Leukotrienes activate the immune system after infection, injury, or contact with allergens. Read on to learn about natural and pharmaceutical options to block them and the genetics that may change the way your body produces and reacts to them.
Leukotrienes are chemical messengers that powerfully activate the immune response. These molecules are formed from the breakdown of arachidonic acid (AA), a fatty acid component of cell membranes that acts as a precursor for a variety of inflammatory chemicals.
Depending on the enzymes present in the cell, LTA4 is then converted into two main types of leukotrienes:
- Leukotriene B4 (LTB4): This type is formed in immune cells with the enzyme LTA4H (neutrophils and monocytes). Its main function is to promote inflammation by activating the production of inflammatory cells (neutrophils) and molecules (cytokines), and recruiting the cells to specific tissues .
- Cysteinyl leukotrienes (CysLT): In immune cells with the enzyme LTC4 synthase (mast cells and eosinophils), LTA4 is transformed into leukotriene C4. Outside the cells, leukotriene C4 is converted to leukotrienes D4 and E4. These types of leukotrienes tighten the airway muscles and produce excess mucus during allergic reactions .
The most useful strategy to decrease leukotriene production is to reduce the activity of:
- Phospholipase A2 (cPLA2 ), the enzyme that releases arachidonic acid from the cell membrane 
- 5-lipoxygenase (5-LOX), the enzyme that initiates the leukotriene pathway 
- FLAP, the activating protein of 5-lipoxygenase 
5-LOX inhibitors include:
The main disadvantage of 5-LOX and FLAP inhibitors is the impaired production of anti-inflammatory compounds (lipoxins and resolvins) .
In this respect, blocking LTA4H and LTC4S is preferable.
The first LTA4H inhibitors were:
LTC4S inhibitors are rare and inefficient, as is the case for:
Leukotriene receptor antagonists (also known as leukotriene modifiers) are drugs that block the action of leukotrienes by preventing their binding to their receptors. The main leukotriene B4 antagonists tested in clinical trials are:
- Etalocib (LY293111): it blocks leukotriene B4 (BLT1) receptor and deactivates 5-LOX. In a cell-based study, it caused cell death in pancreatic cancer cells. However, it failed to increase progression-free survival in a clinical trial on almost 200 people with lung cancer [10, 11].
- CP-105696: this powerful leukotriene B4 receptor (BLT1) blocker successfully reduced the progression of artery hardening in mice [12, 13].
- Amelubant (BIIL284): this leukotriene B4 receptor (BLT1) blocker reduced artery hardening in mice. However, in a clinical trial on over 400 people, this drug increased the incidence of serious side effects in those using it as cystic tissue scarring treatment [14, 15].
- Moxilubant (CGS-25019C): it is a powerful blocker of the leukotriene B4 receptor (BLT1). In mice, it reduced leukotriene B4-induced ear liquid buildup and low white blood cell levels. However, its performance in a clinical trial on 24 people with COPD was poor [16, 17].
- RO5101576: it prevented leukotriene B4-induced lung inflammatory responses in guinea pigs and monkeys, as well as blocking human white blood cell movement .
The most widely used leukotriene receptor blockers are those preventing cysteinyl leukotrienes from binding to their receptor CysLT1. The main commercial drugs in this category are montelukast, zafirlukast, and pranlukast.
- Allergic rhinitis. Its effects are enhanced by antihistamines [19, 20]
- Moderate asthma in adults (including smokers), elderly patients, and children [21, 22, 23, 24]
- Aspirin-, exercise- and allergen-induced asthma [25, 26, 27]
- Chronic obstructive pulmonary disease (COPD) [28, 29]
- Improves nasal airflow in people with allergic rhinitis and reduces nose stuffiness in those allergic to cats [30, 31].
