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PubMed1997

Nitric oxide scavenging by curcuminoids.

Because curcumin, a compound with anti-inflammatory and anticancer activity, inhibits induction of nitric oxide synthase in activated macrophages and has been shown to be a potent scavenger of free radicals we have investigated whether it can scavenge nitric oxide directly. Curcumin reduced the amount of nitrite formed by the reaction between oxygen and nitric oxide generated from sodium nitroprusside. Other related compounds, e.g. demethoxycurcumin, bisdemethoxycurcumin and diacetylcurcumin were as active as curcumin, indicating that the methoxy and the phenolic groups are not essential for the scavenging activity. The results indicate curcumin to be a scavenger of nitric oxide. Because this compound is implicated in inflammation and cancer, the therapeutic properties of curcumin against these conditions might be at least partly explained by its free-radical scavenging properties, including those toward nitric oxide.

Antioxidants↗

PubMed2005

Involvement of Nrf2, p38, B-Raf, and nuclear factor-kappaB, but not phosphatidylinositol 3-kinase, in induction of hemeoxygenase-1 by dietary polyphenols.

The highly inducible enzyme, hemeoxygenase-1 (HO-1), metabolizes heme, thereby protecting a variety of cells against oxidative stress and apoptosis. Up-regulation by cancer chemopreventive agents has been reported, but its regulation and function in transformed cells are unclear. We compared induction by two dietary polyphenols, curcumin and epigallocatechin-3-gallate (EGCG), with that by the endogenous substrate hemin in epithelial and endothelial cells and examined the relevance to apoptosis. Curcumin or hemin (20 microM) induced HO-1 in breast cells from 5 to 24 h. Curcumin (5-40 microM) or hemin (5-100 microM) induced HO-1 and nuclear levels of nuclear factor (erythroid-derived 2)-related factor (Nrf2) in a dose-dependent manner. EGCG had no effect in breast cells, but at 30 microM, it induced nuclear translocation of Nrf2 and HO-1 expression in B-lymphoblasts. In all cases, induction was inhibited by pretreatment with the phosphatidylinositol 3-kinase (PI3K) inhibitor 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002) or the p38 inhibitor 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole (SB203580). The nuclear factor-kappaB (NF-kappaB)-DNA binding inhibitor helenalin (20 microM) also prevented induction. However, wortmannin had no effect, suggesting that PI3K was not involved. Curcumin and hemin also induced nuclear Nrf2 and HO-1 effectively in wild-type mouse embryo fibroblasts (wt MEFs) and in B-Raf(-/-) MEFs but not in Nrf2(-/-) MEFs. However, EGCG (5-20 microM) induced HO-1 only in wt MEFs. Results suggest that signaling through p38 mitogen-activated protein kinase, NF-kappaB, and Nrf2 as well as other unidentified molecules is involved in HO-1 induction by hemin and both polyphenols, but cell-specific factors also play a role, particularly with respect to EGCG. Induction of HO-1 by curcumin, EGCG, or low concentrations (5-10 microM) of helenalin did not protect MDA-MB468 breast cells or B-lymphoblasts from apoptosis.

Animals↗

PubMed2006

Synthetic curcuminoids modulate the arachidonic acid metabolism of human platelet 12-lipoxygenase and reduce sprout formation of human endothelial cells.

