Induction of oxidative DNA damage and early lesions in rat gastro-intestinal 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-hydroxyanisole (BHA) by prostaglandin H synthase on the gastro-intestinal cell proliferation was determined by studies of the nature and the time dependency of early lesions in the forestomach, glandular stomach and colon/rectum of rats given BHA with and without co-administration of acetylsalicyclic acid (ASA: an inhibitor of prostaglandin H synthase), 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 damage in the epithelial cells of the glandular stomach, increasing the level of 7-hydro-8-oxo-2'deoxyguanosine (8-oxodG) with increasing duration of BHA administration. Similar observations were made in colorectal DNA although levels of oxidative DNA damage tend to be smaller.

Peroxidation of linoleic, arachidonic and oleic acid in relation to the induction of oxidative DNA damage and cytogenetic effects.

In the present study, the possible role of the polyunsaturated fatty acids linoleic and arachidonic acid in the chemical induction of carcinogenesis has been investigated. Analysis of 7,8-dihydro-8-oxo-2'-deoxyguanosine (8-oxodG) levels in 2'-deoxyguanosine (dG) and isolated DNA has demonstrated that linoleic and arachidonic acid are capable of inducing this specific genotoxic damage. This effect appears to be related to the degree of fatty acid unsaturation, since it was not induced by monounsaturated oleic acid.

The role of prostaglandin H synthase-mediated metabolism in the induction of oxidative DNA damage by BHA metabolites.

The carcinogenicity of the phenolic food antioxidant butylated hydroxyanisole may be related to its oxidative biotransformation in vivo. In order to determine the ability of BHA, 2-tert-butyl(1,4)hydroquinone (TBHQ) and 2-tert-butyl(1,4)paraquinone (TBQ) to induce oxidative DNA damage, biological inactivation of single-stranded bacteriophage phi X-174 DNA, as well as induction of 7-hydro-8-oxo-2'-deoxyguanosine (8-oxodG) in dG by these compounds was studied in vitro, in the presence and absence of peroxidases. Both test systems showed that BHA and TBQ (probably due to lack of reductase activity in vitro) were not capable of inducting oxidative DNA damage.