EFFECTS OF BUTYLATED HYDROXYANISOLE ON ARACHIDONIC-ACID AND LINOLEIC-ACID METABOLISM IN RELATION TO GASTROINTESTINAL CELL-PROLIFERATION IN THE RAT

In order to determine the effect of oral administration of 2(3)-tert-butyl-4-hydroxyanisole (BHA; dose-level: 1.5% BHA of the diet) on arachidonic acid (AA) and linoleic acid (LA) metabolism in correlation with changes in gastrointestinal cell kinetics, we coadministered two inhibitors of prostaglandin H synthase, acetylsalicylic acid (ASA) and indomethacin (IM), to rats. Coadministration of ASA (0.2%) and IM (0.002%) in the drinking water, resulted in a significant reduction of the BHA-induced enhancement of cell proliferation in forestomach and glandular stomach. ASA completely counteracted the effect of BHA on labeling indices in colon/rectum whereas IM exhibited no effect in this organ. Both inhibitors had no direct effect on cell kinetics in the control groups. ASA, and to a lesser degree IM, inhibited prostaglandin E2 release in all tissues examined. Whereas ASA did inhibit lipoxygenase-mediated metabolism of AA in forestomach tissue, ASA did not affect the release of AA- and LA-derived hydroxy fatty acids in glandular stomach and colon/rectum. IM did not affect lipoxygenase production. BHA, however, appeared to be a strong inhibitor of both routes of AA metabolism. While ASA nor IM affected LA metabolism, BHA inhibited both prostaglandin H synthase-mediated and lipoxygenase-mediated metabolism of AA and LA. A causal role of AA or LA metabolites in the process of cell proliferation enhancement induced by BHA, can therefore be excluded. Prostaglandin H synthase may, however, be involved in BHA activation by converting the hydroquinone metabolite of BHA to the corresponding quinone by redox cycling, which is probably accompanied by reactive intermediate production.