- Reduces excessive airway tightening caused by exercise and moderate asthma in long-term trials [32, 33, 34]
- Reduces inflammation in people with allergic asthma by reducing the influx of white blood cells into the airways and decreasing macrophage (immune cells that capture and digest foreign and harmful material) activation 
- Improves lung function by widening the airways in people with chronic obstructive pulmonary disease (COPD), especially in smokers [36, 37]
- Moderate and severe asthma in people who are not being treated with oral steroids [38, 39]
- Airway inflammation in people treated with oral corticosteroids 
Some natural substances have been found to reduce leukotriene production in animals and cells. However, whether they may help with inflammatory conditions triggered by these molecules in humans remains unknown. If you want to use these compounds as a supportive measure, talk to your doctor to avoid any unexpected interactions.
These plant compounds (alkaloids) blocked the formation of leukotrienes and prostaglandins in cell-based studies:
- Berbamine (found in barberries) 
- Tetrandrine (found in the Chinese medical herb Stephania tetrandra) 
These plant pigments (flavonoids) blocked 5-lipoxygenase (5-LOX), the enzyme that initiates the leukotriene pathway, in cell-based studies:
- Velutin (found in the pink banana) 
- Galangin (found in honey and the herb lesser galangal) 
- Chrysin (found in honey, propolis, honeycomb, passion flowers, and Oroxylum indicum) 
Artonin E (a compound from the root bark of Artocarpus elasticus) effectively blocked 5-LOX purified from pig white cells .
Caffeic acid phenyl ester (CAPE), the active component of honeybee propolis extract, blocks 5-LOX activity and the release of arachidonic acid. In rats, it reduced the production of leukotrienes after stroke [47, 48].
In a cell-based study, capsaicin (found in peppers) and curcumin reduced the conversion of arachidonic into leukotrienes B4 (capsaicin by 46%; curcumin by 61%) and C4 (capsaicin, 48%; curcumin, 34%) in rat macrophages .
A compound in double palm (dammarane triterpenoid 1) triggered cell death in pancreatic and prostate cancer cells in part by inhibiting 5-LOX .
The root of Dystaenia takeshimana contains numerous compounds that inhibited 5-LOX in cell-based studies, namely the coumarins:
and the flavonoids:
A component of fruits from the citrus family (Rutaceae), goshuyuamide II, inhibits leukotriene B4 production by inhibiting 5-LOX .
Diets high in fish oil fatty acids (EPA; mainly found in salmon, sturgeon, eels, oysters, lobsters, shrimps, and crabs and DHA; mainly found in sardines, salmon, trout, tuna, and shellfish) may have anti-inflammatory effects by inhibiting 5-LOX in white blood cells (neutrophils and monocytes) .
Garcinol (found in kokum -Garcinia indica-) blocks leukotriene B4 production .
- Epigallocatechin-3-gallate (EGCG)
- Epigallocatechin (EGC)
- Epicatechin-3-gallate (ECG)
The following compounds from American witch hazel potently inhibited 5-LOX in cell-based studies:
Huang-Lian-Jie-Du-Tang (HLJDT), a traditional Chinese prescription with anti-inflammatory properties, contains the extracts of:
- Baical skullcap (Scutellaria baicalensis): Its compounds baicalein and baicalin powerfully block 5-LOX 
- Coptis Root (Rhizoma coptidis): Its compound coptisine shows moderate blocking of the enzyme that makes leukotriene B4 (LTA4H) .
In rats, lycopene (found in tomatoes, guava, watermelon, sweet red peppers, grapefruit asparagus, and purple cabbage among others) blocked the production of 5-LOX in macrophages found in the thin layer of tissue that lines the stomach and the prostate .
The plant hormone methyl jasmonate triggered cell death in human prostate cancer cells by inhibiting 5-LOX .
In rat white blood cells, treatment with plant-derived oleanolic acid inhibited leukotriene B4 production .
Other compounds acting as potent inhibitors of 5-LOX include:
- Kaempferol (found in apples, grapes, tomatoes, green tea, potatoes, onion, and broccoli among others) 
- Morin (found in Osage orange, old fustic, and common guava) 
- Myricetin (found in Japanese raisin tree and vine tea extracts, parsley, cranberries, broad beans, and blueberries) .
