| In vivo studies have shown that susceptibility of the rat to the hepatotoxic effects of aflatoxin B1 (AFB 1) can be reduced by anticarcinogenic concentrations of dithiolethiones. The events that follow enzyme induction by dithiolethiones that result protection against AFB1-induced toxicity are complex and not fully understood. Aflatoxin B1-aldehyde reductase, specifically AKR7A1, is one of the major enzymes induced by certain dithiolethiones in the rat liver. AKR7A1 catalyzes the conversion of the reactive dialdehyde form of AFB1-dihydrodiol to AFB1-dialcohol. This dialdehyde has been implicated as a major contributor to cellular toxicity of AFB1. Several lines of evidence suggest that the induction of AKR7A1 by dithiolethiones could play an important role in the resistance against AFB1-induced cytotoxicity. To test this hypothesis, a mammalian cell-based expression system for AKR7A1 was developed to demonstrate the functional ability of AKR7A1 to confer resistance to the cytotoxic effects of AFB1. The data presented in this thesis dearly demonstrates the ability of AKR7A1 to protect against the cytotoxic effects of AFB1, and the utility of transgenic cell modeling for these purposes. Another major discovery of this thesis work was the isolation of a new human homolog to the rat AKR7A1, AKR7A3. This finding allowed us to begin initial studies to define a role for AKR7A3 in protection against AFB 1-induced cytotoxicity, and provides a basis for translation of the mechanistic studies from the rat model to relevance in humans. |
