Tetrahydrocurcumin and octahydrocurcumin, the primary and final hydrogenated metabolites of curcumin, possess superior hepatic-protective effect against acetaminophen-induced liver injury: Role of CYP2E1 and Keap1-Nrf2 pathway
Abstract
Acetaminophen (APAP) overdose-induced hepatotoxicity is tightly associated with oxidative stress. Tetrahydrocurcumin (THC) and octahydrocurcumin (OHC), the primary and final hydrogenated metabolites of curcumin (CUR), possess stronger antioxidant activity in vitro. The present study was performed to investigate the potential and mechanism of OHC and THC against APAP-induced hepatotoxicity in parallel to CUR. Our results showed that OHC and THC dose-dependently enhanced liver function (ALT and AST levels) and alleviated histopathological deterioration. Besides, OHC and THC significantly restored the hepatic antioxidant status by miring level of MDA and ROS, and elevated levels of GSH, SOD, CAT and T-AOC. In addition, OHC and THC markedly suppressed the activity and expressions of CYP2E1, and bound to the active sites of CYP2E1. Moreover, OHC and THC activated the Keap1-Nrf2 pathway and enormously enhanced the translational activation of Nrf2-targeted gene (GCLC, GCLM, NQO1 and HO-1) against oxidative stress, via inhibiting the expression of Keap1 and blocking the interaction between Keap1 and Nrf2. Particularly, OHC and THC exerted superior hepato-protective and antioxidant activities to CUR. In conclusion, OHC and THC possess favorable hepato-protective effect through restoring antioxidant status, inhibiting CYP2E1 and activating Keap1-Nrf2 pathway, which might represent promising antioxidants for the treatment of APAP-induced hepatotoxicity.
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Cites
Role of nrf2 in oxidative stress and toxicity
Ma, Q. (2013) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-011112-140320 · Cited by 4,903 · see citing works
Regulation of glutathione synthesis
Lu, S. C.-L. (2008) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2008.05.005 · Cited by 2,131 · see citing works
The Role of Oxidative Stress and Antioxidants in Liver Diseases
Li, S., Tan, H., Wang, N., Zhang, Z.-J., Lao, L., Wong, C.-W., & Feng, Y. (2015) · International Journal of Molecular Sciences · doi:10.3390/ijms161125942 · Cited by 1,837 · see citing works
Self-citationNrf2:INrf2 (Keap1) signaling in oxidative stress
Kaspar, J. W., Niture, S. K., & Jaiswal, A. K. (2009) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2009.07.035 · Cited by 1,646 · see citing works
Curcumin, an active component of turmeric ( Curcuma longa ), and its effects on health
Bozkurt, B. K., & Şanlıer, N. (2015) · Critical Reviews in Food Science and Nutrition · doi:10.1080/10408398.2015.1077195 · Cited by 1,251 · see citing works
The Keap1–Nrf2–ARE Pathway As a Potential Preventive and Therapeutic Target: An Update
Lu, M., Ji, J., Jiang, Z., & You, Q. (2016) · Medicinal Research Reviews · doi:10.1002/med.21396 · Cited by 807 · see citing works
Du, K., Ramachandran, A., & Jaeschke, H. (2016) · Redox Biology · doi:10.1016/j.redox.2016.10.001 · Cited by 573 · see citing works
Metabolism of the cancer chemopreventive agent curcumin in human and rat intestine.
Ireson, C. R., Jones, D. J. L., Orr, S., Coughtrie, M. W. H., Boocock, D. J., Williams, M. L., Farmer, P. B., Steward, W. P., & Gescher, A. J. (2002) · PubMed · Cited by 561 · see citing works
Acetaminophen (APAP) hepatotoxicity—Isn’t it time for APAP to go away?
Lee, W. M. (2017) · Journal of Hepatology · doi:10.1016/j.jhep.2017.07.005 · Cited by 445 · see citing works
Comparative Antioxidant Activities of Curcumin and Its Demethoxy and Hydrogenated Derivatives
Somparn, P., Phisalaphong, C., Nakornchai, S., et al. (2007) · Biological and Pharmaceutical Bulletin · doi:10.1248/bpb.30.74 · Cited by 349 · see citing works
Acetaminophen hepatotoxicity: an updated review
Lancaster, E. M., Hiatt, J. R., & Zarrinpar, A. (2014) · Archives of Toxicology · doi:10.1007/s00204-014-1432-2 · Cited by 337 · see citing works
Molecular Aspects of Paracetamol-Induced Hepatotoxicity and its Mechanism-Based Prevention
Vermeulen, N. P. E., Bessems, J. G. M., & van de Straat, R. (1992) · Drug Metabolism Reviews · doi:10.3109/03602539208996298 · Cited by 320 · see citing works
The pharmacology of curcumin: is it the degradation products?
