Efficacy of oltipraz in preventing acetaminophen-induced liver injury in mice

doi:10.21203/rs.3.rs-2611121/v1

Download PDF

Research Article

Efficacy of oltipraz in preventing acetaminophen-induced liver injury in mice

https://doi.org/10.21203/rs.3.rs-2611121/v1

This work is licensed under a CC BY 4.0 License

Journal Publication

published 03 Aug, 2023

Read the published version in Naunyn-Schmiedeberg's Archives of Pharmacology →

You are reading this latest preprint version

Oltipraz (OPZ) is a synthetic dithiolethione with potential as a cancer chemopreventive agent, which can work by inducing detoxification enzymes. OPZ is an activator of nuclear factor erythroid 2-related factor 2 (Nrf2), suggesting its involvement in enzyme induction and possible protection against drug-induced liver injury. In this study, we present OPZ-induced protection of mice against acetaminophen (APAP)-induced liver injury and discuss its possible contributing factors. Overnight-fasted male CD-1 mice were administered APAP intraperitoneally, and some mice were administered OPZ 16 h before APAP. Hepatotoxicity was assessed by measuring serum alanine aminotransferase leakage and histopathological evaluation. The hepatic mRNA expressions of CYP2E1, glutamate cysteine ligase (GCL), and NAD(P)H:quinone oxidoreductase (NQO1) were measured by real-time reverse-transcription polymerase chain reaction. OPZ protected mice from APAP-induced liver injury in a dose-dependent manner, but did not alter hepatic glutathione (GSH) content or GCL expression in control mice, indicating that its hepatoprotective effect is not due to changes in basal GSH levels. OPZ did not affect CYP2E1 expression or APAP-induced early GSH depletion, suggesting it does not inhibit the metabolic activation of APAP to produce N-acetyl-p-benzoquinone imine. In contrast, after GSH depletion, OPZ accelerated hepatic GSH recovery. APAP significantly increased GCL expression during liver injury, but OPZ treatment only led to additional NQO1 expression. This suggests that NQO1 is responsible for the enhanced GSH recovery and protection against APAP-induced liver injury seen in OPZ-treated mice. In summary, OPZ protects against APAP-induced liver injury by inducing NQO1 expression and resulting in improved GSH recovery.

acetaminophen

drug-induced liver injury

glutathione

oltipraz

Nrf2

NAD(P)H:quinoneoxidoreductase

Acetaminophen (APAP) is a widely used analgesic drug that is usually safe at therapeutic doses, but its overdose can cause severe liver injury. As the mouse model of APAP hepatotoxicity reproduces those in humans, this clinically relevant model is widely used to study the mechanisms underlying drug-induced liver injury (DILI) and examine its therapeutic interventions. The ongoing development of natural and synthetic compounds as potential therapies for APAP hepatotoxicity has contributed to a better understanding of the pathophysiology of DILI (Chang et al. 2020; Jaeschke et al. 2020; Subramanya et al. 2018; Wang et al. 2022; Yan et al. 2018). As APAP is required for metabolic activation to exert its hepatotoxicity by cytochrome P450 (CYP) enzymes, especially CYP2E1 and CYP1A2 (Zaher et al. 1998), these inhibitors could be one of the most effective protective agents against APAP hepatotoxicity. In contrast, protective agents other than CYP inhibitors (such as miscellaneous compounds) often have multiple targets and some of their mechanisms have not yet been fully characterized (Chang et al. 2020; Jaeschke et al. 2020; Subramanya et al. 2018; Wang et al. 2022; Yan et al. 2018). Therapeutic interventions developed using the APAP model that target pathways shared with other DILI have the potential to be broadly applicable to DILI.

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor activated by electrophilic or oxidative stress, whereby regulating its downstream antioxidant genes. Under stress conditions, Nrf2 binds to antioxidant response elements and induces downstream targets such as heme oxygenase-1, glutamate cysteine ligase (GCL), and NADPH-quinone oxidoreductase-1 (NQO1), which could be involved in enhancing the antioxidant status of the liver (Jayasuriya et al. 2021). Nrf2 knockout mice were observed to have increased severity of APAP-induced liver injury, indicating that Nrf2 plays an important role in hepatoprotection against APAP (Enomoto et al. 2001). Therefore, activation of Nrf2 could be a mechanism-based therapeutic intervention against APAP-induced liver injury. Various Nrf2 activators have been reported to protect against APAP hepatotoxicity (Chang et al. 2020; Jaeschke et al. 2020; Subramanya et al. 2018; Wang et al. 2022; Yan et al. 2018). However, the downstream target transcriptionally induced via Nrf2, which could directly attenuate APAP hepatotoxicity, has not been identified.