Stemona species’ alkaloids block leukotriene formation:
- Pinosylvin 
- Dihydropinosylvin 
- Stilbostemin A, B, D, F, and G 
- Stemofuran B, C, D, G, and J 
- Stemanthrene A, B, C, and D 
Genetic variants in FLAP (the activating protein of 5-LOX, the enzyme that initiates the lipoxygenase pathway) (rs17222814) and LTA4H (an enzyme that makes leukotriene B4) (rs2247570) are linked to an increased risk of heart attack [74, 75].
Genetic variants that affect the production of the enzyme that initiates leukotriene synthesis (5-LOX) also increase the risk of artery hardening. This effect can be promoted by dietary omega-6 fatty acids and inhibited by omega-3 fatty acids .
The Cyclooxygenase Pathway 
Prostaglandin D2 (PGD2) is produced following exposure to allergens. Its main functions include:
- Smooth muscle contraction 
- Widening of blood vessels 
- Enhanced responses to histamine 
- Promotion of the migration and activation of white blood cells [85, 86, 87]
Prostaglandin E2 (PGE2):
- Causes the main inflammatory symptoms (redness, swelling, and pain) 
- Generates fever 
- Accelerates wound healing 
- Maintains blood vessel tone 
- Promotes the migration and maturation of Th17 white blood cell 
- Suppresses the production of inflammatory molecules (cytokines) [93, 94]
Prostaglandin F2α (PGF2α):
- Tightens the smooth muscles of the blood vessels and bronchi. It is involved in short-term and chronic inflammation. People with arthritis have high levels of this prostaglandin [95, 96, 97, 98]
Prostaglandin I2 (PGI2):
- Widens blood vessels 
- Causes fluid buildup and pain in inflamed tissues 
- Accelerates wound healing in the blood vessels 
- Promotes inflammation in some conditions (rheumatoid arthritis) while reducing it in others (lung vessel diseases, artery hardening) 
Thromboxane A2 (TXA2):
- Promotes the clumping together of platelets [103, 104]
- Causes smooth muscle contraction [103, 104]
- Activates inflammatory responses [103, 104]
Leukotrienes can interact with prostaglandins in many ways during inflammation or injury. They can either block each other’s production and effects or enhance them.
Antagonistic (opposing) interactions:
- Prostaglandin E2 blocks the release of cysteinyl leukotrienes from white blood cells [105, 106].
- Prostaglandins E1 and E2 inhibit the production of leukotriene B4 .
- Leukotrienes and prostaglandin E2 have opposing effects in promoting and preventing phagocytosis (cell engulfing) by white blood cells .
Synergistic (working together) interactions:
- Leukotriene E4 increases the production of prostaglandin D2 .
- Prostaglandin D2 enhances leukotriene C4 production .
- The combination of leukotriene E4 and prostaglandin D2 enhances Th2 cytokine production [111, 112].
- Leukotriene D4 and prostaglandin E2 increase blood vessel inflammation and prostaglandin D2 production by mast cells .
- The combination of cysteinyl leukotrienes and TXA2 in the nose increase nose stuffiness .
Leukotriene E4 enhances the effects of prostaglandin D2 in activating cytokine production by a type of white blood cells (ILC2s) in people with asthma .
Leukotrienes are compounds made from arachidonic acid which activate the immune and inflammatory responses. Excess leukotrienes may promote an unhealthy inflammatory reaction; some anti-allergic medication targets leukotrienes, and many drugs are currently in development to either block leukotriene production or binding to their receptors. The main drugs currently available to block leukotriene binding are montelukast, zafirlukast, and pranlukast.
Some natural compounds may block either the production of leukotrienes or their binding to their receptors. These include active compounds from plants such as aloe, butterbur, black cumin, and boswellia, as well as the well known antioxidant resveratrol.
Certain genetic variants may also change the way each individual person produces and reacts to leukotrienes. In addition, because arachidonic acid can be used to make leukotrienes or prostaglandins, these two families of compounds have complex interactions with one another.