Effects of Lipoxygenase & Cytochrome P450-Derived Metabolites

Effects of Lipoxygenase & Cytochrome P450-Derived Metabolites

The actions of lipoxygenases generate compounds that can regu-late specific cellular responses important in inflammation and immunity. Cytochrome P450-derived metabolites affect nephron transport functions either directly or via metabolism to active compounds . The biologic functions of the various forms of hydroxy- and hydroperoxyeicosaenoic acids are largely unknown, but their pharmacologic potency is impressive.

A. Blood Cells and Inflammation

LTB₄, acting at the BLT₁ receptor, is a potent chemoattractant for T lymphocytes, eosinophils, monocytes, and possibly mast cells; the cysteinyl leukotrienes are potent chemoattractants for eosino-phils and T lymphocytes. Cysteinyl leukotrienes may also generate distinct sets of cytokines through activation of mast cell cysLT₁ and cysLT₂. At higher concentrations, these leukotrienes also pro-mote eosinophil adherence, degranulation, cytokine or chemokine release, and oxygen radical formation. Cysteinyl leukotrienes also contribute to inflammation by increasing endothelial permeabil-ity, thus promoting migration of inflammatory cells to the site of inflammation. The leukotrienes have been strongly implicated in the pathogenesis of inflammation, especially in chronic diseases such as asthma and inflammatory bowel disease.

Lipoxins have diverse effects on leukocytes, including activa-tion of monocytes and macrophages and inhibition of neutrophil, eosinophil, and lymphocyte activation. Both lipoxin A and lipoxin B inhibit natural killer cell cytotoxicity.

B. Heart and Smooth Muscle

1. Cardiovascular— 12(S)-HETE promotes vascular smoothmuscle cell proliferation and migration at low concentrations; it may play a role in myointimal proliferation that occurs after vas-cular injury such as that caused by angioplasty. Its stereoisomer, 12(R )-HETE, is not a chemoattractant, but is a potent inhibitor of the Na⁺/K⁺-ATPase in the cornea. LTC₄ and LTD₄ reduce myo-cardial contractility and coronary blood flow, leading to cardiac depression. Lipoxin A and lipoxin B exert coronary vasoconstric-tor effects in vitro. In addition to their vasodilatory action, EETs may reduce cardiac hypertrophy as well as systemic and pulmo-nary vascular smooth muscle proliferation and migration.

2. Gastrointestinal—Human colonic epithelial cells synthesizeLTB₄, a chemoattractant for neutrophils. The colonic mucosa of patients with inflammatory bowel disease contains substantially increased amounts of LTB₄.

3. Airways—The cysteinyl leukotrienes, particularly LTC₄andLTD₄, are potent bronchoconstrictors and cause increased micro-vascular permeability, plasma exudation, and mucus secretion in the airways. Controversies exist over whether the pattern and specificity of the leukotriene receptors differ in animal models and humans. LTC₄-specific receptors have not been found in human lung tissue, whereas both high- and low-affinity LTD₄ receptors are present.

C. Renal System

There is substantial evidence for a role of the epoxygenase prod-ucts in regulating renal function although their exact role in the human kidney remains unclear. Both 20-HETE and the EETs are generated in renal tissue. 20-HETE, which potently blocks the smooth muscle cell Ca²⁺-activated K⁺ channel and leads to vasoconstriction of the renal arteries, has been implicated in the pathogenesis of hypertension. In contrast, studies support an anti-hypertensive effect of the EETs because of their vasodilating and natriuretic actions. EETs increase renal blood flow and may protectagainst inflammatory renal damage by limiting glomerular mac-rophage infiltration. Inhibitors of soluble epoxide hydrolase, which prolong the biologic activities of the EETs, are being devel-oped as potential new antihypertensive drugs. In vitro studies, and work in animal models, support targeting soluble epoxide hydro-lase for blood pressure control, although the potential for pulmo-nary vasoconstriction and tumor promotion through antiapoptotic actions require careful investigation.

D. Miscellaneous

The effects of these products on the reproductive organs have not been elucidated. Similarly, actions on the nervous system have been suggested but not confirmed. 12-HETE stimulates the release of aldosterone from the adrenal cortex and mediates a por-tion of the aldosterone release stimulated by angiotensin II but not that by adrenocorticotropic hormone. Very low concentrations of LTC₄ increase and higher concentrations of arachidonate-derived epoxides augment luteinizing hormone (LH) and LH-releasing hormone release from isolated rat anterior pituitary cells.