Leukotrienes

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The leukotrienes are involved in allergic responses and inflammatory processes. An antigen-antibody reaction can result in the release of compounds such as histamine (see page 379) or materials termed slow reacting substance of anaphylaxis (SRSA). These substances are then mediators of hypersensitive reactions such as hay fever and asthma. Structural studies have identified SRSA as a mixture of LTC4, LTD4 and LTE4. These cysteine-containing leukotrienes are powerful bronchoconstrictors and vasoconstrictors, and induce mucus secretion, the typical symptoms of asthma. LTE4 is some 10-100-fold less active than LTD4, so that degradation of the peptide side-chain represents a means of eliminating leukotriene function. LTB4 appears to facilitate migration of leukocytes in inflammation, and is implicated in the pathology of psoriasis, inflammatory bowel disease, and arthritis. The biological effects of leukotrienes are being actively researched to define the cellular processes involved. This may lead to the development of agents to control allergic and inflammatory reactions. Drugs inhibiting the formation of LTC4 and LTB4 are in clinical trials, whilst montelukast and zafirlukast have been introduced as orally active leukotriene (LTD4) receptor antagonists for the prophylaxis of asthma.

CO2H

CO2H

arachidonic acid this reaction is analogous to that initiating prostaglandin formation (Figure 3.17)

hydroperoxide arachidonic acid conjugate nucleophilic attack of H2O on to epoxide hydroperoxide

CO2H

ltb4

CO2H

CO2H

LTA4

nucleophilic attack of glutathione thiol on to epoxide f (y-glutamylcysteinylglycine) OH

CO2H

ltb4

CO2H - Glu

N^,CO2H

partial hydrolysis of glutathione portion O

HO2C

CO2H - Glu

ltd4 o

N^,CO2H

cleavage of peroxide CO2H allows formation of epoxide; overall a dehydration reaction

CO2H

LTA4

nucleophilic attack of glutathione thiol on to epoxide f (y-glutamylcysteinylglycine) OH

CO2H

partial hydrolysis of glutathione portion O

HO2C

NH2 O

LTC4

CO2H

H2N CO2H

CO2H

lte4

H2N CO2H

Figure 3.24

been characterized) (Figure 3.24), arachidonic acid is converted into a hydroperoxide, the point of oxygenation being C-5, rather than C-11 as in the prostaglandin pathway (Figure 3.17). This compound loses water via formation of an epoxide ring, giving leukotriene A4 (LTA4). This unstable allylic epoxide may hydrolyse by conjugate addition giving leukotriene B4 (LTB4), or alternatively the epoxide may be attacked directly by a nucleophile, in this case the sulphur atom of the tripeptide glutathione (y-glutamylcysteinylglycine) (Figure 3.24). The adduct produced in the latter reaction is termed leukotriene C4 (LTC4). Partial hydrolysis in the tripeptide fragment then leads to leukotriene D4 (LTD4) and leukotriene E4 (LTE4). Analogues, e.g. LTA3 and LTA5, are also known, and these are derived from A5'8'11-eicosatrienoic acid and A5'8'1114'17-eicosapen-taenoic acid respectively. The subscript numeral indicates the total number of double bonds in the leukotriene chain.

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Coping with Asthma

Coping with Asthma

If you suffer with asthma, you will no doubt be familiar with the uncomfortable sensations as your bronchial tubes begin to narrow and your muscles around them start to tighten. A sticky mucus known as phlegm begins to produce and increase within your bronchial tubes and you begin to wheeze, cough and struggle to breathe.

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