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. In liver DNA, BHA appeared to be capable of increasing background 8-oxodG levels only after 14 days of 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 forestomach and glandular stomach appeared to increase gradually with continued BHA administration. The hyperplasia induced by BHA was paralleled by inflammatory changes. In colorectal tissue, however, no tissue abnormalities were observed. This indicates that oxidative DNA damage induced by BHA is not a consequence of early lesions in gastro-intestinal epithelium, but might be the initial step in the stimulation of gastro-intestinal cell proliferation which, as shown previously, also occurs in colon epithelium. Co-administration of the prostaglandin H synthase inhibitor ASA resulted in a significant decrease of both epithelial oxidative DNA damage and the incidence of lesions, which indicates that this enzyme system is involved in the enhancement of cellular proliferation induced by BHA. Co-oxidation by prostaglandin H synthase of the BHA-metabolite tert-butylhydroquinone into tert-butylquinone, yielding active oxygen species, might therefore be responsible for the carcinogenic effects of this food antioxidant.
Schilderman
P A
PA
Department of Health Risk Analysis and Toxicology, University of Maastricht, The Netherlands.
ten Vaarwerk
F J
FJ
Lutgerink
J T
JT
Van der Wurff
A
A
ten Hoor
F
F
Kleinjans
J C
JC
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D001241:Aspirin / Q000494:pharmacology; D001711:Biotransformation / Q000187:drug effects; D002083:Butylated Hydroxyanisole / Q000378:metabolism / Q000633:toxicity*; D002455:Cell Division / Q000187:drug effects; D003106:Colon / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004249:DNA Damage / Q000187:drug effects / Q000502:physiology; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000096:biosynthesis; D004064:Digestive System / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004848:Epithelium / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D005503:Food Additives / Q000378:metabolism / Q000633:toxicity*; D006965:Hyperplasia; D007249:Inflammation / Q000139:chemically induced; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008297:Male; D010084:Oxidation-Reduction; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species; D012007:Rectum / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D013270:Stomach / Q000187:drug effects / Q000201:enzymology / Q000473:pathology
D016861:Cyclooxygenase Inhibitors; D005503:Food Additives; D017382:Reactive Oxygen Species; D002083:Butylated Hydroxyanisole; C051362:3-tert-butyl-4-hydroxyanisole; D000080242:8-Hydroxy-2'-Deoxyguanosine; D011451:Prostaglandin-Endoperoxide Synthases; D003849:Deoxyguanosine; D001241:Aspirin