Platelet 12-lipoxygenase (P-12-LOX) is overexpressed in different types of cancers, including prostate cancer, and the level of expression is correlated with the grade of this cancer. Arachidonic acid is metabolized by 12-LOX to 12(S)-hydroxyeicosatetraenoic acid [12(S)-HETE], and this biologically active metabolite is involved in prostate cancer progression by modulating cell proliferation in multiple cancer-related pathways inducing angiogenesis and metastasis. Thus, inhibition of P-12-LOX can reduce these two processes. Several lipoxygenase inhibitors are known, including plant and mammalian lipoxygenases, but only a few of them are known inhibitors of P-12-LOX. Curcumin is one of these lipoxygenase inhibitors. Using a homology model of the three-dimensional structure of human P-12-LOX, we did computational docking of synthetic curcuminoids (curcumin derivatives) to identify inhibitors superior to curcumin. Docking of the known inhibitors curcumin and NDGA to P-12-LOX was used to optimize the docking protocol for the system in study. Over 75% of the compounds of interest were successfully docked into the active site of P-12-LOX, many of them sharing similar binding modes. Curcuminoids that did not dock into the active site did not inhibit P-12-LOX. From a set of the curcuminoids that were successfully docked and selected for testing, two were found to inhibit human lipoxygenase better than curcumin. False-positive curcuminoids showed high LogP (theoretical) values, indicating poor water solubility, a possible reason for lack of inhibitory activity or/and nonrealistic binding. Additionally, the curcuminoids inhibiting P-12-LOX were tested for their ability to reduce sprout formation of endothelial cells (in vitro model of angiogenesis). We found that only curcuminoids inhibiting human P-12-LOX and the known inhibitor NDGA reduced sprout formation. Only limited inhibition of sprout formation at approximately IC(50) concentrations has been seen. At IC(50), a substantial amount of 12-HETE can be produced by lipoxygenase, providing a stimulus for angiogenic sprouting of endothelial cells. Increasing the concentration of lipoxygenase inhibitors above IC(50), thus decreasing the concentration of 12(S)-HETE produced, greatly reduced sprout formation for all inhibitors tested. This universal event for all tested lipoxygenase inhibitors suggests that the inhibition of sprout formation was most likely due to the inhibition of human P-12-LOX but not other cancer-related pathways.

Amino Acid Sequence↗

PubMed2003

Antitumor activity of extract of Zingiber aromaticum and its bioactive sesquiterpenoid zerumbone.

The anticancer properties of zerumbone (2,6,9 humulatriene-8-one, a sesquiterpenoid) from Zingiber aromaticum were compared with those of curcumin from Curcuma longa in an in vitro MTT tetrazolium salt assay using HT-29, CaCo-2, and MCF-7 cancer cells and in an azoxymethane (AOM)-induced animal model of colon cancer using aberrant crypt foci (ACFs) as a preneoplastic marker. The IC50 of zerumbone was approximately 10 mM and that of curcumin was 25 mM. Cell cycle arrest in HT-29 cells was observed at G0/G1 for 10 and 12.5 mM and G2/M for 25 mM after 24 h at concentrations of 10-25 mM of zerumbone, and a concentration-dependent increase in apoptosis (2-6% of viable cells) was observed after 48 h using the same concentration range. Male Sprague-Dawley rats were fed extracts in an AIN diet prepared from the equivalent of 4% by weight of dried rhizomes of Z. aromaticum and C. longa. ACFs were induced by two doses (15 mg/kg body weight) subcutaneously of AOM 1 wk apart, the rats were killed 10 wk later, and the ACFs were assessed in the colon. Total ACFs were significantly reduced by Z. aromaticum extract (down 21%, P < 0.05) relative to control, the effect being most evident with large ACFs (>3 aberrant crypts per focus). Similar reductions were observed with 4% C. longa extract in the diet (down 24%, P < 0.01) and with 2,000 ppm curcumin, the effect being particularly evident with large ACFs. The concentration of zerumbone in the Z. aromaticum extract diet was assayed at 300 ppm and of curcumin in the C. longa extract diet was also 300 ppm, i.e., the extract of C. longa was as effective at one-seventh the concentration of curcumin as the positive control. Zerumbone is effective as an anticancer agent, possibly by its apoptosis-inducing and antiproliferative influences. This latter possibility is currently being investigated.

Animals↗

PubMed2005

Protective role of tetrahydrocurcumin (THC) an active principle of turmeric on chloroquine induced hepatotoxicity in rats.

