LTA4, the primary product of 5-LOX, can also be converted with appropriate stimulation via 12-LOX in platelets in vitro to the lipoxins LXA4 and LXB4. These mediators can also be generated through 5-LOX metabolism of 15(S)HETE, the product of 15-LOX-2 metabolism of arachidonic acid. The stereochemical isomer, 15(R)-HETE, may be derived from the action of aspirin-acetylated COX-2 and further transformed in leukocytes by 5-LOX to 15-epi-LXA4 or 15-epi-LXB4, the so-called aspirin-triggered lipoxins. The 15-LOX-1 isoform prefers linoleic acid as a substrate, forming 13(S)-hydroxyoctadecadienoic acid, while the sequential action of 15-LOX-1 and 5-LOX can convert the omega-3 fatty acid docosahexaenoic acid (DHA) to the resolvins, potentially anti-inflammatory, pro-resolving lipids. Synthetic resolvins, lipoxins, 11,12-EET* 20-HETE* CYP2C, 2J CYP3A, 4A, 4F O COOH COOH OOH COOH COOH 5-LOX 5-LOX FLAP 5(S)-HPETE Arachidonic acid
FIGURE 18–3 Leukotriene (LT) biosynthesis. LTC4, LTD4, and LTE4 are known collectively as the cysteinyl (Cys) LTs. FLAP, 5-LOX-activating protein; GT, glutamyl transpeptidase; GL, glutamyl leukotrienase. * Additional products include 5,6-; 8,9-; and 14,15-EET; and 19-, 18-, 17-, and 16-HETE.
and epi-lipoxins exert anti-inflammatory actions when applied in vivo. Although these compounds can be formed from endogenous substrates in vitro and when synthesized may have potent biologic effects, the importance of the endogenous compounds in vivo in human biology remains ill defined. 12-HETE, a product of 12-LOX, can also undergo a catalyzed molecular rearrangement to epoxyhydroxyeicosatrienoic acids called hepoxilins. Proinflammatory effects of synthetic hepoxilins have been reported although their biologic relevance is unclear.
The epidermal LOXs, 12(R)-LOX and LOX-3, are distinct from “conventional” enzymes both in their natural substrates, which appear to not be arachidonic acid and linoleic acid, and in the products formed. Mutations in the genes for 12(R)-LOX (ALOX12B) or LOX-3 (ALOXE3) are commonly associated with autosomal recessive congenital ichthyosis, and epidermal accumulation of 12(R)-HETE is a feature of psoriasis and ichthyosis. Inhibitors of 12(R)-LOX are under investigation for the treatment of these proliferative skin disorders.