Leukotrienes, Antileukotrienes and Asthma

Abstract

Leukotrienes (LTs), including LTB(4) and cysteinyl-LTs (CysLTs) (LTC(4), LTD(4), and LTE(4)), are potent inflammatory lipid mediators which are derived from 5-lipoxygenase activity. CysLTs, which stimulate CysLT(1) and CysLT(2) receptor subtypes, are functionally involved in the pathophysiology of asthma. Selective CysLT(1) receptor antagonists are effective anti-asthmatic drugs. CysLT(1) receptor antagonists have been developed from leukotriene structural analogs, analogs of FPL 55712, a chromone carboxylic acid, and by random screening of corporate compound banks. This review will examine the biosynthesis, metabolism and mechanism of action of leukotrienes, their role in asthma, the therapeutic implications of the leukotriene pathway inhibition for asthma, and the medicinal chemistry strategies that have been exploited in the design of potent and selective CysLT(1) receptor antagonists.

Endogenous Functions of the Aryl Hydrocarbon Receptor (AHR): Intersection of Cytochrome P450 1 (CYP1)-metabolized Eicosanoids and AHR Biology

“…Specific receptors for prostaglandins (24 -26) and for other eicosanoids (27)(28)(29) are being characterized, many of which are G-protein-coupled receptors, but the field is still in its infancy; perhaps other heretofore unknown reception systems also exist (Fig. 1C).…”

Expression of Inactive Glutathione Peroxidase 4 Leads to Embryonic Lethality, and Inactivation of theAlox15Gene Does Not Rescue Such Knock-In Mice

“…Among the six human LOX isoforms ALOX15 is somewhat unique (24) because it is capable of oxidizing phospholipids (36) and cholesterol esters (1) as constituents of biomembranes and lipoproteins. Alox5 has a central role in chronic airway diseases including asthma (31). Glutathione peroxidases reduce hydroperoxides (7) and among the eight human GPX-isoforms GPX4 is unique because of its capability of reducing complex hydroperoxy lipids (43, 45).…”

Electrophilic Fatty Acid Species Inhibit 5-Lipoxygenase and Attenuate Sepsis-Induced Pulmonary Inflammation

“…Inflammatory responses are induced, in part, by proinflammatory COX-2-derived prostaglandins (PG) and lipoxygenase (LO)-dependent leukotriene (LT) synthesis (24). Eicosanoids such as PGE 2 and LTB 4 are potent modulators of inflammation, regulating leukocyte recruitment and activation and thus increasing vascular permeability and edema formation (10,25).…”