PURPOSE: Tetrahydrocurcumin (THC) is an antioxidative substance, which is derived from curcumin, the component of turmeric. In the present investigation, the effect of THC and curcumin against chloroquine (CQ) induced hepatotoxicity were studied in female Wistar rats. METHODS: On single oral administration of CQ (970 mg/kg body weight) the activities of serum marker enzymes namely aspartate transaminase, alanine transaminase and alkaline phosphatase and the levels of bilirubin were significantly increased with significant alterations of lipids in serum and lipidperoxidation markers such as thiobarbituric acid reactive substances (TBARS) and hydroperoxides in plasma and liver were also elevated in CQ treated rats. The levels of non-enzymic antioxidants (vitamin C, vitamin E and reduced glutathione) and enzymic antioxidants (superoxide dismutase, catalase and glutathione peroxidase) were also decreased in CQ treated rats. Administration of THC (80 mg/kg body weight) and curcumin (80 mg/kg body weight) for 8 days before and 7 days after single administration of CQ significantly decreased the activities of serum markers and lipids in serum. In addition, the level of TBARS and hydroperoxides were significantly decreased with significant increase in non-enzymic and enzymic antioxidants on treatment with THC and curcumin. The biochemical observation was supplemented by histopathological examination of liver section. The results of the study reveal that THC shows more pronounced protective effect than curcumin against CQ induced toxicity.

Animals↗

PubMed1995

Inhibition of nitrite induced oxidation of hemoglobin by curcuminoids.

Curcumin, demethoxy curcumin, bis demethoxy curcumin and diacetyl curcumin inhibited nitrite induced oxidation of hemoglobin in both erythrocytes and purified human hemoglobin. The activities of all the compounds except diacetyl curcumin were similar suggesting that the methoxy substituents have very little role in this biological activity. Acetylation of phenolic groups resulted in significant reduction of activity.

Acetylation↗

PubMed2003

Sublethal hemorrhage induces tolerance in animals exposed to cecal ligation and puncture by altering p38, p44/42, and SAPK/JNK MAP kinase activation.

BACKGROUND: We have shown that SLH induces tolerance to endotoxin in vivo and in vitro, and is associated with alterations in MAP kinase (p38, p44/42, and SAPK/JNK) activation and TNF production. This study investigates the effect of sublethal hemorrhage (SLH) on cecal ligation and puncture (CLP) polymicrobial sepsis and examined the effect of the bioflavinoid, curcumin, a MAP kinase inhibitor, on this relationship. MATERIALS AND METHODS: Sprague-Dawley rats underwent SLH (hemorrhage and MAP = 30 mm Hg for 15 min, with shed blood returned) or sham operation. After 24 h, rats had CLP (cecal base ligation with double puncture). Survival was determined +/- curcumin pretreatment (n = 10/group). Lung tissue, serum, and bronchoalveolar lavage (BAL) fluid were obtained 30 min after SLH and 4 and 12 h after CLP (n = 8/group). Lung tissue was analyzed for p38, p44/42 SAPK/JNK, and HSP-70 phosphorylation (Western). Lung myeloperoxidase (MPO) activity was measured as an index of neutrophil infiltration. TNF ELISA was performed on serum and BAL sample. RESULTS: SLH significantly improved survival after CLP (21.5 vs. 7.5 h vs. sham, p = 0.008), and curcumin reversed this benefit (7.3 h, p = 0.0007 vs. SLH + CLP). MAP kinase activity was significantly greater in SLH rats 4 h post-CLP (p38: 720 vs. 331, p = 0.03, p44/42: 2759 vs. 1295, p = 0.006, SAPK: 413 vs. 254). Curcumin significantly inhibited MAPK activity both 30 min after SLH (p38: 297 vs. 3260, p44/42: 370 vs. 2628, SAPK: 748 vs. 1764, all p < 0.01 vs. SLH 30 min) and 4 h post CLP (p38: 146 vs. 720, p44/42: 616 vs. 2759, all p < 0.01 vs. SLH + CLP4 h). Four hours after CLP, SLH rats expressed more HSP72. Lung MPO activity was significantly lower in SLH + CLP rats at both 4 h (9.5 vs. 15.6, p = 0.02 vs. sham) and 12 h (18.1 vs. 37.5, p = 7 x 10(-5), vs. sham). Serum and BAL TNF levels were higher in SLH rats initially (serum: 145 vs. 28 pg/mL, p = 2 x 10(-5) BAL: 83 vs. 57 vs. sham + CLP4h); however, BAL TNF was significantly lower in SLH animals 12 h post-CLP (37 vs. 72.7 pg/mL, p = 0.003 vs. sham + CLP12h). CONCLUSION: SLH induces tolerance to CLP. This tolerance is dependent on early MAP kinase activation, since the survival benefit is reversed by curcumin. Decreases in tissue cytokine levels and neutrophil infiltration are potential mechanisms by which SLH induces tolerance to CLP (polymicrobial sepsis), attenuates acute lung injury, and improves survival.

