Abstract
Aflatoxin B₁ (AFB₁) is a DNA-binding toxin that contributes to the burden of liver cancer in tropical areas. AFB₁-DNA adducts are powerful biomarkers that discern individual and population risk from exposure to this carcinogen. The discovery of concordance between the metabolic pathways of the male Fischer rat and humans allowed data from rats to guide the development of chemoprevention strategies employed in clinical trials in high-risk regions. In this study, the variables of strain and sex are studied in the rat model, as a step toward understanding how ethnic differences and sex influence DNA adduct formation and the induction of enzymes by chemoprotective agents. Sulforaphane (SF), which induces phase II enzymes including glutathione S-transferases (GSTs), was evaluated for its ability to induce GST activity and reduce the AFB₁-DNA adducts in livers of both sexes of two rat strains that differ in susceptibility to AFB₁ hepatocarcinogenesis. A dose-dependent relationship was found for SF for both induction of GST and reduction in of AFB₁-N⁷-guanine in both Fischer (sensitive to AFB₁) and Sprague-Dawley rats (relatively resistant). Sprague-Dawley rats exhibited the greatest increase in GST levels and the largest reduction in AFB₁-N⁷-guanine in liver DNA. Males and females of each strain were also compared to determine if the ability of SF to induce GST and reduce AFB₁-N⁷-guanine correlated with gender differences in sensitivity to AFB₁ carcinogenesis. No gender-specific responses to SF were observed. These results support the view that SF induction of liver GST activity may play a role in its chemoprotective activity.
Highlights
Aflatoxin B1 (AFB1) is a known carcinogen, along with hepatitis B, that contributes to the burden of human liver cancer (Kensler et al, 2010)
We evaluated the chemopreventive activity of sulforaphane, the predominant isothiocyanate found in broccoli (Fahey et al, 1997), which has been used in clinical trials and shown to reduce aflatoxin-DNA adduct biomarkers in exposed populations (Kensler et al, 2005)
We compared the effects of sulforaphane in the Sprague Dawley rat, which is relatively resistant to aflatoxin-induced liver carcinogenesis, and the Fischer rat, which is comparatively sensitive (Busby and Wogan, 1984)
Summary
Aflatoxin B1 (AFB1) is a known carcinogen, along with hepatitis B, that contributes to the burden of human liver cancer (Kensler et al, 2010). Of particular importance is the lack of data concerning the influences of strain and sex on levels of key xenobiotic metabolizing enzymes and their inducibility by chemoprotective agents This fundamental work is required to refine our understanding of relationships between humans and experimental animal models and is of particular relevance to the design of intervention studies in genetically diverse human populations. We evaluated the chemopreventive activity of sulforaphane, the predominant isothiocyanate found in broccoli (Fahey et al, 1997), which has been used in clinical trials and shown to reduce aflatoxin-DNA adduct biomarkers in exposed populations (Kensler et al, 2005) These data emphasize the importance of further elucidation of sulforaphane effects in experimental animal models to strengthen a mechanistic understanding of the potential of this agent to decrease cancer risk. We compared responses of males and females in both strains to assess the potential role of sex as a modulator of response to chemopreventive agents
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