The glutathione-S-transferases (GST) are a family of enzymes present in high concentrations in liver, lung and other tissues, and play a very important role in the detoxification of many epoxide forming carcinogens. Thus species and individual differences in GST isozyme activities may be responsible for differences in susceptibility to carcinogenic chemicals. Aflatoxin B1 (AFB) is a potent chemical carcinogen that occurs naturally in many grain products. Although it has been known for many years that there are large species differences in susceptibility to the hepatocarcinogenic effects of AFB, it has only recently been demonstrated that the principal, if not sole, reason for such differences is related to differences in GST activity towards the putative AFB-epoxide intermediate. It has recently been found that Swiss-Webster mice, which are resistant to the carcinogenic effects of AFB, have very high GST activity towards AFB when compared with the sensitive rat. Of particular interest was the finding that this difference appeared to be specific for AFB; while the mouse had a 2.5 fold higher GST activity towards the general substrate 1-chloro-2,4-dintrobenzene (CDNB), it had a 52 fold higher activity towards AFB-epoxide, relative to Sprague-Dawley rats. The long range objectives of this study are to determine the specific characteristics of the form(s) of GST present in mice that seems to confer resistence to this species, and to determine the relative ability of other species, especially non-human primates and eventually humans, to detoxify AFB and other epoxide carcinogens via GST conjugation.
Specific aims are: 1) to determine the relative activity of previously identified mouse liver isozymes of GST towards AFB-epoxide, relative to other commonly used substrates (e.g. CDNB, benzo(a)pyrene 4,5- oxide,p-nitrostyrene oxide); 2) determine if the selectiver activity of mouse GST toward AFB-epoxide is evident towards other epoxide carcinogens; 3) determine if previously reported strain differences in mice towards CDNB are exagerated or attenuated when examined towards AFB-epoxide; 4) determine the relative activity of non-human primates (macaca) GST towards AFB- epoxide, and isolate and characterize specific forms of GST isozymes of this species; 5) determine the stability of non-human primate GST activity under different conditions of storage following death. Future studies that will follow this will then examine human liver GST activity towards GST obtained at autopsy or from organ donors.
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