Animals↗

PubMed2000

Plant phenolics decrease intestinal tumors in an animal model of familial adenomatous polyposis.

Epidemiological studies consistently indicate that consumption of fruits and vegetables lowers cancer risk in humans and suggest that certain dietary constituents may be effective in preventing colon cancer. Plant-derived phenolic compounds manifest many beneficial effects and can potentially inhibit several stages of carcinogenesis in vivo. In this study, we investigated the efficacy of several plant-derived phenolics, including caffeic acid phenethyl ester (CAPE), curcumin, quercetin and rutin, for the prevention of tumors in C57BL/6J-Min/+ (Min/+) mice. These animals bear a germline mutation in the Apc gene and spontaneously develop numerous intestinal adenomas by 15 weeks of age. At a dietary level of 0.15%, CAPE decreased tumor formation in Min/+ mice by 63%. Curcumin induced a similar tumor inhibition. Quercetin and rutin, however, both failed to alter tumor formation at dietary levels of 2%. Examination of intestinal tissue from the treated animals showed that tumor prevention by CAPE and curcumin was associated with increased enterocyte apoptosis and proliferation. CAPE and curcumin also decreased expression of the oncoprotein beta-catenin in the enterocytes of the Min/+ mouse, an observation previously associated with an antitumor effect. These data place the plant phenolics CAPE and curcumin among a growing list of anti-inflammatory agents that suppress Apc-associated intestinal carcinogenesis.

Adenomatous Polyposis Coli↗

PubMed1992

Protective role of aqueous turmeric extract against mutagenicity of direct-acting carcinogens as well as benzo [alpha] pyrene-induced genotoxicity and carcinogenicity.

Turmeric (Curcuma longa Linn.) has been shown to inhibit chemical carcinogenesis. In this study, we compared the chemopreventive efficacy of an aqueous turmeric extract (AqTE) and its constituents, curcumin-free aqueous turmeric extract (CFAqTE) and curcumin, using the Salmonella typhimurium mutagenicity assay and the bone marrow micronucleus test in female Swiss mice. AqTE exhibited antimutagenic activity against direct-acting mutagens, 4-nitro-O-phenylenediamine and 1-methyl-3-nitro-1-nitrosoguanidine, in strains TA 98 and TA 100 respectively. Both AqTE and CFAqTE inhibited the mutagenicity of benzo [alpha]pyrene in the two strains in the presence of Aroclor-1254-induced rat liver homogenate. The inhibition in both studies was dose-dependent. Administration of AqTE, CFAqTE and curcumin at a dose of 3 mg/animal 18 h prior to i.p. benzo [alpha]pyrene injection (250 mg/kg) significantly inhibited bone marrow micronuclei formation in female Swiss mice by 43%, 76%, and 65% respectively. Furthermore, the incidence and multiplicity of forestomach tumours induced by benzo [alpha]pyrene (1 mg/animal, twice weekly, p.o. for 4 weeks) in female Swiss mice were significantly inhibited by AqTE, CFAqTE and curcumin given 2 weeks before, during and after the carcinogen treatment. These data indicate that the protection against genomic damage by turmeric extract and its components tested could be necessary for some aspects of its cancer chemoprevention.

Animals↗

PubMed2006

The role of nuclear factor-kappa B in bacterial translocation in cholestatic rats.

