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Failure of the inhibition of rat gastric mucosal 5‐lipoxygenase by novel acetohydroxamic acids to prevent ethanol‐induced damage
Author(s) -
BoughtonSmith N.K.,
Whittle B.J.R.
Publication year - 1988
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1988.tb16559.x
Subject(s) - acetohydroxamic acid , gastric mucosa , ex vivo , leukotriene , lipoxygenase , chemistry , in vivo , ethanol , prostaglandin , thromboxane a2 , thromboxane , prostaglandin e2 , pharmacology , cyclooxygenase , leukotriene d4 , medicine , stomach , endocrinology , biochemistry , enzyme , antagonist , in vitro , biology , platelet , receptor , microbiology and biotechnology , asthma , urease
1 The role of leukotriene B 4 (LTB 4 ) and LTC 4 as mediators of gastric mucosal damage following ethanol challenge in vivo has been investigated using two selective 5‐lipoxygenase inhibitors, BW A4C and BW A137C. 2 Oral administration of ethanol to rats in vivo , induced macroscopic damage to the gastric mucosa and markedly increased the formation of the 5‐lipoxygenase products, LTB 4 and LTC 4 , from the mucosa ex vivo . 3 Pretreatment with the acetohydroxamic acids BW A4C and BW A137C (5–50 mg kg −1 p.o.) dose‐dependently reduced ethanol‐stimulated LTB 4 and LTC 4 formation by the gastric mucosa, with an ID 50 of approximately 5 mg kg −1 p.o. 4 A single oral dose of BW A4C (20 mg kg −1 ) induced near‐maximal inhibition of mucosal LTB 4 formation within 30 min, which was well maintained for 5h, whereas BW A137C (20 mg kg −1 p.o.) induced maximal inhibition between 30 and 60 min after administration, which then diminished over the subsequent 5 h. 5 The mucosal formation of the cyclo‐oxygenase product, 6‐keto‐prostaglandin F 1α , which was unaltered following ethanol challenge, was not inhibited by the acetohydroxamic acids. Likewise, the small increase in mucosal thromboxane B 2 formation following challenge was not inhibited by BW A4C. 6 Neither BW A4C nor BW A137C, at doses that almost completely inhibited the mucosal synthesis of LTB 4 or LTC 4 , reduced the macroscopic gastric mucosal damage induced by ethanol. 7 Pretreatment with the lipoxygenase inhibitor BW 755C (5–50 mg kg −1 p.o.) did reduce mucosal damage, but there was a dissociation between the degree of protection and the inhibition of leukotriene biosynthesis. 8 Oral administration of high doses of either BW A4C or BW A137C (300 mg kg −1 ) did not induce macroscopic gastric damage over a 3 h period. 9 These findings suggest that the leukotrienes, LTB 4 and LTC 4 are not the primary mediators of ethanol‐induced acute mucosal damage, but do not exclude their role in more chronic gastric damage and inflammation.