Alcohol. limited clinical relevance. Therefore, effort is being made to generate DAS analogs, which are potent and selective inhibitor of CYP2E1 and poor substrate of CYP2E1. This review summarizes current advances in the field of DAS, its anticancer properties, role as a CYP2E1 inhibitor, preventing agent of cellular toxicities from alcohol, analgesic drugs, xenobiotics, as well as, from diseases like HIV and diabetes. Finally, this review also provides insights toward developing novel DAS analogues for chemical intervention of many disease conditions by targeting CYP2E1 enzyme. inheritance of specific CYP2E1 polymorphism or overexpression of CYP2E1 mRNA have been observed in clinical samples [31C34]. CYP2E1-mediated metabolism has also been implicated in generating carcinogenic DNA adducts, further underscoring the importance of this metabolic enzyme in carcinogenicity [35]. Based on these observations, DAS-mediated inhibition of CYP2E1 (discussed in section 5) can be postulated as an additional mechanisms regulating its anticancer effects. 3. PROTECTIVE EFFECTS OF DAS In addition to studies reporting anti-cancer properties of DAS, several studies have indicated enhanced survival and protective effects following DAS treatment (Fig. 3B). For instance, protective effects of DAS treatment were observed in N-nitrosodiethylamine (NDEA)-induced liver tumorigenesis [36]. While NDEA treatment compromised several indices of liver function, DAS treatment normalized all non-enzymatic and enzymatic liver functions affected by NDEA. Importantly, DAS blocked the formation of free radicals in liver and restored Glutathione-S-transferase (GST) activity thereby reestablishing the redox homeostasis. In Wistar rats, DAS was found to be protective against gentamicin induced-nephrotoxicity [37]. While gentamicin treatment inhibited activity of C25-140 major antioxidant enzymes (AOEs) in kidney of treated rats, DAS treatment (in both presence and absence of gentamicin) was marked by increased activity for AOEs. Moreover, DAS-treated animals exhibited decreased immunohistochemical staining for tumor necrosis factor (TNF)- and NFB in renal tissues. These protective antioxidant effects of DAS were attributed to enhanced expression of transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2) in DAS-treated Wistar rats. Nrf-2-mediated antioxidants effects of DAS were also observed in rat lung and MRC-5 lung cells [38]. Through modulation of Nrf2 expression and subsequent nuclear translocation in rat lung, DAS treatment was associated with significant upregulation in activity and transcription of several antioxidant enzymes compared to untreated animals. Increased enzyme activity was observed for GST, glutathione reductase, and catalase, while increased transcription of superoxide dismutase (SOD), glutathione C25-140 peroxidase, and catalase FLNC were reported in DAS-treated animals. In addition, DAS-treated rats exhibited increased C25-140 GSH/GSSG ratio suggesting increased pulmonary antioxidant capacity or reduced oxidative stress. Interestingly, DAS treatment was also associated with enhanced protein levels of heme oxygenase-1 (HO-1), an enzyme responsible for cellular heme metabolism, in lungs. Furthermore, investigations employing human embryonic MRC-5 cells confirmed that DAS causes nuclear translocation of Nrf2, which is usually regulated by enhanced phosphorylation of signaling molecules p38 MAPK and ERK. Anti-inflammatory effects of DAS were further highlighted in a study conducted with rat aortic easy muscle A7r5 cells [39]. Pretreatment with DAS was shown to block TNF– and histamine-mediated inflammatory responses. Specifically, DAS pretreatment attenuated TNF–induced enhanced expression of TNF- and in-terleukin (IL)-1 transcription in A7r5 cells. In addition, DAS treatment inhibited TNF–mediated nuclear translocation of p65, a subunit of NFB, along with decreased expression of TNF-receptor-associated death domain name (TRADD) and TNF receptor-associated factor 2 (TRAF2). Inhibition of TRADD and TRAF2 by DAS concurrent with blocked NFB signaling contributed to an anti-inflammatory response. Histamine-induced inflammation, on the other hand, was inhibited by DAS modulation of ROS production. In addition, DAS was found to inhibit histamine-induced upregulation of PI3K and Akt expressions and their downstream signaling proteins NFB and activator protein-1 (AP-1). Importantly, DAS pretreatment induced upregulation of Nrf2 expression, C25-140 which was reported to be the crucial molecular change responsible for the antioxidant effects observed in A7r5 cells. DAS-mediated anti-inflammatory effects were also found to be effective in animal model studying bleomycin-induced pulmonary fibrosis [40]. In rats exposed to bleomycin, DAS treatment normalized the activity of several AOEs and restored glutathione levels in rat lungs. In addition, DAS blocked the bleomycin-induced increase in lipid peroxidation and myeloperoxidase activity thereby functioning.