Xanthinoxidase (XO) derived radical species are involved in bacterial translocation (BT) in cholestatic rats. The mechanism by which XO influences remains unclear. It has been shown recently that nuclear factor-kappa B (NF-kappaB), a ubiquitous transcription factor, can be activated by oxidative stress and thereby promote the process of BT. We investigated the effects of NF-kappaB inactivation on the incidence of BT in cholestatic rats. Sprague-Dawley rats were randomly assigned to one of eight groups: groups 1-4 were sham laparotomized rats either untreated (S1) or treated for 5 days with thalidomide (S2), curcumin (S3), or Inchin-ko (ICK; S4); groups 5-8 underwent common bile duct ligation (CBDL) for 5 days and were either untreated (C1) or treated with thalidomide (C2), curcumin (C3), or ICK (C4). After 5 days bacteriological cultures were performed from portal blood and V. cava, from the central mesenteric lymph node complex (MLN), spleen, and liver. The intensity of the activated NF-kappaB-subunit p65/p50 in the ileum mucosa was estimated by light microscopy and a scoring system from 1 to 20. Malondialdehyde (MDA) and myeloperoxidase activity (MPO) in the ileum were evaluated and expressed as U/g dry weight. Thalidomide and ICK reduced in CBDL-rats significantly the BT rate (63% vs. 18%, 63% vs. 30%, P<0.01). Enzyme estimations (MDA, MPO, and GSH) in sham operated animals showed no significant changes in the untreated groups compared with the treated groups. CBDL-rats pre-treatment with all three compounds caused a significant increase of MDA levels if groups were compared with the untreated C1-group (C1 31.6+/-7.7, C2 54.5+/-12.2, C3 53.3+/-11.2, and C4 47.2+/-9.4). GSH was reduced after the pre-treatment by all compounds but only significantly after curcumin pre-treatment (C1 vs. C3: 13.9+/-1.8 vs. 7.1+/-1.8; P<0.05). MPO estimations were significantly higher in the untreated C1-group if compared with groups C2, C3, and C4 (C1 1036.4+/-340.9, C2 709.9+/-125.9, C3 545.2+/-136.6, and C4 556.7+/-247.4; P<0.05). Thalidomide inhibited significantly the activation of NF-kappaB (C2 vs. C1: 6.0+/-4.5 vs. 12.7+/-5.3; P<0.01). Likewise, Curcumin and ICK suppressed NF-kappaB activation, but this did not reach significance in this experiment. NF-kappaB is involved in the process of BT in cholestatic rats and may be activated by XO derived ROS. We assume that the activated NF-kappaB initiates transcription of target genes inducing cytokine production, which in turn disrupts the tight junctions leading to BT from the intestinal lumen to the MLNs and circulation.

Analysis of Variance↗

PubMed2004

Matrix metalloproteinase-2: mechanism and regulation of NF-kappaB-mediated activation and its role in cell motility and ECM-invasion.

Matrix metalloproteinases belong to a family of enzymes that degrade the extracellular matrix (ECM) components and play an important role in tissue repair, tumor invasion, and metastasis. ECM proteins, cytokines, and certain other factors regulate MMP activity. OPN, an ECM protein, has been found to be overexpressed in various cancers, and it has been shown to correlate with the metastatic potential. Although such reports indicate that OPN plays an important role in the ability of tumor cells to survive and metastasize to secondary sites, the mechanism by which OPN regulates these processes is yet to be understood. In this study we report that native purified human OPN can induce cell migration and ECM invasion. Increased invasiveness and migration correlates with enhanced expression and activation of MMP-2. Our study provides evidence showing that OPN increases gelatinolytic activity by inducing MT1-MMP expression via activation of the NF-kappaB pathway. Suppression of MMP-2 by ASMMP-2 reduces the OPN-induced cell migration and ECM invasion. Curcumin blocks OPN-induced MT1-MMP expression and pro-MMP-2 activation. Curcumin, a known anti-inflammatory and anticarcinogenic compound, suppresses OPN-induced cell migration, invasion and induces apoptotic morphology in OPN-treated cells. The mechanism by which curcumin suppresses the OPN-induced effects has also been delineated. Curcumin inhibits MT1-MMP gene expression by blocking signals leading to IKK activation. This in turn inhibits IkappaBalpha phosphorylation and NF-kappaB activation.

Animals↗

PubMed1995

Antifungal activity of turmeric oil extracted from Curcuma longa (Zingiberaceae).