Oltipraz (OPZ) is a synthetic dithiolethione that has been extensively studied as a cancer chemopreventive agent and acts through the induction of various detoxification enzymes. OPZ is a known activator of Nrf2 (Kwak et al. 2001; Ramos-Gomez et al. 2001), suggesting the involvement of Nrf2 in enzyme induction and possible protection against DILI by OPZ. OPZ has been shown to ameliorate APAP hepatotoxicity in studies using female mice (Ansher et al. 1983) and male hamsters (Davies et al. 1991). However, these animal models may not be universally applicable as APAP models, and replication studies have not been conducted. Recently, a study with male mice reported that OPZ attenuated APAP-induced liver injury (Ma et al. 2018), whereas a relatively lower dose of APAP used in this study caused only mild serum ALT leakage, which requires further experiments with a hepatotoxic dose of APAP to exert full toxicity and evaluate the underlying mechanism. In the present study, we examined whether OPZ protects male mice against APAP-induced liver injury and discussed the possible contributing factors related to Nrf2 activation.

Chemicals and reagents

APAP was purchased from Sigma-Aldrich (St. Louis, MO, USA). OPZ was purchased from LKT Laboratories (St. Paul, MN, USA). Glutathione (GSH) was purchased from Wako Pure Chemical Industries (Osaka, Japan). All the other chemicals and solvents used in this study were of biological or analytical grade.

Animals And Treatment

A mouse model of APAP hepatotoxicity was developed according to previously published methods (Masubuchi et al. 2011; Masubuchi et al. 2005). Male CD-1 mice were purchased from Japan SLC Inc. (Shizuoka, Japan). Mice were acclimatized for at least one week to a 12-h light/dark cycle in a climate-controlled room and were allowed to ad libitum access to food and water. All animal experiments were performed in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals and were approved by the Animal Care and Use Committee of the Chiba Institute of Science. Mice 9–10 weeks of age were used in the experiments and were fasted overnight before experimentation. APAP was administered intraperitoneally (i.p.; 350 mg/kg) in saline, along with control mice that received only the saline vehicle. OPZ dissolved in corn oil was administered i.p. to mice at doses of 37.5, 75, or 150 mg/kg, to assess its protective effects. Mice were sacrificed 0.5, 3, 6, or 24 h after APAP administration to collect blood and livers.

Assessment Of Hepatotoxicity

Hepatotoxicity was assessed by serum alanine aminotransferase (ALT) levels and histological examination of livers tissues. Serum ALT levels were measured using a specific test kit (Sigma-Aldrich, St. Louis, MO, USA). Liver sections were fixed in buffered formalin and stained with hematoxylin-eosin (KAC, Shiga, Japan) for histological examination.

Assay Of Hepatic Gsh

Hepatic GSH levels were assayed in 100 mg of liver tissues homogenized in 1.0 mL of 0.5% sulfosalicylic acid. GSH was determined by dithionitrobenzoic acid-glutathione disulfide reductase recycling assay (Anderson 1985) using a GSH test kit (Dojindo Laboratories, Kumamoto, Japan).

Real-time Reverse-transcription Polymerase Chain Reaction (Rt-pcr)

Real-time reverse-transcription polymerase chain reaction (RT-PCR)

