- and 12-hydroxyeicosatetraenoic acid (5- and 12-HETE) and leukotriene B4 (LTB4) in an in vitro chemokinesis assay. There was no significant difference in either the random migration or the chemokinetic response of psoriatic PMN to LTB4 when compared to the responses of PMN from a group of age- and sex-matched healthy controls. Psoriatic PMN migrated further in response to low doses of 5- and 12-HETE although the distance moved after maximal stimulation was no different to that observed in controls. No significant difference was observed in the responses of PMN obtained from patients with less than 20% skin involvement when compared to those with more extensive psoriasis. The small differences measured between the chemokinetic responses of psoriatic and control PMN to the lipoxygenase products tested are unlikely to be of pathogenetic significance.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Adolescent; Adult; Aged; Arachidonate Lipoxygenases; Chemotaxis, Leukocyte; Female; Humans; Hydroxyeicosatetraenoic Acids; In Vitro Techniques; Leukotriene B4; Lipoxygenase; Male; Middle Aged; Neutrophils; Psoriasis; Skin

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Chromatography, High Pressure Liquid; Humans; Hydroxyeicosatetraenoic Acids; Leukotriene B4; Lipoxygenase Inhibitors; Naphthalenes; Psoriasis; Skin

5-lipoxygenase-derived products of arachidonic acid are implicated in the pathophysiology of psoriasis, a common hyperproliferative and inflammatory skin disease. We therefore examined whether there is an activation of this enzymatic pathway in extracutaneous tissues. For this purpose, we measured the conversion of 14C-arachidonic acid by polymorphonuclear leukocytes from psoriatic patients and controls. No significant difference in the generation of leukotriene B4 and 5-hydroxyeicosatetraenoic acid by polymorphonuclear leukocytes was noted between the two groups. We conclude that in psoriasis there is no enhanced activity of the 5-lipoxygenase pathway in circulating polymorphonuclear leukocytes.

Topics: Adult; Aged; Arachidonate Lipoxygenases; Arachidonic Acid; Arachidonic Acids; Female; Humans; Hydroxyeicosatetraenoic Acids; Leukotriene B4; Lipoxygenase; Male; Middle Aged; Neutrophils; Psoriasis

Skin biopsies and scale extracts from 22 patients with psoriasis were examined for the presence of chemotactic lipoxygenase products of arachidonate metabolism. Heat-stable leukocyte chemotactic activity in aqueous extracts of 2-mm punch biopsies from involved and uninvolved patient skin was significantly elevated, compared to healed psoriatic skin and to skin of normal controls. Ether extracts (pH 3.0) from 13 mg of psoriatic scales contained a mean chemotactic activity corresponding to that of leukotriene B4, 5 X 10(-8) M. On reverse phase high-pressure liquid chromatography, the main chemotactic lipids in scale extracts were leukotriene B4 and 5-HETE. Since lipoxygenase products are potent mediators of inflammation, they may play an important role in the evolution and maintenance of psoriatic lesions.

Topics: Arachidonic Acid; Arachidonic Acids; Biopsy, Needle; Chemotactic Factors; Chemotaxis, Leukocyte; Chromatography, High Pressure Liquid; Humans; Hydroxyeicosatetraenoic Acids; Leukotriene B4; Lipoxygenase; Psoriasis; Skin

Topics: Arachidonic Acids; Chemotaxis, Leukocyte; Humans; Hydroxyeicosatetraenoic Acids; Leukotriene B4; Psoriasis