The leukotrienes are potent inflammatory mediators which may have a role in inflammatory diseases such as allergic rhinitis, inflammatory bowel disease and asthma. The clinically important leukotrienes are LTB4 and the cysteinyl leukotrienes (CysLTs). To make leukotrienes, cells need 5-lipoxygenase and a protein co-factor, 5-lipoxygenase activating protein (FLAP). Drugs that act on either 5-lipoxygenase or FLAP will inhibit the synthesis, and hence the actions, of both the CysLTs and LTB4. There are two distinct receptor types for the CysLTs (CysLT1 and CysLT2 receptors) and one for LTB4 (BLT receptor). LTB4 is a potent chemotactic agent and attracts pro-inflammatory cells, e.g. neutrophils and eosinophils, into tissues. The CysLTs contract airway and some vascular smooth muscle, stimulate mucus secretion and increase microvascular permeability.

Leukotrienes, together with the prostaglandins and other related compounds, are derived from 20 carbon (eicosa) fatty acids that contain double bonds (enoic). Hence this group of substances is called the eicosanoids. The name leukotriene derives from the original discovery of these substances in white blood cells (polymorphonuclear leucocytes) and the fact that they all have in common 4 double bonds (hence the 4 subscript), 3 of which are in a conjugated triene structure.

Leukotrienes do not exist preformed in cells. They are formed from the breakdown of arachidonic acid, a polyunsaturated 20 carbon fatty acid. In its esterified form, arachidonic acid is bound to the phospholipids of the cell membranes. Both immunological and non-immunological stimuli can release arachidonic acid from membrane phospholipids by activating phospholipase A2. The glucocorticosteroid drugs can inhibit phospholipase A2 and thereby decrease the production of all the leukotrienes and hence leukotriene-mediated responses.

The released arachidonic acid can be metabolised to oxygenated products by several distinct enzyme pathways (Fig. 1). The main ones are:

  • the cyclooxygenase pathway that results in the formation of the prostaglandins and thromboxanes (together known as the prostanoids)
  • the lipoxygenase pathway that produces several, chemically different leukotrienes (and other intermediate compounds).

Biosynthesis of leukotrienes from arachidonic acid
The first steps in the generation of leukotrienes are catalysed by the calcium and ATP-dependent enzyme 5-lipoxygenase. This is one of a family of lipoxygenase enzymes that metabolise arachidonic acid to hydroperoxyeicosatetraenoic acids (HPETEs). Each enzyme catalyses the insertion of an oxygen moiety at a specific position in the arachidonic acid backbone. 5-lipoxygenase forms 5-HPETE, the precursor of the leukotrienes.

When cells are activated, cytosolic 5-lipoxygenase is translocated to the nuclear membrane. A nuclear membrane protein, 5-lipoxygenase activating protein (FLAP), is required before 5-lipoxygenase can synthesise 5-HPETE from arachidonic acid. Compounds are now available that block the biosynthesis of the leukotrienes through specific inhibition of 5-lipoxygenase e.g. zileuton (approved for asthma treatment in the U.S.A.). Experimental drugs are also available that inhibit leukotriene synthesis by inhibition of FLAP.

The rearrangement of 5-HPETE to form the unstable LTA4 is the rate-limiting step in the synthesis of the leukotrienes. This step is catalysed by LTA synthase. LTA4 is then converted to either LTB4 or LTC4. LTC4 is actively transported out of cells and rapidly metabolised to LTD4 and then to LTE4 (see Fig. 1 for enzymes involved in these steps). LTC4, LTD4 and LTE4 are referred to as the cysteinyl (Cys) leukotrienes because of their chemical structure. LTE4 is either excreted in the urine or metabolised to a variety of biologically less active, or inactive, metabolites, including LTF4.

In summary, the ability of cells to synthesise leukotrienes depends on

  • their enzymic capacity to cleave arachidonic acid from its phosphorylated store
  • the 5-lipoxygenase system to synthesise LTA4

The lungs contain cells that have the full capacity to synthesise all the leukotrienes de novo. Hence, there has been significant interest in their effects on the lung.

Fig. 1

The main pathways to the formation of the leukotrienes and the sites of action of the current drug groups (in boxes) that can attenuate leukotriene responses.

Normal font - main pathways
Bold - enzymes
Boxed italics - drug groups (in red)

Leukotriene receptors
Early studies of the leukotrienes focused on their functional responses and their rank order of potency as agonists for various responses. These studies revealed that responses to LTB4, and hence possibly its receptor, were distinguishable from those of the CysLTs. There was also an indication that there may be subtypes of receptors for the CysLTs. Since then, attempts have been made to classify and satisfactorily name the leukotriene receptors. An IUPHAR (International Union of Pharmacology) committee on drug classification and nomenclature developed recommendations for the leukotriene receptors. The current (1998) nomenclature is summarised in Table 1, together with the order of potency of the leukotrienes and the names of some selective antagonist drugs.

The classification, based mainly on functional data, recognises a distinct receptor for LTB4 (now called the BLT receptor) and subtypes of receptors for the CysLTs (now called the CysLT1 and CysLT2 receptors). At present, there are no useful selective agonist compounds for any of the leukotriene receptor types. Numerous compounds have been shown to be selective antagonists of BLT or CysLT1 receptors in animal studies. Some of the CysLT1 receptor antagonists are now being used in the treatment of asthma. There is no selective antagonist for the CysLT2 receptors. The compound, BAY u9773, appears to be a non-selective blocker of both CysLT1 and CysLT2 receptors. Hence, at present, those responses that are not blocked by one of the selective CysLT1 receptor antagonists are assumed to be mediated by CysLT2 receptors.