RNA isolation and RT-PCR were performed as described previously (Masubuchi et al. 2011). Total cellular RNA was isolated from approximately 60 mg of the liver tissues according to the manufacturer’s instructions (Qiagen Inc., Valencia, CA, USA). RNA concentration was quantified by measuring the absorbance at 260 nm. Total RNA (0.8 µg) was transcribed to complementary DNA (cDNA) using high-capacity cDNA reverse transcription kits (Applied Biosystems, Foster City, CA, USA). Real-time RT-PCR was performed to quantify the mRNA expression levels of following genes using TaqMan Gene Expression Assays (Applied Biosystems) for mouse cyp2e1 (Mm00491127_m1), mouse GCL catalytic subunit (GCLC) (Mm00802655_m1), mouse NQO1 (Mm00500821_m1), and mouse glyceraldehyde 3-phosphate dehydrogenase (G3PDH, Mm99999915_g1) as probes. The reaction mixture contained one of the probes, TaqMan Universal PCR Master Mix (Applied Biosystems), and cDNA obtained from the mouse liver. Genes were amplified and further analyzed using an ABI 7500 Real-Time PCR System (Applied Biosystems), which was initiated at 50°C for 2 min and 95°C for 10 min, followed by 40 cycles of denaturation at 95°C for 15 s, and annealing/extension at 60°C for 1 min. The mRNA expression was normalized relative to G3PDH expression in each sample.

Statistical analysis

Statistical analyses between any two groups were performed using the Student’s t-test. Analyses of more than two groups were performed using analysis of variance followed by Tukey's multiple comparison test.

Protection of mice against APAP-induced liver injury by OPZ in male CD-1 mice

The serum ALT leakage assessment revealed that treatment of overnight-fasted male CD-1 mice with an APAP dose of 350 mg/kg resulted in severe liver injury. OPZ at a dose of 37.5 mg/kg tended to decrease ALT levels, but without a significant difference from vehicle-pretreated mice (Fig. 1). In contrast, OPZ at doses of 75 and 150 mg/kg significantly suppressed serum ALT levels. Moreover, OPZ did not affect serum ALT leakage in mice that were not administered APAP (Fig. 1). Therefore, pretreatment with OPZ protected the mice against APAP-induced liver injury in a dose-dependent manner. Histological analysis revealed hemorrhagic necrosis surrounding the central veins in the livers of APAP-treated mice (Fig. 2B). This necrosis was apparently eliminated in mice pretreated with OPZ, which was assessed at an OPZ dose of 75 mg/kg (Fig. 2D). Moreover, no histological changes were observed in the livers of the mice treated with OPZ alone (Fig. 2C).

Effects Of Opz On Availability Of Hepatic Gsh

The effects of OPZ on hepatic GSH levels were determined based on a previous study that reported an increase in basal GSH levels after OPZ administration (Davies et al. 1991). The time point to measure GSH was 16 hours after OPZ treatment at which APAP was usually administered. In the present study, there was no evidence of an increase in basal hepatic GSH levels following the administration of OPZ alone (Fig. 3). Administration of APAP led to early depletion of hepatic GSH, which is a response to trap N-acetyl-p-benzoquinone imine (NAPQI), a reactive metabolite of APAP. OPZ pretreatment tended to attenuate the depletion of hepatic GSH 30 minutes after APAP, but the difference was not statistically significant compared to mice treated with APAP alone (Fig. 4). GSH depletion continued up to 3 h after APAP treatment, which was partially recovered in mice pretreated with OPZ. At 6 h after APAP treatment, when GSH was partially recovered in mice without OPZ, GSH was fully restored to the basal level in mice pretreated with OPZ (Fig. 4). These results suggest that OPZ accelerates the recovery of hepatic GSH after depletion rather than inhibiting the metabolic activation of APAP to generate NAPQI. Moreover, we confirmed that OPZ did not affect hepatic CYP2E1 mRNA expression (Fig. 3), which supports the lack of effects of OPZ on the metabolic activation of APAP.

3.3. Hepatic mRNA expression of enzymes related to GSH turnover.

The mRNA expression of hepatic GCLC and NQO1 was determined 16 h after the treatment of mice with OPZ, which was the time point for the administration of APAP. GCLC is the catalytic subunit of GCL, which is a rate-limiting enzyme in glutathione synthesis. NQO1 is an enzyme with antioxidant properties responsible for the reduction of cellular quinones. Treatment of mice with OPZ tended to increase GCLC, but without a significant difference compared to control mice (Fig. 5). In contrast, OPZ significantly induced NQO1 expression in a dose-dependent manner (Fig. 5). The expression of hepatic GCLC and NQO1 was also determined 3 h after the APAP treatment (Fig. 6), when GSH was depleted in the APAP-treated mice, but began to recover in the OPZ-pretreated mice before APAP administration. The mRNA expression of GCLC was significantly increased by APAP administration, whereas the induction of GCLC by APAP was unaffected by pretreatment with OPZ (Fig. 6). However, the mRNA expression of NQO1 was not significantly induced by the administration of APAP alone, whereas it was significantly induced by OPZ, and a further increase was observed after APAP administration (Fig. 7).

