The enteropathy of prostaglandin deficiency.
BACKGROUND
Small intestinal ulcers are frequent complications of therapy with nonsteroidal anti-inflammatory drugs (NSAIDs). We present here a genetic deficiency of eicosanoid biosynthesis that illuminates the mechanism of NSAID-induced ulcers of the small intestine.


METHODS
Eicosanoids and metabolites were measured by isotope dilution with mass spectrometry. cDNA was obtained by reverse transcription and sequenced following amplification with RT-PCR.


RESULTS
We investigated the cause of chronic recurrent small intestinal ulcers, small bowel perforations, and gastrointestinal blood loss in a 45-year-old man who was not taking any cyclooxygenase inhibitor. Prostaglandin metabolites in urine were significantly depressed. Serum thromboxane B2 (TxB2) production was 4.6% of normal controls (P<0.006), and serum 12-HETE was 1.3% of controls (P<0.005). Optical platelet aggregation with simultaneous monitoring of ATP release demonstrated absent granule secretion in response to ADP and a blunted aggregation response to ADP and collagen, but normal response to arachidonic acid (AA). LTB4 biosynthesis by ionophore-activated leukocytes was only 3% of controls, and urinary LTE4 was undetectable. These findings suggested deficient AA release from membrane phospholipids by cytosolic phospholipase A2-alpha (cPLA2-alpha), which regulates cyclooxygenase- and lipoxygenase-mediated eicosanoid production by catalyzing the release of their substrate, AA. Sequencing of cPLA2-alpha cDNA demonstrated two heterozygous nonsynonymous single-base-pair mutations: Ser111Pro (S111P) and Arg485His (R485H), as well as a known single nucleotide polymorphism (SNP), Lys651Arg (K651R).


CONCLUSIONS
Characterization of this cPLA2-alpha deficiency provides support for the importance of prostaglandins in protecting small intestinal integrity and indicates that loss of prostaglandin biosynthesis is sufficient to produce small intestinal ulcers.
Adler
David H
DH
Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University, Vanderbilt Medical Center, 1211 Medical Center Drive, Nashville, TN 37232, USA.
Phillips
John A
JA
Cogan
Joy D
JD
Iverson
Tina M
TM
Schnetz-Boutaud
Nathalie
N
Stein
Jeffrey A
JA
Brenner
David A
DA
Milne
Ginger L
GL
Morrow
Jason D
JD
Boutaud
Oliver
O
Oates
John A
JA
D016718:Arachidonic Acid / Q000378:metabolism; D020137:Base Pair Mismatch; D001483:Base Sequence; D018076:DNA, Complementary; D015777:Eicosanoids / Q000378:metabolism*; D054513:Group IV Phospholipases A2 / Q000172:deficiency / Q000235:genetics*; D006801:Humans; D007410:Intestinal Diseases / Q000235:genetics / Q000473:pathology*; D007421:Intestine, Small / Q000473:pathology; D007975:Leukotriene B4 / Q000378:metabolism; D017999:Leukotriene E4 / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D014456:Ulcer / Q000235:genetics / Q000473:pathology*
D018076:DNA, Complementary; D015777:Eicosanoids; D007975:Leukotriene B4; D016718:Arachidonic Acid; D017999:Leukotriene E4; D054513:Group IV Phospholipases A2