## 4 Discussion
These results suggest that exposure of intestinal epithelial cells to 13-HPODE may promote pre-systemic metabolism and reduced bioavailability of xenobiotics as they pass through the intestinal epithelium. Although peroxisomes and cytochrome P450 have a role in detoxifying substrates and protecting cells from oxidative stress, they can also produce ROS and lipid peroxidation, which might form adducts creating an environment for development of carcinogenesis and disease progression [74; 79]. In addition, peroxisomal proliferation has been linked to tumor development, and induction of intestinal cytochrome P450 has been linked to gastrointestinal cancer [80; 81; 82]. Treatment of PDiff Caco-2 cells with 13-HPODE caused upregulation of _STS_, _CYP17A1_, and _AKR1C2_/C3 genes involved in steroid hormone biosynthesis, which has been shown to affect intestinal function and transport of nutrients [83]. Aldo/keto reductases, AKR1 Cs, also play a role in bile acid binding and detoxification by reducing lipid peroxide product, 4-HNE, to battle oxidative stress-related injury [84]. Thus, upregulated expression of AKR1 Cs might be an indicative of increase intracellular toxic aldehydes. In addition, _AKR1C3_ has been studied as a marker for progression of colorectal and prostate cancers in which aldehyde levels appear to be elevated [85; 86; 8]. Therefore, AKR1 Cs may provide a potential therapeutic strategy to treat aldehyde-related pathologies. Of note, increased expression of AKR1 Cs has been implicated in the resistance of anti-colon cancer therapies [87], which proposes a mechanism by which dietary LOOHs could promote drug resistance through upregulation of the detoxifying AKR1 Cs. ROS have been strongly linked to the initiation and progression of colorectal cancer (CRC) [88]. In addition, not only LOOHs have been implicated in the pathogenesis of CRC [89] but also levels of lipid peroxidation products due to oxidative stress have shown to be elevated in CRC tissue compared to normal colon mucosa [90]. Moreover, increased antioxidant enzyme activity in CRC has been reported which enhances adaptive response that enables cells to battle stress [90]. This is consistent with our results showing increased expression of genes involved in antioxidant defense mechanisms. Within this context, we observed upregulation of several Nrf2-regulated genes involved in antioxidant defense mechanisms in 13-HPODE-treated cells. Among those were genes involved in glutathione (GSH) antioxidant system such as _SLC7A11_, which facilitates cystine essential for GSH synthesis, _GCLC_, the rate-limiting step of GSH synthesis, _GSR_, which maintains high levels of reduced GSH, and _GSTA2_, that detoxifies compounds by conjugating them to GSH. We also observed upregulation of quinone reductase, _NQO1_, and _CAT_, which also have a role in detoxification of ROS and xenobiotics. This is consistent with previous studies demonstrated activation of Nrf2-mediated antioxidant response via oxidized lipids [91; 92]. Moreover, cytochrome p450 oxidoreductase, _POR_, which catalyzes formation of tocopherly hydroquinone, which is a powerful antioxidant, was upregulated in 13-HPODE-treated cells. This antioxidant response could be triggered by 13-HPODE exposure, disturbed redox status, oxidative stress, or a combination of them. In LA-treated cells, there was upregulation of some Nrf2-targeted antioxidant genes including _SLC7A11_, _GCLC_, _GSR_, and _CAT_; however, 13-HPODE triggered a more powerful antioxidant response than LA. It is worth to mention that none of the lipoxygenase genes were differentially expressed in either 13-HPODE- or LA-treated cells. However, _PTGS2_ (also called _COX2_), which has been shown to be overexpressed in some cancers including CRC [93], appeared to be downregulated in both 13-HPODE- and LA-treated cells. This is consistent with a previous study reported that 13-HPODE inhibited prostaglandin synthesis by inhibiting cyclooxygenase activity [94].