In the present study, we used OPZ, a synthetic dithiolethione, as a potential hepatoprotective agent because OPZ is known to activate Nrf2 (Kwak et al. 2001; Ramos-Gomez et al. 2001). Previous reports have suggested that OPZ could ameliorate DILI using various models of APAP hepatotoxicity (Ansher et al. 1983; Davies et al. 1991; Ma et al. 2018), whereas selection of animal species, sex, and experimental conditions, including the dose of APAP, should be reconsidered to develop a better model of APAP-induced liver injury for the assessment of hepatoprotective agents. In the present study, according to our previously described regimen (Masubuchi et al. 2005), male CD-1 mice were subjected to APAP hepatotoxicity after overnight fasting. Mice were administered APAP at a dose of 350 mg/kg, and hepatotoxicity was assessed 24 h after APAP administration. In this study, we found that OPZ protected mice against APAP-induced liver injury in a dose-dependent manner, as assessed by serum ALT leakage and histochemical examination of liver sections. Thus, for the first time, we report that OPZ, an Nrf2 activator, is an effective protective agent against APAP-induced liver injury in a mouse model.

As APAP is required for metabolic activation to induce hepatotoxicity, mainly by CYP2E1 (Zaher et al. 1998), its inhibitors could effectively lower the susceptibility to APAP. In practice, OPZ has been reported to induce and inhibit CYP enzymes; OPZ was shown to highly induce CYP2E1 like other CYP enzymes in rats (Mahéo et al. 1998), whereas an in vitro study revealed that the inhibitory potency of OPZ on CYP2E1 was considerably lower than that of other CYP enzymes (Langouët et al. 2000). These results implied that the effects of OPZ on CYP2E1 did not lead to a reduction in the metabolic activation of APAP. In this study, we confirmed that OPZ did not affect CYP2E1 expression at the time of APAP administration. In addition, the depletion of hepatic GSH 30 min after APAP, which is an indication of NAPQI formation, was not significantly affected by OPZ, suggesting that the protective effects of OPZ on APAP hepatotoxicity are not mainly mediated through its effects on CYP enzymes. The role of GSH in OPZ-induced protection against APAP hepatotoxicity has been discussed. One report showed that OPZ administration increases basal hepatic GSH levels, but this increase in GSH may not be central to the protection against hepatotoxicity (Davies et al. 1991). On the other hand, other studies reported that OPZ did not affect basal GSH levels (Ansher et al. 1983; Ma et al. 2018), which might be dependent on the animal species and/or experimental conditions. In the present study, we also observed that basal hepatic GSH levels were unchanged after OPZ treatment, indicating that OPZ may not enhance hepatic GSH biosynthesis, at least in intact mice. This idea is supported by the observation that OPZ did not affect the hepatic mRNA expression of GCL (Fig. 5), a rate-limiting enzyme of GSH synthesis.

After APAP-induced depletion of hepatic GSH at 30 min after dosing, GSH levels remained at their lowest until 3 h. Whereas OPZ tended to attenuate the depletion at 30 min, it was not significantly different from that in the vehicle-treated mice. However, mice treated with OPZ showed an accelerated recovery of hepatic GSH at 3 h and 6 h after APAP administration (Fig. 4), which may be closely related to the protection against APAP hepatotoxicity provided by OPZ. Protection of mice against APAP hepatotoxicity associated with the accelerated recovery of GSH has been reported in APAP-pretreated mice (autoprotection) (Aleksunes et al. 2008), and in female mice compared to male mice (Masubuchi et al. 2011).

Enhanced biosynthesis of GSH in OPZ-pretreated mice suggests the induction of GCL, a late-limiting enzyme of GSH synthesis, as GCL has been known to have important roles against APAP hepatotoxicity via Nrf2 activation (Botta et al. 2008). In the present study, we observed that GCL was induced by APAP administration, which may be an adaptive response that limits the progression of hepatotoxicity. However, the induction of GCL in OPZ-pretreated mice was similar to that in vehicle-treated mice, suggesting that GCL may not play a central role in the OPZ-induced enhanced recovery of hepatic GSH after APAP depletion or protection against APAP-induced liver injury.

