Studies with 1,2-dithiole-3-thione as a chemoprotector of hydroquinone-induced toxicity to DBA/2-derived bone marrow stromal cells.

Abstract

Stromal cells from DBA/2 mouse bone marrow have been shown to be susceptible to cytotoxicity induced by several redox-active metabolites of benzene, including hydroquinone (HQ). Treatment with HQ also alters the composition of stromal cell populations by preferentially killing stromal macrophages compared to stromal fibroblasts. This cytotoxicity can be prevented by 1,2-dithiole-3-thione (DTT) as a result of the induction of quinone reductase (QR), a quinone-processing enzyme, and glutathione. The inductive activities of DTT protected stromal cells against HQ-induced cytotoxicity and against HQ-induced impairment of stromal cell ability to support myelopoiesis. In vivo feeding of DTT to DBA/2 mice increased QR activity within the bone marrow compartment and protected bone marrow stromal cells isolated from the DTT-fed animals from ex vivo HQ challenge. Thus, the inducibility of cellular defense mechanisms and xenobiotic-processing enzymes by chemoprotective agents such as DTT may be a useful strategy for protecting against chemically induced bone marrow toxicities.

Analysis of target cell susceptibility as a basis for the development of a chemoprotective strategy against benzene-induced hematotoxicities.

“…Renz and Kalf (51) have shown that the administration of recombinant IL-1 overcomes the bone marrow suppressive effects of benzene. We have also observed that in vitro D3T treatment can prevent the effects of HQ in suppressing the ability of stromal cells to support colony-forming activity (49). Treatment of DBA/2 mouse-derived stromal cells with a noncytotoxic concentration of HQ inhibits colony-forming activity by nearly 50% (Table 4).…”

“…Although t-BHQ is an effective inducer, it also has cytotoxic effects that limit its usefulness for this purpose. Thus, 1,2-dithiole-3-thione (D3T) was used as the monofunctional inducer in subsequent studies (13,21,29,49). The data summarized in Figure 5, demonstrate that D3T is an effective inducer of QR and GSH in mouse and rat bone marrow stromal cells and the HL-60 and ML-1 cell lines.…”

“…Moreover, as shown in Table 4, stromal cells treated with HQ 12 days in the presence of HQ or HQ/D3T. After the conditioned medium was concentrated by centrifugation in centricells, the CSA of the media was determined as described in Twerdok et al (49). maintain their full function when pretreated with D3T.…”

“…As such, in vivo D3T feeding to DBA/2 mice was undertaken to determine if D3T has an inductive effect in the bone marrow (49). The data presented in Table 5 indicate that feeding 0.1% D3T in the diet for 6 days resulted in a significant induction of QR activity in bone marrow stromal cells.…”

Novel three-dimensional live skin-like in vitro composite for safety tests

“…Supplementary gure S1 shows weak IL8-SLR3 intensity, indicating that IL-8 upregulation was not observed, which is expected to observable after adding HQ. In contrast, HQ dose-dependently downregulated UBC-SLG 21 . We established the 3D-skin model based on these results to overcome the weak luminescence intensity of IL8-SLR3, because 3D culture can alter the expression of numerous genes 22 23 .…”