Degradation of Curcumin: From Mechanism to Biological Implicationsby Claus Schneider, Odaine N. Gordon, Rebecca L. Edwards, Paula B. Luis

J. Agric. Food Chem.

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Year
2015
DOI
10.1021/acs.jafc.5b00244
Subject
Chemistry (all) / Agricultural and Biological Sciences (all)

Text

Degradation of Curcumin: From Mechanism to Biological

Implications

Claus Schneider,* Odaine N. Gordon,† Rebecca L. Edwards, and Paula B. Luis

Department of Pharmacology and Vanderbilt Institute of Chemical Biology, Vanderbilt University School of Medicine, Nashville,

Tennessee 37232, United States

ABSTRACT: Curcumin is the main bioactive ingredient in turmeric extract and widely consumed as part of the spice mix curry or as a dietary supplement. Turmeric has a long history of therapeutic application in traditional Asian medicine. Biomedical studies conducted in the past two decades have identified a large number of cellular targets and effects of curcumin. In vitro curcumin rapidly degrades in an autoxidative transformation to diverse chemical species, the formation of which has only recently been appreciated. This paper discusses how the degradation and metabolism of curcumin, through products and their mechanism of formation, provide a basis for the interpretation of preclinical data and clinical studies. It is suggested that the previously unrecognized diversity of its degradation products could be an important factor in explaining the polypharmacology of curcumin.

KEYWORDS: turmeric, bioactivity, metabolism, curcuminoids, polyphenol, quinone methide, protein adduction, Michael reaction ■ INTRODUCTION

The number of clinical trials investigating the therapeutic potential of curcumin has increased exponentially over the past decade. The registry clinicaltrials.gov listed 106 trials in 2014 compared to only 4 in 2004 for the search term “curcumin” (Figure 1). Curcumin is evaluated in arthritis, cancer, depression, and neurodegenerative diseases, to list only a few.1−6 The rise in expectation that the dietary agent curcumin can be a remedy for human disease has been fueled by a large number of cell culture-based and animal studies, reflected in a nearly exponential increase in publications for “curcumin” in the past two decades. With >100 cellular targets reported,7 the number and diversity of biological effects of curcumin in disease models are staggering, ranging from anti-inflammatory, antioxidant, and antiviral to antitumor effects.8,9

Curcumin is not the only dietary polyphenol that has received increasing attention. Other dietary polyphenols, such as resveratrol, quercetin, and epigallocatechin gallate (EGCG), have experienced a similar upward trend, both in preclinical research and in human clinical trials.10−13

The biological effects of curcumin in cellular and animal models are surprising considering its chemical and metabolic instability. Little if any curcumin is present unchanged in the systemic circulation.14,15 Furthermore, curcumin undergoes rapid nonenzymatic degradation in cell culture medium and possibly in vivo as well.16 Chemical transformation does not necessarily mean a loss in activity. Here we argue that understanding the molecular mechanisms of degradation of curcumin is necessary for interpreting in vitro and in vivo studies. ■ METABOLISM OF CURCUMIN IN VIVO

Curcumin is metabolized primarily by reduction and conjugation after oral administration (Figure 2). Consecutive reduction of the double bonds in the heptadienedione chain results in the formation of di-, tetra-, hexa-, and octahydrocurcumin. Reduction can already occur in the gut by the

NADPH-dependent reductase CurA that has been identified in intestinal Escherichia coli.17,18 After systemic absorption, alcohol dehydrogenase reduces curcumin to tetra- and hexahydrocurcumin in the liver, whereas formation of di- and octahydrocurcumin required an unidentified microsomal enzyme.19−21 The reduced metabolites, especially tetra- and hexahydrocurcumin, represent the largest portion of curcumin metabolites.14 With few exceptions their biological activities are strongly reduced compared to those of curcumin.22,23

Curcumin and its reduced metabolites exist almost exclusively as conjugates with glucuronic acid and sulfate in plasma.14,21 Two additional pathways for the degradation of curcumin in vitro have been described (Figure 2).16,24 Whether and how the degradation and oxidation pathways contribute to

Special Issue: 27th ICP and 8th Tannin Conference (Nagoya 2014)

Received: January 14, 2015

Revised: March 23, 2015

Accepted: March 29, 2015

Figure 1. Numbers of publications in PubMed and human trials in www.clinicaltrials.gov with the keyword “curcumin” from 1994 to 2014.

Review pubs.acs.org/JAFC © XXXX American Chemical Society A DOI: 10.1021/acs.jafc.5b00244

J. Agric. Food Chem. XXXX, XXX, XXX−XXX the in vivo and in vitro biological activities of curcumin will be discussed in the following. ■ DEGRADATION OF CURCUMIN IN CELL CULTURE

Although the chemical instability of curcumin is widely recognized, this fact is less considered in the interpretation of studies with cultured cells in vitro. Curcumin degrades quickly at physiological pH but more slowly when incubated in the presence of serum or with cultured cells.24 Protein increases the half-life of curcumin from a few minutes to 1−2 h.24

Nevertheless, there is sufficient time for curcumin to degrade during a typical 4−8 h incubation before cultured cells are harvested and analyzed. When cells have been treated with curcumin for several hours, it is impossible to decide whether the observed effects are due to curcumin or its degradation products. Unless interpreted with a consideration of what active or inactive metabolites of curcumin may be formed (or not) during an assay, results can be misleading and give only limited insight into the in vivo biological activity of curcumin.

Similar considerations are relevant for studies claiming that the mechanism of action of curcumin is due to the induction of oxidative stress (“reactive oxygen species”, ROS) in cells. In many instances, the role of curcumin-induced ROS has been shown indirectly, that is, by addition of a reducing antioxidant, for example, N-acetylcysteine, that abolished the effects of curcumin.25−29 The action of the antioxidant, however, is not only to reduce ROS formation but also to delay or prevent degradation of curcumin. Thus, unless specific probes against