OPZ dose-dependently induced NQO1 expression, and a marked increase in NOQ1 expression was observed after treatment with the highest dose of OPZ. In contrast to GCL, NQO1 did not increase 3 h after administration of APAP, but NQO1 was induced by APAP in OPZ-pretreated mice (Fig. 6). As the adaptive response was observed only in OPZ-pretreated mice, it was suggested that this could be involved in OPZ-induced protection against APAP-induced hepatotoxicity. As NQO1 mediates the reduction of NAPQI to APAP (Lee et al. 1999), enhancing this detoxification process may decrease the availability of NAPQI, potentially attenuating hepatotoxicity and contributing to the apparent increase in the recovery of hepatic GSH after depletion by NAPQI generated from APAP (Fig. 7). Subsequent studies have suggested that NQO1 may play a role in the maintenance of mitochondrial function and ATP homeostasis (Hwang et al. 2015), which could also be involved in NQO1-mediated hepatoprotection by OPZ. Contrastingly, another study suggested that enhanced NQO1 activity in the mouse liver is insufficient to explain clofibrate-mediated hepatoprotection against APAP (Moffit et al. 2007).

Both NQO1 and GCL are regulated by Nrf2 (Jayasuriya et al. 2021). GSH-mediated formation of oxygen free radicals by the major metabolite of OPZ has been reported, which suggests a possible mechanism by which OPZ might increase the transcription of enzymes that are mediated by Nrf2 (Velayutham et al. 2005). In contrast, an Nrf2 independent hepatoprotective effect of OPZ was also reported in experimental steatohepatitis in high-fat diet-fed Nrf2-null mice (Kamisako and Tanaka 2022). In the present study, we did not examine whether the hepatoprotective effect of OPZ against APAP-induced liver injury is mediated by Nrf2. The differential effects on NQO1 and GCLC suggest that these two enzymes are regulated via different mechanisms; or that transcription factors other than Nrf2 contribute to the induction of NQO1 and GCL. One possibility is that OPZ also activates the constitutive androstane receptor (Merrell et al. 2008). In conclusion, the identification of NOQ1 as a key enzyme involved in the protection against APAP-induced liver injury is an important finding of this study, but the role of Nrf2 in the induction of NQO1 requires further investigation.

The development of natural and synthetic compounds as potential therapies for APAP-induced liver injury has contributed to a better understanding of the underlying mechanisms of drug-induced liver injury(Chang et al. 2020; Jaeschke et al. 2020; Subramanya et al. 2018; Wang et al. 2022; Yan et al. 2018). Similar to many other proposed interventions, in the present study, mice were pretreated with OPZ prior to APAP administration, but not post-treatment. This regimen is not intended for the development of an antidote instead of N-acetylcysteine used when patients accidently overdose APAP. Rather, OPZ could make the liver less susceptible to APAP hepatotoxicity, which could provide mechanistic information for predisposing factors of DILI and hints for the development of health foods and supplements that make the liver healthy. In conclusion, ours is the first study to demonstrate that OPZ effectively protects mice against APAP-induced liver injury. This study also suggests early recovery of liver GSH as a key event and NQO1 as a direct contributor to OPZ-induced hepatoprotection.

Ethical Approval All animal experiments were performed in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals and were approved by the Animal Care and Use Committee of the Chiba Institute of Science.

Competing interests The authors declare that they have no conflict of interest to disclose.

Authors' contributions Masubuchi designed the research, conducted the experiments, performed the data analysis, and wrote the manuscript. Mikami conducted the experiments and performed data analysis. The authors have read and approved the final manuscript.

Acknowledgements The authors thank Ayano Shiiki and Miri Nomura (Chiba Institute of Science) for animal care and technical assistance.

Funding This research was supported by JSPS KAKENHI (22K06749, Yasuhiro Masubuchi).

Availability of data and materials The authors confirm the availability of all required data and materials.