The classification of the type(s) of receptor mediating the different responses to the leukotrienes is still evolving because of the lack of a complete range of selective agonists and antagonists and a lack of success in cloning and sequencing the CysLT receptors.

BLT receptors
LTB4 is a potent chemotactic agent for neutrophils, eosinophils and monocytes. It promotes the adhesion of neutrophils to the vascular endothelium and enhances their migration across the endothelial wall into the surrounding tissue. LTB4 also increases the release of toxic oxygen products, lysosomal enzymes and cytokines from pro-inflammatory cells.

CysLT receptors
It was shown in the 1930s that, if the lungs from sensitised guinea-pigs were perfused with sensitising antigen, a substance was released that could cause a slow contraction of isolated smooth muscle preparations. This substance was called slow reacting substance. It was later renamed slow reacting substance of anaphylaxis and, in the early 1980s, it was identified as a mixture of the CysLTs.

In addition to the contractile responses in the lung, CysLTs have been shown to contract human coronary artery and distal and mesenteric pulmonary artery. They have no effect on most systemic large arteries or on the renal vasculature.

In the early studies, the contractile effects of the leukotrienes in airway, lung, vascular and other tissue preparations were explored. Data from these studies, together with that from ligand binding studies and from experiments with FPL 55712, the first drug shown to block responses to the leukotrienes, indicated that there might be distinct receptors for LTD4 and LTC4. Subsequently, the effects of the newer, more selective, CysLT1 receptor antagonists and BAY u9773 on responses to LTD4, LTE4 and/or LTC4 have allowed us to predict the receptor type(s) likely to be involved in some tissues.

Human bronchi may have a homogeneous population of CysLT1 receptors, whereas guinea-pig trachea and ileum probably have both CysLT1 and CysLT2 receptors. Some tissues, e.g. guinea-pig and human lung, may have an additional receptor, but this is controversial. The current classification may be an oversimplification and it is likely to be modified as more data accumulate, appropriate tools are found and the molecular features of the receptors are unravelled.

Table 1
Current nomenclature for the leukotriene receptors, based on that published by the IUPHAR nomenclature subcommittee.1 Also shows relative potency of agonists and some key selective antagonists.

Leukotriene receptor type

BLT receptor CysLT1 receptor CysLT2 receptor
Previously known as LTB4 receptor LTD4 receptor LTC4 receptor
Order of potency of agonists LTB4>12(R)-HETE (LTC4 and LTD4 are mainly inactive) LTD4=LTC4>LTE4 (LTE4 is a partial agonist in some tissues) LTC4>LTD4>LTE 4 (LTE4 is a partial agonist in some tissues)
Selective antagonists LY 293111 montelukast BAY u9773 is a
SC 53228 iralukast non-selective
SB209247 pobilukast antagonist at
CP 105696 zafirlukast CysLT1 and
CGS 25019C pranlukast CysLT2 receptors

Action in asthma
The leukotrienes are primarily endogenous mediators of inflammation. They contribute to the signs and symptoms seen in acute inflammatory responses. This includes responses resulting from the interaction of allergens with IgE antibodies on mast cells. In vivo, the CysLTs are bronchoconstrictors. After inhalation of these leukotrienes, bronchospasm occurs in about 30 minutes and lasts up to 2 hours. They also stimulate airway mucus secretion and are very potent at increasing the permeability of post capillary venules, including those in the bronchial circulation - hence they cause plasma protein exudation and oedema. Recent evidence suggests that the CysLTs also promote eosinophil migration into the airways of animals and asthmatic patients. They may also increase bronchial hyper responsiveness through an action on sensory nerves. Some of these responses can be blocked by the new CysLT1 receptor antagonists, but other responses are yet to be characterised.

Drug development
The CysLTs have been implicated as important mediators in the pathogenesis of a number of inflammatory disorders in addition to asthma, including allergic rhinitis, chronic bronchitis and inflammatory bowel disease. To date, most attention has been directed towards their effects in the lungs and to their possible role in asthma. This has led to the development of drugs which prevent the actions of the CysLTs in the airways. Two groups of drugs are currently available for clinical use in the U.S.A. One group prevents the synthesis (and hence effects) of all the leukotrienes by inhibiting the enzyme 5-lipoxygenase (no drug in this group is currently registered in Australia). The other group contains the selective antagonists of CysLT1 receptors (montelukast and zafirlukast) which block the effects of the CysLTs in human airways.

Further reading

Gorenne I, Norel X, Brink C. Cysteinyl leukotriene receptors in the human lung: what's new? Trends Pharmacol Sci 1996;17:342-5.

Hay DW, Torphy TJ, Undem BJ. Cysteinyl leukotrienes in asthma: old mediators up to new tricks. Trends Pharmacol Sci 1995;16:304-9.


Self-test questions

The following statements are either true or false.

1. Leukotrienes cause bronchoconstriction.

2. Montelukast and zafirlukast act by blocking the synthesis of leukotrienes.

Answers to self-test questions

1. True

2. False


Stella R. O'Donnell

Professor of Pharmacology, Department of Physiology and Pharmacology, University of Queensland, Brisbane