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.
Schilderman
P A
PA
Department of Health Risk Analysis and Toxicology, University of Limburg, Maastricht, The Netherlands.
Engels
W
W
Wenders
J J
JJ
Schutte
B
B
Ten Hoor
F
F
Kleinjans
J C
JC
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism*; D001241:Aspirin / Q000494:pharmacology; D002083:Butylated Hydroxyanisole / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D004064:Digestive System / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D007213:Indomethacin / Q000494:pharmacology; D019787:Linoleic Acid; D008041:Linoleic Acids / Q000378:metabolism*; D008084:Lipoxygenase / Q000502:physiology; D008297:Male; D011451:Prostaglandin-Endoperoxide Synthases / Q000502:physiology; D051381:Rats; D011919:Rats, Inbred Strains
D008041:Linoleic Acids; D002083:Butylated Hydroxyanisole; D016718:Arachidonic Acid; D019787:Linoleic Acid; D008084:Lipoxygenase; D011451:Prostaglandin-Endoperoxide Synthases; D001241:Aspirin; D007213:Indomethacin