Oltipraz is an HIF-1α inhibitor (IC50=10μM) and an Nrf2 activator. Oltipraz disrupts the Keap1-Nrf2 interaction and promotes Nrf2 nuclear translocation to induce NQO1, GST, UGT, and GSH for accelerated clearance of exogenous toxins. Oltipraz alleviates oxidative stress-related inflammation by enhancing antioxidant responses. Oltipraz can be used for research on aflatoxin-associated liver cancer, bladder cancer, colorectal cancer, and chemoprevention[1-4].
In vitro, treatment of HepG2 cells transfected with a CYP2B6 promoter luciferase reporter plasmid with 5-100μM Oltipraz for 24 hours activated CYP2B6 promoter luciferase activity[5]. Treatment of Caco-2 cells with 50μM Oltipraz for 2-24 hours increased CYP1A1 mRNA, protein, and EROD activity, and elevated intracellular calcium concentration[6]. Pretreatment of RSC96 cells with 20μM Oltipraz for 24 hours followed by culture with 50mM glucose for 24 hours improved cell viability, reduced apoptosis, decreased ROS and MDA levels, increased SOD levels, attenuated mitochondrial membrane potential depolarization, and increased Nrf2 and NQO1 protein expression[7].
In vivo, oral administration of 8.6mg/kg/day Oltipraz to male Nrf2-null mice fed a high-fat diet for 4 weeks reduced liver inflammation and fibrosis, decreased hepatic Mcp-1 mRNA expression, and induced fatty acid oxidation-related gene expression including Pparα, Acox, and Cpt1[8]. Intraperitoneal injection of 10mg/kg Oltipraz to chronic constriction injury (CCI) C57BL/6J mouse models once daily for 11 days inhibited mechanical allodynia, thermal hyperalgesia, and cold allodynia, and decreased CD11b/c, PI3K, p-Akt, p-IkBα, p-JNK, p-ERK1/2, and p-P38 expression in the spinal cord, CD11b/c in the hippocampus, and p-IkBα in the prefrontal cortex[9]. Oral administration of 150mg/kg Oltipraz to diabetic C57BL/6J mouse models every other day for 4 weeks reduced fasting blood glucose and HOMA-IR, improved IPGTT glucose tolerance, and alleviated pancreatic and hepatic tissue damage[10].
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[6] Le Ferrec E, Lagadic-Gossmann D, Rauch C, et al. Transcriptional Induction of CYP1A1 by Oltipraz in Human Caco-2 Cells Is Aryl Hydrocarbon Receptor- and Calcium-dependent. J Biol Chem. 2002 Jul 5;277(27):24780-24787.
[7] Jiang Z, Bian M, Wu J, et al. Oltipraz Prevents High Glucose-Induced Oxidative Stress and Apoptosis in RSC96 Cells through the Nrf2/NQO1 Signalling Pathway. BioMed Research International. 2020 Jun 24;2020:5939815.
[8] Shen H, He J, Wang Y, et al. Geldanamycin Induces Heat Shock Protein 70 and Protects against MPTP-induced Dopaminergic Neurotoxicity in Mice. J Biol Chem. 2005 Dec 2;280(48):39962-39969.
[9] Diaz A, Polo S, Gallardo N, et al. Analgesic and Antidepressant Effects of Oltipraz on Neuropathic Pain in Mice by Modulating Microglial Activation. J Clin Med. 2019 Jun 21;8(6):890.
[10] Luo Y, Sun S, Zhang Y, et al. Effects of Oltipraz on the Glycolipid Metabolism and the Nrf2/HO-1 Pathway in Type 2 Diabetic. Drug Des Devel Ther. 2024 Dec 5;18:5685-5700.