The ability of three dithiolethione
cancer chemopreventives,
oltipraz 1, anetholedithione (ADT) 2,
1,2-dithiole-3-thione (D3T) 3, and the major metabolite, 4, of 1, to induce the cytoprotective
enzyme NQO1 in Hepa 1c1c7 cells and the inhibition of this induction by
catalase are demonstrated. The ability of 1, 3, and 4 to form O(2)(*) has been reported, and it is here demonstrated that 2 decomposes in the presence of GSH to form, upon addition of the nitrone spin trap DMPO, the
DMPO-OH adduct that is detectable by EPR. Decomposition of 2 in the presence of GSH elicits, upon the addition of
hydroethidine and excitation at 510 nm, fluorescence at 580 nm that is diminished by the addition of
superoxide dismutase. The compound 4, is a product of the reduction of 1, and it is demonstrated that 2 and 3 decompose in the presence of
reductants such as thiolates and NaBH(4), followed by addition of CH(3)I, to form the dimethylated products of reductive cleavage of the S(1)-S(2) bond. The same products are isolated subsequent to lysis in
buffer containing CH(3)I of Hepa 1c1c7 cells treated with 2 or 3. Reductive cleavage of 2 and 3 in aqueous
ethanol by NaBH(4) in an
argon atmosphere, followed by acidic destruction of remaining
borohydride and neutralization and introduction of O(2) results in the reformation of 2 and 3 to the extent of 80 and 33%, respectively. The data in
toto are consistent with a model in which dithiolethiones, generally, undergo reductive cleavage in Hepa 1c1c7 cells, thereby resulting in the generation of O(2)(*) that dismutates to H(2)O(2), that subsequently, by direct or indirect means, effects the nuclear translocation of
transcription factor Nrf2, that upregulates phase 2
enzyme expression.