Shen, L., & Ji, H. (2012) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2012.01.004 · Cited by 296 · see citing works
Nrf2—a Promising Therapeutic Target for Defensing Against Oxidative Stress in Stroke
Zhang, R., Xu, M., Wang, Y., Xie, F., Zhang, G., & Qin, X. (2016) · Molecular Neurobiology · doi:10.1007/s12035-016-0111-0 · Cited by 243 · see citing works
Pang, C., Zheng, Z., Shi, L., Sheng, Y., Wei, H., Wang, Z., & Ji, L. (2015) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2015.12.024 · Cited by 210 · see citing works
Role of the Nrf2-ARE Pathway in Liver Diseases
Shin, S. M., Yang, J. H., & Ki, S. H. (2013) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2013/763257 · Cited by 205 · see citing works
The Potential and Action Mechanism of Polyphenols in the Treatment of Liver Diseases
Li, S., Tan, H., Wang, N., Cheung, F., Hong, M., & Feng, Y. (2018) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2018/8394818 · Cited by 199 · see citing works
Recent studies on the biofunctions and biotransformations of curcumin
Lin, J., Pan, M., & Lin‐Shiau, S. (2000) · BioFactors · doi:10.1002/biof.5520130125 · Cited by 197 · see citing works
Nakmareong, S., Kukongviriyapan, U., Pakdeechote, P., Donpunha, W., Kukongviriyapan, V., Kongyingyoes, B., Sompamit, K., & Phisalaphong, C. (2011) · Naunyn-Schmiedeberg s Archives of Pharmacology · doi:10.1007/s00210-011-0624-z · Cited by 183 · see citing works
Emergency Department Visits for Overdoses of Acetaminophen-Containing Products
Budnitz, D. S., Lovegrove, M. C., & Crosby, A. E. (2011) · American Journal of Preventive Medicine · doi:10.1016/j.amepre.2011.02.026 · Cited by 181 · see citing works
How does curcumin work with poor bioavailability? Clues from experimental and theoretical studies
Shen, L., Liu, C., An, C.-Y., & Ji, H. (2016) · Scientific Reports · doi:10.1038/srep20872 · Cited by 139 · see citing works
Protective role of tetrahydrocurcumin against erythromycin estolate-induced hepatotoxicity
Pari, L. (2004) · Pharmacological Research · doi:10.1016/j.phrs.2003.11.005 · Cited by 132 · see citing works
Wang, X., Wu, Q., Liu, A., Anadón, A., Rodríguez, J.-L., Martínez-Larrañaga, M.-R., Yuan, Z., & Martínez, M. (2017) · Drug Metabolism Reviews · doi:10.1080/03602532.2017.1354014 · Cited by 124 · see citing works
Oh, S.-W., Cha, J. Y., Jung, J., Chang, B. C., Kwon, H., Lee, B., & Kim, D.-Y. (2010) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2010.07.026 · Cited by 113 · see citing works
Murugan, P., & Pari, L. (2007) · Basic & Clinical Pharmacology & Toxicology · doi:10.1111/j.1742-7843.2007.00109.x · Cited by 87 · see citing works
Xie, W., Jiang, Z., Wang, J., Zhang, X., & Melzig, M. F. (2016) · Chemico-Biological Interactions · doi:10.1016/j.cbi.2016.01.004 · Cited by 77 · see citing works
Silymarin nanoparticle prevents paracetamol-induced hepatotoxicity
Mukherjee, A., Das, Roy, P., et al. (2011) · International Journal of Nanomedicine · doi:10.2147/ijn.s15160 · Cited by 76 · see citing works
Lin, G., Luo, D., Liu, J., et al. (2018) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2018/6962439 · Cited by 74 · see citing works
Self-citationZhao, F., Gong, Y., Hu, Y., et al. (2014) · Molecular Medicine Reports · doi:10.3892/mmr.2014.3079 · Cited by 68 · see citing works
Ko, J., Shin, J., Kim, J., et al. (2017) · Food and Chemical Toxicology · doi:10.1016/j.fct.2017.02.021 · Cited by 64 · see citing works
Saradhi, U. V. R. V., Ling, Y., Wang, J., et al. (2010) · Journal of Chromatography B · doi:10.1016/j.jchromb.2010.08.039 · Cited by 58 · see citing works
