Modulation of hepatic drug metabolizing enzymes by the natural polyphenol curcumin

Rhonda J. Rosengren, Shuli Chen


Curcumin, the yellow pigment found in turmeric, has potent chemopreventative properties towards cancer in both in vivo and in vitro models. Phase I cytochrome P450 (CYP) enzymes and phase II conjugation enzymes play a critical role in carcinogen metabolism and hence could be an important target for cancer chemoprevention and treatment. Various studies have been undertaken to evaluate the effects of curcumin on the activity of phase I and phase II enzymes. Phase I enzymes are functionalization enzymes and Phase II enzymes perform conjugative reactions. This review summarizes the studies on curcumin modulation of phase I and II activities in the last decade. Various studies have shown that curcumin inhibits the  activity of different CYPs including CYP1A1 and CYP1B1 CYP1A1, CYP1A2, CYP2A6, CYP3A4, CYP2B1 and CYP2E1 in vitro and in vivo. However, a few studies have also reported the induction of CYPs. Curcumin also modulates the activity of phase II enzymes. Phase II enzymes have attracted much less attention than CYPs, especially in clinical pharmacology. Most studies focus on the inhibition or induction of glutthione S-transferase (GST). Also modulating of sulfotransferases (SULTs) and glucuronosyltransferases (UGTs) has been reported. However, more studies in humans following oral adminstration of curcumin are required in order to fully elucidate the potential for curcumin to be used as an effective potential chemopreventative.


cur cumin; phase II enzymes; CYP450s; inhibition; in vitro

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Aggarwal BB, Kumar A, Bharti AC. Anticancer potential of curcumin: preclinical and clinical studies. Anticancer Res. 2003;23(1A):363-98.

Kunnumakkara AB, Anand P, Aggarwal BB. Curcumin inhibits proliferation, invasion, angiogenesis and metastasis of different cancers through interaction with multiple cell signaling proteins. Cancer Lett. 2008;269(2):199-225.

Anand P, Sundaram C, Jhurani S, Kunnumakkara AB, Aggarwal BB. Curcumin and cancer: an “old-age” disease with an “age-old” solution. Cancer Lett. 2008;267(1):133-64.

Lee W-H, Loo C-Y, Bebawy M, Luk F, Mason RS, Rohanizadeh R. Curcumin and its derivatives: their application in neuropharmacology and neuroscience in the 21st century. Curr Neuropharmacol. 2013;11(4):338-78.

Zorofchian Moghadamtousi S, Abdul Kadir H, Hassandarvish P, Tajik H, Abubakar S, Zandi K. A review on antibacterial, antiviral, and antifungal activity of curcumin. BioMed research international. 2014;2014.

Sandur SK, Pandey MK, Sung B, Ahn KS, Murakami A, Sethi G, et al. Curcumin, demethoxycurcumin, bisdemethoxycurcumin, tetrahydrocurcumin and turmerones differentially regulate anti-inflammatory and anti-proliferative responses through a ROS-independent mechanism. Carcinogenesis. 2007;28(8):1765-73.

Sheweita SA. Drug-metabolizing enzymes mechanisms and functions. Curr Drug Metab. 2000;1(2):107-32.

Guengerich FP. Cytochrome p450 and chemical toxicology. Chem Res Toxicol. 2007;21(1):70-83.

Zanger UM, Schwab M. Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol Ther. 2013;138(1):103-41.

Rendic S, Guengerich FP. Update information on drug metabolism systems—2009, part II. Summary of information on the effects of diseases and environmental factors on human cytochrome P450 (CYP) enzymes and transporters. Curr Drug Metab. 2010;11(1):4-84.

Nelson DR. The cytochrome p450 homepage. Human genomics. 2009;4(1):59.

Pelkonen O, Turpeinen M, Hakkola J, Honkakoski P, Hukkanen J, Raunio H. Inhibition and induction of human cytochrome P450 enzymes: current status. Arch Toxicol. 2008;82(10):667-715.

Koe XF, Muhammad T, Sifzizul T, Chong ASC, Wahab HA, Tan ML. Cytochrome P450 induction properties of food and herbal‐derived compounds using a novel multiplex RT‐qPCR in vitro assay, a drug–food interaction prediction tool. Food science & nutrition. 2014;2(5):500-20.

Jancova P, Anzenbacher P, Anzenbacherova E. Phase II drug metabolizing enzymes. Biomedical Papers. 2010;154(2):103-16.