Aleksunes LM, Campion SN, Goedken MJ, Manautou JE (2008) Acquired resistance to acetaminophen hepatotoxicity is associated with induction of multidrug resistance-associated protein 4 (Mrp4) in proliferating hepatocytes. Toxicol Sci 104(2):261–73 doi:10.1093/toxsci/kfn093
Anderson ME (1985) Determination of glutathione and glutathione disulfide in biological samples. Methods Enzymol 113:548–55 doi:10.1016/s0076-6879(85)13073-9
Ansher SS, Dolan P, Bueding E (1983) Chemoprotective effects of two dithiolthiones and of butylhydroxyanisole against carbon tetrachloride and acetaminophen toxicity. Hepatology 3(6):932–5 doi:10.1002/hep.1840030608
Botta D, White CC, Vliet-Gregg P, et al. (2008) Modulating GSH synthesis using glutamate cysteine ligase transgenic and gene-targeted mice. Drug Metab Rev 40(3):465–77 doi:10.1080/03602530802186587
Chang L, Xu D, Zhu J, Ge G, Kong X, Zhou Y (2020) Herbal Therapy for the Treatment of Acetaminophen-Associated Liver Injury: Recent Advances and Future Perspectives. Front Pharmacol 11:313 doi:10.3389/fphar.2020.00313
Davies MH, Schamber GJ, Schnell RC (1991) Oltipraz-induced amelioration of acetaminophen hepatotoxicity in hamsters. I. Lack of dependence on glutathione. Toxicol Appl Pharmacol 109(1):17–28 doi:10.1016/0041-008x(91)90187-j
Enomoto A, Itoh K, Nagayoshi E, et al. (2001) High sensitivity of Nrf2 knockout mice to acetaminophen hepatotoxicity associated with decreased expression of ARE-regulated drug metabolizing enzymes and antioxidant genes. Toxicol Sci 59(1):169–77 doi:10.1093/toxsci/59.1.169
Hwang JH, Kim YH, Noh JR, et al. (2015) The protective role of NAD(P)H:quinone oxidoreductase 1 on acetaminophen-induced liver injury is associated with prevention of adenosine triphosphate depletion and improvement of mitochondrial dysfunction. Arch Toxicol 89(11):2159–66 doi:10.1007/s00204-014-1340-5
Jaeschke H, Akakpo JY, Umbaugh DS, Ramachandran A (2020) Novel Therapeutic Approaches Against Acetaminophen-induced Liver Injury and Acute Liver Failure. Toxicol Sci 174(2):159–167 doi:10.1093/toxsci/kfaa002
Jayasuriya R, Dhamodharan U, Ali D, Ganesan K, Xu B, Ramkumar KM (2021) Targeting Nrf2/Keap1 signaling pathway by bioactive natural agents: Possible therapeutic strategy to combat liver disease. Phytomedicine 92:153755 doi:10.1016/j.phymed.2021.153755
Kamisako T, Tanaka Y (2022) Oltipraz ameliorates the progression of steatohepatitis in Nrf2-null mice fed a high-fat diet. J Clin Biochem Nutr 70(2):147–153 doi:10.3164/jcbn.21-58
Kwak MK, Egner PA, Dolan PM, et al. (2001) Role of phase 2 enzyme induction in chemoprotection by dithiolethiones. Mutat Res 480–481:305–15 doi:10.1016/s0027-5107(01)00190-7
Langouët S, Furge LL, Kerriguy N, Nakamura K, Guillouzo A, Guengerich FP (2000) Inhibition of human cytochrome P450 enzymes by 1,2-dithiole-3-thione, oltipraz and its derivatives, and sulforaphane. Chem Res Toxicol 13(4):245–52 doi:10.1021/tx990189w
Lee SM, Cho TS, Kim DJ, Cha YN (1999) Protective effect of ethanol against acetaminophen-induced hepatotoxicity in mice: role of NADH:quinone reductase. Biochem Pharmacol 58(10):1547–55 doi:10.1016/s0006-2952(99)00248-8
Ma X, Chang Y, Zhang Y, et al. (2018) Effects of C2-Ceramide and Oltipraz on Hepatocyte Nuclear Factor-1 and Glutathione S-Transferase A1 in Acetaminophen-Mediated Acute Mice Liver Injury. Front Pharmacol 9:1009 doi:10.3389/fphar.2018.01009
