Miten LTE4 eliminoituu kehosta? Leukotrieenit

LTE elimination

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J Biol Chem. 1990 Dec 15;265(35):21771-8.
Leukotriene E4 elimination and metabolism in normal human subjects.
Sala A1, Voelkel N, Maclouf J, Murphy RC.
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Abstract

Radiolabeled leukotriene (LT) E4 was infused into three healthy subjects in order to assess
 the production and elimination of sulfidopeptide leukotriene metabolites in urine.
 Three different radiolabeled tracers were employed,
[14,15-3H]LTE4,
[35S]LTE4,
 and [14C] LTE4
in five separate infusion studies.

 There was a rapid disappearance of
radioactivity from the vascular compartment in an apparent two-phase process.
 The first elimination phase had an apparent half-life of approximately 7 min.
Radioactivity quickly appeared in the urine with 10-16% eliminated during the
first 2 h following intravenous infusion; 7%,
 2-5 h; 4%,
5-8 h; 4%,
8-15 h;
and 1.5%, 15-24 h from the [14C] LTE4 experiments.
Unmetabolized LTE4 was the major radioactive component in the first urine collection,
but at later times two more polar compounds predominated.
After extensive purification by normal phase-solid phase extraction and reverse-phase
 high performance liquid chromatography, these compounds were characterized by UV spectroscopy,
 co-elution with synthetic standards, negative ion electron capture gas chromatography/mass spectrometry,
and tandem mass spectrometry. The two major urinary metabolites were structurally determined
to be 14-carboxy-hexanor-LTE3 and
the conjugated tetraene, 16-carboxy-delta 13-tetranor-LTE4.
 Three other minor metabolites were detectable in the first urine collection
 only and were characterized by co-elution with synthetic standards as
16-carboxy-tetranor-LTE3,
 18-carboxy-dinor-LTE4, and
20-carboxy-LTE4. 

omega-Oxidation and subsequent beta-oxidation from the methyl terminus appeared to be the major metabolic
fate for sulfidopeptide leukotrienes in man.

The accumulation of the 14-COOH-LTE3 and 16-COOH-delta 13-LTE4
may reflect a rate-limiting step in further oxidation of these compounds which places a conjugated triene or conjugated tetraene, respectively,
two carbons removed from the CoA ester moiety.

 Also in the first urine collection there was another minor metabolite identified as N-acetyl-LTE4,
however, no subsequent beta-oxidation of this metabolite was observed.

The major metabolites of LTE4 might be useful in assessing in vivo production of sulfidopeptide leukotrienes in humans.

PMID:
    2174886

    [Indexed for MEDLINE]

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(Jossain huomasin myös maininnan siitä, että terve maksa ja munuainen on edellytys LTE-;n hyvään eliminaatioon).
Lieneekö sekin niiät kehon luonnollisen immunologisen puolustuksen molekyylejä joita on tietty olevainen määrä  valmiina näihin äkkireaktioihin, joisa tarkoitus on tietysti ensisijassa   kynnystasossa puolustuksellinen, vaikka  ylivoimakkaana reaktiona  ilmeneekin astma-anafylaksia ja  siihen  ei mene  yli 10 minuuttia.
Jos LTE  minimimäärässä olisi fysiologinen sillä olisi jokin  normaali pitoisuus.   Tosin se on  aggressiivisena vaikuttajana  nopeasti kehkeytettävissä  järjestelmänsä lopputuotteena  (AA-  LTA4 linja LTC4,LTDF4-LTE4).
Toisaalta  LTE4:n  nopea katoaminen voisi  merkitä sitäkin, että sillä on tietty jatkuva muodostuminen  ja jos ei ole  reagoimisen  tarvetta niin se nopeasti katoaakin ja poistuu kehosta -  kuten IgA-virta  on jatkuvaa ja  erittyy sitten limakalvoilta pois kehostaa.
Entä jos LTE4 ei pystyisi muodostumaan ollenkaan? Otan yhden sitaatin netistä:

Lancet. 1998 Nov 7;352(9139):1514-7.

Leukotriene C4-synthesis deficiency: a new inborn error of metabolism linked to a fatal developmental syndrome.

Mayatepek E¹, Flock B.

Abstract

BACKGROUND:

Cysteinyl leukotrienes (LTC4, LTD4, LTE4) are potent lipid mediators derived from arachidonic acid in the 5-lipoxygenase pathway that exert profound biological effects. We investigated synthesis and metabolism of leukotrienes in an infant who presented with muscular hypotonia, psychomotor retardation, failure to thrive, and microcephaly. The course of the disease was rapidly progressive and the infant died aged 6 months.

METHODS:

Cysteinyl leukotrienes and LTB4 were analysed in cerebrospinal fluid, plasma, urine, and stimulated monocytes by EIA. We measured [3H]-LTC4 formation from [3H]-LTA4 in monocytes and platelets by radio-high-pressure liquid chromatography.

FINDINGS:

Concentrations of LTC4 and its metabolites were below the detection limit in the cerebrospinal fluid, plasma and urine. LTC4 could not be generated in stimulated monocytes, whereas LTB4 synthesis was increased. [3H]-LTC4 could not be made from [3H]-LTA4 in the patient's monocytes or platelets.

INTERPRETATION:

In this patient, inability to synthesise LTC4 suggests a deficiency of LTC4 synthase. This defect is a new inborn error of human eicosanoid metabolism and may be associated with the clinical disorder. Leukotriene analysis should be done in all patients with neurological symptoms who are candidates for metabolic diseases.

Comment in

• Leukotrienes and the brain. [Lancet. 1998]