INDUCTION OF OXIDATIVE DNA-DAMAGE AND EARLY LESIONS IN RAT GASTROINTESTINAL EPITHELIUM IN RELATION TO PROSTAGLANDIN-H SYNTHASE-MEDIATED METABOLISM OF BUTYLATED HYDROXYANISOLE

The effect of metabolic activation of the food additive 3-tert-butyl-4 -hydroxyanisoIe (BHA) by prostaglandin H synthase on the gastro-intest inal cell proliferation was determined by studies of the nature and th e time dependency of early lesions in the forestomach, glandular stoma ch and colon/rectum of rats given BHA with and without co-administrati on of acetylsalicyclic acid (ASA; an inhibitor of prostaglandin I-I sy nthase), in combination with the formation of oxidative DNA damage in the epithelial cells of glandular stomach and colon/rectum as well as in the liver. BHA appeared to be a strong inducer of oxidative DNA dam age in the epithelial cells of the glandular stomach, increasing the l evel of 7-hydro-8-oxo-2'deoxyguanosine (8-oxodG) with increasing durat ion of BHA administration. similar observations were made in colorecta l DNA although levels of oxidative DNA damage tend to be smaller. In l iver DNA, BHA appeared to be capable of increasing background 8-oxodG levels only after 14 days or treatment. This relatively slow response may be related to very low prostaglandin H synthase activity of liver cells. The severity of hyperplasia and inflammation in both forestomac h and glandular stomach appeared to increase gradually with continued BHA administration. The hyperplasia induced by BHA was paralleled by i nflammatory changes. In colorectal tissue, however, no tissue abnormal ities were observed. This indicates that oxidative DNA damage induced by BHA is not a consequence of early lesions in gastro-intestinal epit helium, but might be the initial step in the stimulation of gastro-int estinal cell proliferation which, as shown previously, also occurs in colon epithelium. Co-administration of the prostaglandin H synthase in hibitor ASA resulted in a significant decrease of both epithelial oxid ative DNA damage and the incidence of lesions, which indicates that th is enzyme system is involved in the enhancement of cellular proliferat ion induced by BHA. Co-oxidation by prostaglandin H synthase of the BH A-metabolite tert-butylhydroquinone into tert-butylquinone, yielding a ctive oxygen species, might therefore be responsible for the carcinoge nic effects of this food antioxidant.