Journal Article

Mechanisms of protection against aflatoxin B<sub>1</sub> genotoxicity in rats treated by organosulfur compounds from garlic

Denis Guyonnet, Christine Belloir, Marc Suschetet, Marie-Hélène Siess and Anne-Marie Le Bon

in Carcinogenesis

Volume 23, issue 8, pages 1335-1341
Published in print August 2002 | ISSN: 0143-3334
Published online August 2002 | e-ISSN: 1460-2180 | DOI:
Mechanisms of protection against aflatoxin B1 genotoxicity in rats treated by organosulfur compounds from garlic

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Diallyl sulfide (DAS) and diallyl disulfide (DADS), two garlic constituents, were found previously to inhibit aflatoxin B1 (AFB1)-initiated carcinogenesis in rat liver, DADS being the most effective. In order to study the mechanisms involved in this protection, we have examined the ability of liver microsomes and cytosols from DAS- and DADS-treated rats to modulate the mutagenicity and the metabolism of AFB1. We also examined the effects of these compounds on the expression of cytochromes P450 (CYP) and phase II enzymes known to be involved in AFB1 metabolism. Administration of DAS (1 mmol/kg for 4 days) to rats resulted in significant inhibition of microsome-mediated mutagenicity of AFB1, whereas DADS treatment did not alter AFB1 mutagenicity. DAS treatment increased the metabolism of AFB1 mainly towards the formation of AFQ1 and AFM1, which might account for the reduction of AFB1 microsomal-mediated mutagenicity. DADS treatment slightly affected the oxidative metabolism of AFB1. DAS and DADS induced CYP3A2, CYP2B1 and CYP2B2, DAS being more potent. Cytosols from DAS- and DADS-treated rats produced a significant inhibition of AFB1-8,9-epoxide (AFBO)-induced mutagenicity and significantly increased the cytosolic formation of AFB1-glutathione conjugates, DADS treatment being more effective. Western blot analysis showed that DADS is a potent inducer of glutathione S-transferase A5 (rGSTA5) and AFB1 aldehyde reductase 1 (rAFAR1), while DAS is a weak inducer of these enzymes. Finally, we demonstrated that antibodies raised against rGSTA5 strongly reduced the antimutagenic activity of cytosols from DAS- and DADS-treated rats against AFBO. All together, these results demonstrate that DAS prevents AFB1 mutagenicity through a dual mechanism, i.e. by modulating both the phase I and II metabolism of AFB1, whereas DADS acts mainly by increasing the phase II metabolism of AFB1. The induction of rGSTA5 and rAFAR1 is probably the main mechanism by which allyl sulfides give protection against AFB1-induced carcinogenesis.

Keywords: AFAR, aflatoxin aldehyde reductase; AFB1, aflatoxin B1; AFBO, AFB1-8,9-epoxide; BHT, butylhydroxytoluene; CYP, cytochromes P450; DAS, diallyl sulfide; DADS, diallyl disulfide; EQ, ethoxyquin; GSH, glutathione; GST, glutathione S-transferases; I3C, indole-3-carbinol; NQO, NAD(P)H:quinone oxidoreductase

Journal Article.  5943 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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