TY - JOUR
AU - Denis Guyonnet, Christine Belloir, Marc Suschetet, Marie-Hélène Siess, Anne-Marie Le Bon
AB - Diallyl sulfide (DAS) and diallyl disulfide (DADS), two garlic constituents, were found previously to inhibit aflatoxin B 1 (AFB 1 )-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 AFB 1 . We also examined the effects of these compounds on the expression of cytochromes P450 (CYP) and phase II enzymes known to be involved in AFB 1 metabolism. Administration of DAS (1 mmol/kg for 4 days) to rats resulted in significant inhibition of microsome-mediated mutagenicity of AFB 1 , whereas DADS treatment did not alter AFB 1 mutagenicity. DAS treatment increased the metabolism of AFB 1 mainly towards the formation of AFQ 1 and AFM 1 , which might account for the reduction of AFB 1 microsomal-mediated mutagenicity. DADS treatment slightly affected the oxidative metabolism of AFB 1 . DAS and DADS induced CYP3A2, CYP2B1 and CYP2B2, DAS being more potent. Cytosols from DAS- and DADS-treated rats produced a significant inhibition of AFB 1 -8,9-epoxide (AFBO)-induced mutagenicity and significantly increased the cytosolic formation of AFB 1 -glutathione conjugates, DADS treatment being more effective. Western blot analysis showed that DADS is a potent inducer of glutathione S -transferase A5 (rGSTA5) and AFB 1 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 AFB 1 mutagenicity through a dual mechanism, i.e. by modulating both the phase I and II metabolism of AFB 1 , whereas DADS acts mainly by increasing the phase II metabolism of AFB 1 . The induction of rGSTA5 and rAFAR1 is probably the main mechanism by which allyl sulfides give protection against AFB 1 -induced carcinogenesis. Key words AFAR, aflatoxin aldehyde reductase AFB 1 , aflatoxin B 1 AFBO, AFB 1 -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 © Oxford University Press « Previous | Next Article » Table of Contents This Article Carcinogenesis (2002) 23 (8): 1335-1341. doi: 10.1093/carcin/23.8.1335 » Abstract Free Full Text (HTML) Free Full Text (PDF) Free Classifications Molecular Epidemiology and Cancer Prevention Services Article metrics Alert me when cited Alert me if corrected Find similar articles Similar articles in Web of Science Similar articles in PubMed Add to my archive Download citation Request Permissions Citing Articles Load citing article information Citing articles via CrossRef Citing articles via Scopus Citing articles via Web of Science Citing articles via Google Scholar Google Scholar Articles by Guyonnet, D. 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TI - Mechanisms of protection against aflatoxin B1 genotoxicity in rats treated by organosulfur compounds from garlic
JO - Carcinogenesis
DO - 10.1093/carcin/23.8.1335
DA - 2002-08-01
UR - https://www.deepdyve.com/lp/oxford-university-press/mechanisms-of-protection-against-aflatoxin-b1-genotoxicity-in-rats-d93lyMDPSD
SP - 1335
VL - 23
IS - 8
DP - DeepDyve
ER -