Xu C, Li CY-T, Kong A-NT. Induction of phase I, II and III drug metabolism/transport by xenobiotics. Arch Pharmacal Res. 2005;28(3):249.

Glatt H. Sulfotransferases in the bioactivation of xenobiotics. Chem-Biol Interact. 2000;129(1):141-70.

Choi H, Chun YS, Shin YJ, Ye SK, Kim MS, Park JW. Curcumin attenuates cytochrome P450 induction in response to 2, 3, 7, 8‐tetrachlorodibenzo‐p‐dioxin by ROS‐dependently degrading AhR and ARNT. Cancer Sci. 2008;99(12):2518-24.

Hayes CL, Spink DC, Spink BC, Cao JQ, Walker NJ, Sutter TR. 17 beta-estradiol hydroxylation catalyzed by human cytochrome P450 1B1. Proceedings of the National Academy of Sciences. 1996;93(18):9776-81.

Firozi P, Aboobaker V, Bhattacharya R. Action of curcumin on the cytochrome P450-system catalyzing the activation of aflatoxin B1. Chem-Biol Interact. 1996;100(1):41-51.

Zhang N-Y, Qi M, Zhao L, Zhu M-K, Guo J, Liu J, et al. Curcumin prevents aflatoxin B1 hepatoxicity by inhibition of cytochrome P450 isozymes in chick liver. Toxins (Basel). 2016;8(11):327.

Kirby G, Wolf C, Neal G, Judah D, Henderson C, Srivatanakul P, et al. In vitro metabolism of aflatoxin B1 by normal and tumorous liver tissue from Thailand. Carcinogenesis. 1993;14(12):2613-20.

Muhammad I, Sun X, Wang H, Li W, Wang X, Cheng P, et al. Curcumin Successfully Inhibited the Computationally Identified CYP2A6 Enzyme-Mediated Bioactivation of Aflatoxin B1 in Arbor Acres broiler. Front Pharmacol. 2017;8.

Shamsi S, Tran H, Tan RSJ, Tan ZJ, Lim LY. Curcumin, Piperine, and Capsaicin: A Comparative Study of Spice-Mediated Inhibition of Human Cytochrome P450 Isozyme Activities. Drug Metab Disposition. 2017;45(1):49-55.

Williams JA, Hyland R, Jones BC, Smith DA, Hurst S, Goosen TC, et al. Drug-drug interactions for UDP-glucuronosyltransferase substrates: a pharmacokinetic explanation for typically observed low exposure (AUCi/AUC) ratios. Drug Metab Disposition. 2004;32(11):1201-8.

Oesch F, Fabian E, Guth K, Landsiedel R. Xenobiotic-metabolizing enzymes in the skin of rat, mouse, pig, guinea pig, man, and in human skin models. Arch Toxicol. 2014;88(12):2135-90.

Mori Y, Tatematsu K, Koide A, Sugie S, Tanaka T, Mori H. Modification by curcumin of mutagenic activation of carcinogenic N‐nitrosamines by extrahepatic cytochromes P‐450 2B1 and 2E1 in rats. Cancer Sci. 2006;97(9):896-904.

Valentine SP, Le Nedelec MJ, Menzies AR, Scandlyn MJ, Goodin MG, Rosengren RJ. Curcumin modulates drug metabolizing enzymes in the female Swiss Webster mouse. Life Sci. 2006;78(20):2391-8.

Banks LD, Amoah P, Niaz MS, Washington MK, Adunyah SE, Ramesh A. Olive oil prevents benzo (a) pyrene [B (a) P]-induced colon carcinogenesis through altered B (a) P metabolism and decreased oxidative damage in Apc Min mouse model. J Nutr Biochem. 2016;28:37-50.

Niranjan B, Wilson N, Jefcoate C, Avadhani N. Hepatic mitochondrial cytochrome P-450 system. Distinctive features of cytochrome P-450 involved in the activation of aflatoxin B1 and benzo (a) pyrene. J Biol Chem. 1984;259(20):12495-501.

Garg R, Gupta S, Maru GB. Dietary curcumin modulates transcriptional regulators of phase I and phase II enzymes in benzo [a] pyrene-treated mice: mechanism of its anti-initiating action. Carcinogenesis. 2008;29(5):1022-32.

Zhang W, Tan TMC, Lim L-Y. Impact of curcumin-induced changes in P-glycoprotein and CYP3A expression on the pharmacokinetics of peroral celiprolol and midazolam in rats. Drug Metab Disposition. 2007;35(1):110-5.

