연구분야

The aryl hydrocarbon receptor (AhR) signalling pathway is activated by ligands binding to its receptor, AhR, and modulates expression of a wide range of xenobiotics-metabolizing phase I (CYPs) and phase II [e.g., glutathione S-transferases (GSTs)] biotransformation enzymes. When it comes to cancer prevention, inhibition of CYPs was thought to be beneficial because PhIP (and other procarcinogens) is metabolically activated by CYPs. However, the notion is controversial; although procarcinogens are activated by CYP1A-mediated N2 hydroxylation, the hydroxylation not only makes carcinogens more water soluble, but also opens a site for further phase II conjugations that render them easily excreted. The notion is supported by a study in which the incidence of PhIP-induced colon tumors was significantly higher in cyp1a2-null mice than in their wild type (WT) counterparts. Likewise, we showed that, in rat colon and prostate, PhIP-DNA adducts were reduced when our apiaceous vegetable intervention increased CYP1A2 activity and protein expression. In contrast, we recently reported that, through the integration of hepatic transcriptomics and proteomics analyses, ad libitum intake of fructose suppressed AhR signaling; such suppression of AhR target genes was not recapitulated when the cells were treated with the same dose/time of glucose, indicating specific effects of fructose on hepatic carcinogen metabolism. Below is a list of publications I have authored regarding the effects of dietary constituents on biotransformation enzymes and/or xenobiotics metabolism (* denotes corresponding authors):

• Kim JK et al., and Trudo SP. Intake of apiaceous vegetables decreases PhIP-induced genotoxicity and increases methylated PhIP metabolites in the urine metabolome in rats. J. Nutr. (2015) 145 (3): 442-451 (IF=4.735)
• Kim JK et al., and Trudo SP. PEITC and I3C from cruciferous vegetables but not furanocoumarins in apiaceous vegetables reduced PhIP-induced DNA adducts in Wistar rats. Mol. Nutr. Food Res. (2016) 60 (9): 1956-1966 (IF=6.575)
• Kim JK et al., and Trudo SP. Comparison of short- and long-term exposure effects of cruciferous and apiaceous vegetables on carcinogen metabolizing enzymes in Wistar rats. Food Chem. Tox. (2017) 108 (Part A): 194-202 (IF=5.572)
• Pan JH et al., and Kim JK*. Hepatic transcriptomics reveals that fructose exposure downregulated xenobiotics metabolizing enzymes through aryl hydrocarbon receptor signaling suppression in C57BL/6N mice. Br. J. Nutr. (2019) 122 (7): 769-779 (IF=4.125)
• Jo EH et al., and Kim JK*, and JH Lee*. Sensitization of GSH synthesis by curcumin curtails acrolein-induced alveolar epithelial apoptosis via Keap1 cysteine conjugation: a randomized controlled trial and experimental animal model of pneumonitis. J. Adv. Res. (2022) (Accepted; IF=12.822)

Acrolein (Acr; 2-propenal) ubiquitously occurs from incomplete combustion of organic matter, and it is one of the most abundant and reactive aldehydes present in cigarette smoke. The United States Environmental Protection Agency lists Acr as a high priority toxicant. When it comes to Acr detoxification, GSTs play major roles by conjugating Acr with GSH therefore, chronic exposure to Acr disrupts the cellular antioxidative defense by rapidly depleting GSH. In contrast, we found that apiaceous vegetables increase hepatic Acr-metabolizing enzyme activity and intracellular GSH. Further, we demonstrated that plaque lipid deposition was induced in the aortic valve by nasal administration of Acr, while such lesions were not apparent in mice fed with apiaceous vegetables for 1-wk. Importantly, in the same mice, we noted that apiaceous vegetables reduced TNF-α and increased interleukin (IL)-1ra (an inhibitor of IL-1β) in plasma. TNF-α and IL-1β are two well established pro-inflammatory cytokines regulated by NF-κB signaling. Collectively, these results suggest that apiaceous vegetables may be protective against Acr-facilitated cardiovascular diseases via either enhancing systematic detoxification or suppressing inflammatory responses caused by nasal administration of Acr. To test our hypotheses, I am conducting a NIH-funded project in which apolipoprotein E deficient mice are exposed to Acr over 4 wk to induce atherosclerosis phenotypes; low dose (21% wt:wt) and high dose (42% wt:wt) apiaceous vegetables were included as intervention groups. In addition to the apiaceous vegetables, currently, we are also conducting a human intervention study to investigate how dietary curcumin supplementation can influence the systemic clearance of Acr (via prevention of GSH depletion), the lung microbiome, and clinical immune markers in human. Below is a publication I authored regarding the effects of dietary constituents on respiratory toxicity:

