Interindividual differences in response to chemoprotection against aflatoxin-induced hepatocarcinogenesis: implications for human biotransformation enzyme polymorphisms.
It is now evident that most, if not all, of the remarkable species differences in susceptibility to AFB hepatocarcinogenesis is due in large part, if not exclusively, to differences in biotransformation. Certainly the relative rate of oxidative formation of the proximate carcinogen, AFB-8,9-exo-epoxide, is an important determinant of species and interindividual differences in susceptibility to AFB. However, mice produce relatively large amounts of exo-AFBO, yet are highly resistant to AFB-hepatocarcinogenesis because they express a particular form of GST with remarkably high catalytic activity toward the exo-epoxide of AFB. Rats, which are highly susceptible to AFB hepatocarcinogenesis,can be made resistant through dietary induction of an orthologous form of GST that is normally expressed in only very small amounts. Based on these findings in laboratory animal models, there is great interest in identifying chemicals and/or specific dietary constituents that could offer protection against AFB-hepatocarcinogenesis to humans. Current experimental strategies have focused on the antiparasitic drug, oltipraz, which induces protection in rats and has also shown some promise in humans. The mechanism of protection in rats appears to be via induction of an alpha class GST with high catalytic activity toward AFBO (rGSTA5-5). vet human alpha class GST proteins that are constitutively expressed in the liver (hGSTA1 and hGSTA2) have little, if any activity toward AFBO. Rather, it appears that mu class GSTs may be responsible for the very low, but potentially significant, detoxification activity toward AFBO. Oltipraz and certain dietary constituents may induce mu class GSTs in human liver, and this could afford some protection against the genotoxic effects of AFBO. However, it also appears that oltipraz, and perhaps certain dietary constituents, act as competitive inhibitors of human CYP1A2. As CYP1A2 appears to mediate most of the activation of AFB to exo-AFBO in human liver at low dietary concentrations of AFB encountered in the human diet, much of the putative protective effects of oltipraz could be mediated via inhibition of CYP1A2 rather than induction of GSTs. There is now evidence that human microsomal epoxide hydrolase (mEH) could play a role in protecting human DNA from the genotoxic effects of AFB, although the importance of this detoxification pathway, relative to mu class GSTs, remains to be elucidated. Oltipraz is an effective inducer of mEH in rats (Lamb Franklin, 2000), and thus induction of this pathway in humans could also potentially contribute to the protective effects of this drug toward AFB genotoxicity. Because the dihydrodiol of AFB may contribute indirectly to the carcinogenic effects of AFB via protein adduction and subsequent hepatotoxicity, the recently characterized human aflatoxin aldehyde reductase (AFAR) may also offer some protection against AFB-induced carcinogenicity in humans. Current and future dietary and/or chemointervention strategies aimed at reducing the carcinogenic effects of AFB in humans should consider all of the possible mechanistic approaches for modifying AFB-induced genotoxicity.
Eaton
D L
DL
Center for Ecogenetics and Environmental Health, Department of Environmental Health, University of Washington, Seattle 98195, USA.
Bammler
T K
TK
Kelly
E J
EJ
D016604:Aflatoxin B1 / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D000348:Aflatoxins / Q000009:adverse effects / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D000818:Animals; D002273:Carcinogens / Q000009:adverse effects / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004851:Epoxide Hydrolases / Q000378:metabolism*; D005982:Glutathione Transferase / Q000378:metabolism*; D006801:Humans; D008658:Inactivation, Metabolic; D008113:Liver Neoplasms / Q000378:metabolism*; D011110:Polymorphism, Genetic; D013045:Species Specificity
D000348:Aflatoxins; D002273:Carcinogens; C006426:aflatoxin B1-2,3-oxide; D003577:Cytochrome P-450 Enzyme System; D016604:Aflatoxin B1; D005982:Glutathione Transferase; D004851:Epoxide Hydrolases