Carcinogenesis 1994 Sep;15(9):1769-1772
Department of Gastroenterology, University Hospital St Radboud, Nijmegen, The Netherlands.
Four dietary, naturally occurring anticarcinogens (flavone, coumarin, alpha-angelicalactone and ellagic acid) were studied with respect to their effects on oesophageal, gastric and pancreatic (i) glutathione S-transferase (GST) enzyme activity, (ii) GST isozyme levels and (iii) glutathione (GSH) content in male Wistar rats. GST enzyme activity was significantly increased in the oesophagus by flavone, coumarin and alpha-angelicalactone (125, 240 and 155% respectively) and in the stomach by coumarin and alpha-angelicalactone (140 and 230%). No change in pancreatic GST activity was observed. In addition, class- and tissue-specific changes in GST isozyme levels occurred. Class alpha GSTs were induced in the oesophagus by flavone, coumarin and alpha-angelicalactone (570, 1580 and 570%), but did not change in the stomach. GST-alpha was undetectable in the pancreas. GST-mu was expressed at high levels in all three tissues investigated, but only pancreatic GST-mu levels of ellagic acid-fed rats were increased (160%). GST-pi was induced in the stomach by coumarin and alpha-angelicalactone (470 and 1120%) and in the pancreas by flavone (200%). GST-pi was detectable at low levels in rat oesophageal epithelium of coumarin-fed animals only. GSH concentrations were uninfluenced by the dietary anticarcinogens in all tissues. These results suggest that dietary ellagic acid and, more especially, flavone, coumarin and alpha-angelicalactone may exert strong chemoprotective effects by selective enhancement of members of the GST detoxification system in the oesophagus or stomach and, to a lesser extent, in the pancreas.
Department of Medicinal Chemistry, University of Utah, Salt Lake City 84112.
Nine thiol chemoprotective compounds were compared for their abilities to reduce the urotoxicity induced by a high dose (1.5 mmol/kg i.p.) of the cancer chemotherapeutic agent, cyclophosphamide (CTX) in male Swiss-Webster mice. Toxicity was assessed by the change in body weight at 48 h, as well as the relative bladder weight (rbw), both a macroscopic and a microscopic rating of bladder damage, and the glutathione (GSH) status of the bladder and the liver. In addition, the rbw, macroscopic assessment, and GSH measurements were also carried out at 4 h, the point of maximal damage and GSH depletion. The powerful effects of compounds with the D-configuration indicated that direct action by the thiols is their most likely mechanism of action. Indirect action through GSH is unlikely because the D-amino acid cannot support GSH's biosynthesis.
Department of Medicinal Chemistry, University of Utah, Salt Lake City 84112.
2(R,S)-D-ribo-(1',2',3',4'-tetrahydroxybutyl) thiazolidine-4(R)-carboxylic acid (RibCys) is a prodrug of L-cysteine, which can facilitate the detoxication of numerous substances either directly or by providing the limiting amino acid for the biosynthesis of glutathione (GSH). RibCys was studied for its chemoprotective activity against the potent urotoxicity associated with the common anticancer agent, cyclophosphamide (CTX). In Swiss-Webster mice, RibCys given between 30 min before the toxin to 30 min after, either in a single or a split dose, exhibited powerful ability to protect against CTX-induced bladder inflammation and GSH depletion.
Department of Environmental Health, University of Washington, Seattle 98195.
Much progress has been made in elucidating the biochemical and molecular mechanisms that underlie aflatoxin carcinogenesis. In humans, biotransformation of AFB1 to the putative carcinogenic intermediate. AFB-8,9-exo-epoxide, occurs predominantly by cytochromes P450 1A2 and 3A4, with the relative importance of each dependent upon the relative magnitude of expression of the respective enzymes in liver. Genetic variability in the expression of these and other cytochromes P450 may result in substantial interindividual differences in susceptibility to the carcinogenic effects of aflatoxins. Detoxification of AFB-8,9-epoxide by a specific alpha class glutathione S-transferase is an important protective mechanism in mice, and it accounts for the resistance of this species to the carcinogenic effects of AFB. This particular form of GST is expressed constitutively only at low levels in rats, but it is inducible by antioxidants such as ethoxyquin, and it accounts for much of the chemoprotective effects of a variety of substances, including natural dietary components that putatively act via an "antioxidant response element" (ARE). In humans, the constitutively expressed GSTs have very little activity toward AFB1-8,9-exo-epoxide, suggesting that--on a biochemical basis--humans should be quite sensitive to the genotoxic effects of aflatoxins. If a gene encoding a high aflatoxin-active form of GST is present in the human genome, but is not constitutively expressed, and is inducible by dietary antioxidants (as occurs in rats), then chemo- and/or dietary intervention measures aimed at inducing this enzyme could be highly effective. However, as it is possible that human CYP 1A2 may also be inducible by these same chemicals (because of the possible presence of an ARE in this gene), the ultimate consequence of dietary treatment with chemicals that induce biotransformation enzymes via an ARE is uncertain. The balance of the rate of activation (exo-epoxide production) to inactivation (GST conjugation plus other P450-mediated non-epoxide oxidations) may be a strong indicator of individual and species susceptibility to aflatoxin carcinogenesis, if the experimental conditions are reflective of true dietary exposures. There is strong evidence that AFB-8,9-exo-epoxide binds to G:C rich regions of DNA, forming an adduct at the N7-position of guanine. Substantial evidence demonstrates that AFB1-8,9-epoxide can induce activating mutations in the ras oncogene in experimental animals, primarily at codon 12.