Eicosanoids modulate the response of gastrointestinal mucosa to noxious stimuli. Though these compounds have been extensively investigated in the stomach, their role in the esophagus has received less attention. Thus, the metabolism of 14C-arachidonic acid by homogenates of rabbit esophageal mucosa was investigated. The major metabolites formed and separated by TLC and HPLC had the chromatographic characteristics of (percent conversion follows each metabolite) 6-keto-prostaglandin F1 alpha (3.80 +/- 1.15), prostaglandin F2 alpha (2.05 +/- 0.37), prostaglandin E2 (5.92 +/- 1.65) and 12-hydroxyeicosatetraenoic acid (26.03 +/- 4.58). Indomethacin, a cyclooxygenase inhibitor, caused a significant decrease in prostaglandin formation without affecting 12-hydroxyeicosatetraenoic acid. BW755C, a combined cyclooxygenase-lipoxygenase inhibitor, dramatically decreased formation of all metabolites. It is concluded that esophageal mucosa metabolizes arachidonic acid primarily to a lipoxygenase derived product. This is the most abundantly produced eicosanoid yet described in the gastrointestinal tract. The importance of this compound to esophageal function is unknown but its presence suggests that future studies of eicosanoids in the esophagus should focus on lipoxygenase metabolites.