Mahéo K, Morel F, Antras-Ferry J, et al. (1998) Endotoxin suppresses the oltipraz-mediated induction of major hepatic glutathione transferases and cytochromes P450 in the rat. Hepatology 28(6):1655–62 doi:10.1002/hep.510280627
Masubuchi Y, Nakayama J, Watanabe Y (2011) Sex difference in susceptibility to acetaminophen hepatotoxicity is reversed by buthionine sulfoximine. Toxicology 287(1–3):54–60 doi:10.1016/j.tox.2011.05.018
Masubuchi Y, Suda C, Horie T (2005) Involvement of mitochondrial permeability transition in acetaminophen-induced liver injury in mice. J Hepatol 42(1):110–6 doi:10.1016/j.jhep.2004.09.015
Merrell MD, Jackson JP, Augustine LM, et al. (2008) The Nrf2 activator oltipraz also activates the constitutive androstane receptor. Drug Metab Dispos 36(8):1716–21 doi:10.1124/dmd.108.020867
Moffit JS, Aleksunes LM, Kardas MJ, Slitt AL, Klaassen CD, Manautou JE (2007) Role of NAD(P)H:quinone oxidoreductase 1 in clofibrate-mediated hepatoprotection from acetaminophen. Toxicology 230(2–3):197–206 doi:10.1016/j.tox.2006.11.052
Ramos-Gomez M, Kwak MK, Dolan PM, et al. (2001) Sensitivity to carcinogenesis is increased and chemoprotective efficacy of enzyme inducers is lost in nrf2 transcription factor-deficient mice. Proc Natl Acad Sci U S A 98(6):3410–5 doi:10.1073/pnas.051618798
Subramanya SB, Venkataraman B, Meeran MFN, Goyal SN, Patil CR, Ojha S (2018) Therapeutic Potential of Plants and Plant Derived Phytochemicals against Acetaminophen-Induced Liver Injury. Int J Mol Sci 19(12) doi:10.3390/ijms19123776
Velayutham M, Villamena FA, Navamal M, Fishbein JC, Zweier JL (2005) Glutathione-mediated formation of oxygen free radicals by the major metabolite of oltipraz. Chem Res Toxicol 18(6):970–5 doi:10.1021/tx049687h
Wang J, Zhang L, Shi Q, et al. (2022) Targeting innate immune responses to attenuate acetaminophen-induced hepatotoxicity. Biochem Pharmacol 202:115142 doi:10.1016/j.bcp.2022.115142
Yan M, Huo Y, Yin S, Hu H (2018) Mechanisms of acetaminophen-induced liver injury and its implications for therapeutic interventions. Redox Biol 17:274–283 doi:10.1016/j.redox.2018.04.019
Zaher H, Buters JT, Ward JM, et al. (1998) Protection against acetaminophen toxicity in CYP1A2 and CYP2E1 double-null mice. Toxicol Appl Pharmacol 152(1):193–9 doi:10.1006/taap.1998.8501

No competing interests reported.

Download PDF

Journal Publication

published 03 Aug, 2023

Read the published version in Naunyn-Schmiedeberg's Archives of Pharmacology →

Editorial decision: Major revision
13 Jun, 2023
Reviews received at journal
08 Jun, 2023
Reviewers agreed at journal
19 May, 2023
Reviewers invited by journal
05 Mar, 2023
Editor assigned by journal
22 Feb, 2023
Submission checks completed at journal
22 Feb, 2023
First submitted to journal
21 Feb, 2023

You are reading this latest preprint version

Efficacy of oltipraz in preventing acetaminophen-induced liver injury in mice

Status:

Journal Publication

Version 1

Abstract

Figures

Introduction

Materials And Methods

Chemicals and reagents

Animals And Treatment

Assessment Of Hepatotoxicity

Assay Of Hepatic Gsh

Real-time Reverse-transcription Polymerase Chain Reaction (Rt-pcr)

Statistical analysis

Results

Protection of mice against APAP-induced liver injury by OPZ in male CD-1 mice

Effects Of Opz On Availability Of Hepatic Gsh

Discussion

Declarations

References

Additional Declarations

Status:

Journal Publication

Version 1