Song, K. I., Park, J. T., Lee, S., et al. (2015) · Planta Medica · doi:10.1055/s-0035-1545696 · Cited by 45 · see citing works
Liu, W., Zhang, Z., Lin, G., et al. (2017) · Food & Function · doi:10.1039/c7fo00484b · Cited by 43 · see citing works
Self-citationRoh, T., De, U., Lim, S. K., et al. (2018) · Food and Chemical Toxicology · doi:10.1016/j.fct.2018.02.017 · Cited by 43 · see citing works
Curcumin Ameliorates Ischemia-Induced Limb Injury Through Immunomodulation
Liu, Y., Chen, L., Shen, Y., et al. (2016) · Medical Science Monitor · doi:10.12659/msm.896217 · Cited by 34 · see citing works
Protective effects of thiopronin against isoniazid-induced hepatotoxicity in rats
Yue, J., Dong, G., He, C., et al. (2009) · Toxicology · doi:10.1016/j.tox.2009.08.006 · Cited by 33 · see citing works
Retinol Potentiates Acetaminophen-Induced Hepatotoxicity in the Mouse: Mechanistic Studies
Bray, B. J., & Rosengren, R. J. (2001) · Toxicology and Applied Pharmacology · doi:10.1006/taap.2001.9170 · Cited by 30 · see citing works
Zhang, Z., Luo, D., Xie, J., Lin, G., Zhou, J., Liu, W., Li, H.-L., Yi, T., Su, Z., & Chen, J. (2018) · Food & Function · doi:10.1039/c7fo02048a · Cited by 26 · see citing works
Self-citationLeong, P. K., Chiu, P. Y., & Ko, K. M. (2012) · Biological and Pharmaceutical Bulletin · doi:10.1248/bpb.35.464 · Cited by 17 · see citing works
Kong, S., Lin, G., Liu, J., Su, L., Zeng, L., Luo, D., Su, Z., & Wang, H. (2018) · Food Science and Technology Research · doi:10.3136/fstr.24.339 · Cited by 4 · see citing works
Self-citation
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Rungratanawanich, W., Qu, Y., Wang, X., Essa, M. M., & Song, B.-J. (2021) · Experimental & Molecular Medicine · doi:10.1038/s12276-021-00561-7 · Cited by 411 · see citing works
LeFort, K. R., Rungratanawanich, W., & Song, B.-J. (2024) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-023-05061-7 · Cited by 202 · see citing works
- Authors
- Luo, D.-D., Chen, J.-F., Liu, J.-J., Xie, J.-H., Zhang, Z.-B., Gu, J.-Y., Zhuo, J.-Y., Huang, S., Su, Z.-R., & Sun, Z.-H.
- Affiliations
- Guangzhou University of Chinese Medicine (CN)
- Corresponding author
- Sun, Zhang-Hua
- Venue
- Food and Chemical Toxicology
- Publisher
- Elsevier BV
- Published
- 2019-01
- Volume
- 123
- Pages
- 349-362
- ISSN
- 0278-6915 (ISSN-L)
- OpenAlex
- W2899756717
- Cited by
- 77
- References
- 40
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 10 · 2023: 16 · 2022: 13 · 2021: 10 · 2020: 11 · 2019: 7
- FWCI
- 7.75
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Food and Chemical Toxicology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Guangzhou Municipal Science and Technology Project (201704030028)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Medicine › Curcumin's Biomedical Applications
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Keywords
- tetrahydrocurcumin, curcumin, acetaminophen hepatotoxicity, acetaminophen overdose, hepatoprotection, CYP2E1, Nrf2/Keap1 pathway, oxidative stress, antioxidant activity, Nrf2 target genes, glutathione S-transferase, reactive oxygen species, lipid peroxidation
- MeSH terms
- Kelch-Like ECH-Associated Protein 1, Acetaminophen, Animals, Curcumin, Humans, Hydrogenation, Liver, Male, Signal Transduction, Oxidative Stress, Cytochrome P-450 CYP2E1, Protective Agents, NF-E2-Related Factor 2, Mice, Chemical and Drug Induced Liver Injury
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