Kim S-B, Cho S-S, Cho H-J, Yoon I-S. Modulation of Hepatic Cytochrome P450 Enzymes by Curcumin and its Pharmacokinetic Consequences in Sprague–dawley Rats. Pharmacogn Mag. 2015;11(Suppl 4):S580.

Appiah-Opong R, Commandeur JN, van Vugt-Lussenburg B, Vermeulen NP. Inhibition of human recombinant cytochrome P450s by curcumin and curcumin decomposition products. Toxicology. 2007;235(1):83-91.

Miners JO, Birkett DJ. Cytochrome P4502C9: an enzyme of major importance in human drug metabolism. Br J Clin Pharmacol. 1998;45(6):525-38.

Emoto C, Murase S, Iwasaki K. Approach to the prediction of the contribution of major cytochrome P450 enzymes to drug metabolism in the early drug-discovery stage. Xenobiotica. 2006;36(8):671-83.

Zhou S-F, Zhou Z-W, Yang L-P, Cai J-P. Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675.

Wang Z, Sun W, Huang C-K, Wang L, ia M-M, Cui X, et al. Inhibitory effects of curcumin on activity of cytochrome P450 2C9 enzyme in human and 2C11 in rat liver microsomes. Drug Dev Ind Pharm. 2015;41(4):613-6.

Zhou S-F. Drugs behave as substrates, inhibitors and inducers of human cytochrome P450 3A4. Curr Drug Metab. 2008;9(4):310-22.

Zaza G, Tomei P, Ria P, Granata S, Boschiero L, Lupo A. Systemic and nonrenal adverse effects occurring in renal transplant patients treated with mTOR inhibitors. Clin Dev Immunol. 2013;2013.

Hsieh Y-W, Huang C-Y, Yang S-Y, Peng Y-H, Yu C-P, Chao P-DL, et al. Oral intake of curcumin markedly activated CYP 3A4: in vivo and ex-vivo studies. Sci Rep. 2014;4.

Liu Y, Wu Y, Yu Y, Cao C, Zhang J, Li K, et al. Curcumin and resveratrol in combination modulate drug-metabolizing enzymes as well as antioxidant indices during lung carcinogenesis in mice. Hum Exp Toxicol. 2015;34(6):620-7.

Garige M, Walters E. Curcumin inhibits development and cell adhesion in Dictyostelium discoideum: Implications for YakA signaling and GST enzyme function. Biochem Biophys Res Commun. 2015;467(2):275-81.

Nelson WG, Angelo M. De Marzo and William B. Isaacs Prostate Cancer NEJM. 2003;349(4):366-81.

Lin X, Tascilar M, Lee W-H, Vles WJ, Lee BH, Veeraswamy R, et al. GSTP1 CpG island hypermethylation is responsible for the absence of GSTP1 expression in human prostate cancer cells. The American journal of pathology. 2001;159(5):1815-26.

Nakayama M, Bennett CJ, Hicks JL, Epstein JI, Platz EA, Nelson WG, et al. Hypermethylation of the human glutathione S-transferase-π gene (GSTP1) CpG island is present in a subset of proliferative inflammatory atrophy lesions but not in normal or hyperplastic epithelium of the prostate: a detailed study using laser-capture microdissection. The American journal of pathology. 2003;163(3):923-33.

Jones SB, Brooks JD. Modest induction of phase 2 enzyme activity in the F-344 rat prostate. BMC Cancer. 2006;6(1):62.

Jenkinson C, Petroczi A, Naughton DP. Effects of dietary components on testosterone metabolism via UDP-glucuronosyltransferase. Front Endocrinol (Lausanne). 2013;4.

James MO, Ambadapadi S. Interactions of cytosolic sulfotransferases with xenobiotics. Drug Metab Rev. 2013;45(4):401-14.

Volak LP, Ghirmai S, Cashman JR. Curcuminoids inhibit multiple human cytochromes P450, UDP-glucuronosyltransferase, and sulfotransferase enzymes, whereas piperine is a relatively selective CYP3A4 inhibitor. Drug Metab Disposition. 2008;36(8):1594-605.

Van der Logt E, Roelofs H, Nagengast F, Peters W. Induction of rat hepatic and intestinal UDP-glucuronosyltransferases by naturally occurring dietary anticarcinogens. Carcinogenesis. 2003;24(10):1651-6.



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