• Kim JK et al., and Lee JH. Naringin protects acrolein-induced pulmonary injuries through modulation apoptotic signaling and inflammation signaling pathways in mice. J. Nutr. Biochem. (2018) 59 (9): 10-16 (IF=6.117)
• Redding MC et al., and Kim JK*. Apiaceous vegetables protect acrolein-induced pulmonary injuries by modulating hepatic detoxification and inflammation in C57BL/6 male mice. J. Nutr Biochem. (2022) (Accepted; IF=6.117)
• Williams L, et al., and Kim JK*. Acrolein, a cardiovascular toxicant and its applications to in vivo and in vitro cardiovascular models: an update. Environ. Toxicol. Pharmacol. (2022) (Accepted; IF=5.785)

Mitochondrial IDH2 is an evolutionarily conserved protein that catalyzes the oxidative decarboxylation of isocitrate into α-ketoglutarate with concurrent reduction of NADP+ to NADPH; NADPH is necessary for the reduction of intracellular redox buffer, GSH. Therefore, IDH2 not only acts as a NADP+ consuming metabolic regulatory enzyme in the forward TCA cycle but also is a major redox regulatory enzyme that produces NADPH for the maintenance of the reduced GSH. Importantly, GSTs, key phase II conjugation enzymes,only utilize the reduced form of GSH to detoxify xenobiotics/carcinogens (e.g., PhIP). Recently, attention has focused on IDH2 mutations that confer a gain of function to produce the oncometabolite 2-hydroxyglutarate at the expense of consuming NADPH. However, it is relatively unexplored how changes in the enzymatic activity of non-mutant IDH2 are implicated in other pathologies. Using an IDH2 KO mice model, we found that hepatic lipid accumulation was dramatically increased in IDH2 KO female mice in response to fructose supplementation compared to WT mice, which indicates sex-specific implication(s) of IDH2 in fructose-induced perturbation of hepatic lipid metabolism. Also, we observed that the ratio of skeletal muscle weight to body weight was lower in IDH2 KO mice (male and female) than in WT mice. Of note, a marked shift in fiber size distribution was found in IDH2 KO mice. Further, IDH2 KO mice showed higher rectal temperature than WT mice under cold stress, with concomitant UCP1 upregulation in skeletal muscle. Last, to further understand the effects of IDH2 on gastrointestinal pathologies, we subjected IDH2 KO mice to either acute PhIP exposure (24 hr) or an 8-wk protocol of PhIP/dextran sodium sulfate treatment. In the 24-hr treatment, a DNA damage and apoptosis were all higher in IDH2 KO mouse colons. In the 8-wk protocol, IDH2 KO mice developed significantly more isolated lymphoid follicles in the colon than WT mice. Collectively, data from our group demonstrates that non-mutant IDH2 enzyme activity impacts disease susceptibility, such as in the context of diet-induced lipid metabolism and chemical-induced gastrointestinal pathologies in addition to abnormal myogenesis. Below is a list of publications I have authored regarding the effects of IDH2 on disease phenotypes (* denotes corresponding authors):

• Pan JH et al., and Kim JK*. IDH2 deficiency aggravates fructose-induced NAFLD by modulating hepatic fatty acid metabolism and activation of inflammatory signaling in female mice. Nutrients (2018) 10 (6), 679 (IF=6.706)
• Pan JH et al., and Kim JK*. Hepatic transcriptomics reveals that lipogenesis is a key signaling pathway in isocitrate dehydrogenase 2 deficient mice. Genes (2019) 10 (9), 1-16 (IF=4.141)
• Pan JH et al., and Kim JK*. IDH2 deficiency is critical in myogenesis and fatty acid metabolism in mice skeletal muscle. Int. J. Mol. Sci. (2020) 21 (16), 5596 (IF=6.208)