Turmeric oil and curcumin, isolated from Curcuma longa L., were studied against fifteen isolates of dermatophytes, four isolates of pathogenic molds and six isolates of yeasts. The inhibitory activity of turmeric oil was tested in Trichophyton-induced dermatophytosis in guinea pigs. The results showed that all 15 isolates of dermatophytes could be inhibited by turmeric oil at dilutions of 1:40-1:320. None of the isolates of dermatophytes were inhibited by curcumin. The other four isolates of pathogenic fungi were inhibited by turmeric oil at dilutions of 1:40-1:80 but none were inhibited by curcumin. All six isolates of yeasts tested proved to be insensitive to both turmeric oil and curcumin. In the experimental animals, turmeric oil (dilution 1:80) was applied by dermal application on the 7th day following dermatophytosis induction with Trichophyton rubrum. An improvement in lesions was observed in 2-5 days and the lesions disappeared 6-7 days after the application of turmeric oil.

Animals↗

PubMed2005

Inhibition of multidrug resistance proteins MRP1 and MRP2 by a series of alpha,beta-unsaturated carbonyl compounds.

To study the possible interplay between glutathione metabolism of and MRP inhibition by thiol reactive compounds, the interactions of a series of alpha,beta-unsaturated carbonyl compounds with multidrug resistance proteins 1 and 2 (MRP1/ABCC1 and MRP2/ABCC2) were studied. Alpha,beta-unsaturated carbonyl compounds react with glutathione, and therefore either their parent compound or their intracellularly formed glutathione metabolite(s) can modulate MRP-activity. Inhibition was studied in Madin-Darby canine kidney cells stably expressing MRP1 or MRP2, and isolated Sf9-MRP1 or Sf9-MRP2 membrane vesicles. In the latter model system metabolism is not an issue. Of the series tested, three distinct groups could be discriminated based on differences in interplay of glutathione metabolism with MRP1 inhibition. Curcumin inhibited MRP1 transport only in the vesicle model pointing at inhibition by the parent compound. The glutathione conjugates of curcumin also inhibit MRP1 mediated transport, but to a much lesser extent than the parent compound curcumin. In the cellular model system, it was demonstrated that glutathione conjugation of curcumin leads to inactivation of its inhibitory potential. Demethoxycurcumin and bisdemethoxycurcumin inhibited MRP1 in both the vesicle and cellular model pointing at inhibitory potency of at least the parent compound and possibly their metabolites. A second group, including caffeic acid phenethyl ester inhibited MRP1-mediated calcein transport only in the MDCKII-MRP1 cells, and not in the vesicle model indicating that metabolism appeared a prerequisite to generate the active inhibitor. Finally cinnamaldehyde, crotonaldehyde, trans-2-hexanal, citral, and acrolein did not inhibit MRP1. For MRP2, inhibition was much less in both model systems, with the three curcuminoids being the most effective. The results of this study show the importance to study the complex interplay between MRP-inhibitors and their cellular metabolism, the latter affecting the ultimate potential of a compound for cellular MRP-inhibition.

Aldehydes↗

PubMed1998

Inhibitory effect of curcuminoids on MCF-7 cell proliferation and structure-activity relationships.

Curcumin, demethoxycurcumin and bisdemethoxycurcumin are the yellow coloring phenolic compounds isolated from the spice turmeric. This study was part of a program correlating the biological activity and molecular structure of antitumor agents; the effect of these curcuminoids and cyclocurcumin (Cyclocur) was examined on the proliferation of MCF-7 human breast tumor cells. Curcuminoids appeared to be potent inhibitors, whereas Cyclocur was less inhibitory. To contribute to our understanding of the mechanism of antiproliferative activity of curcumin, cell cycle analysis was performed by propidium iodide staining and a flow cytometry technique. Curcumin exerts a cytostatic effect at G2/M which explains its antiproliferative activity. The presence of the diketone moiety in the curcumin molecule seems to be essential for the inhibitory activity.

Anticarcinogenic Agents↗

PubMed2006

Metabolism of curcuminoids in tissue slices and subcellular fractions from rat liver.

Curcumin and its natural congeners are of current interest because of their putative anti-inflammatory and anticarcinogenic activities, but knowledge about their metabolic fate is scant. In the present study conducted with precision-cut liver slices from male and female Sprague-Dawley rats, five reductive but no oxidative metabolites of curcumin and its demethoxy and bis-demethoxy analogues were observed and identified by HPLC and GC-MS analysis, mostly by comparison with authentic reference compounds. The major reductive metabolites were the hexahydrocurcuminoids in both male and female rat liver slices, whereas male rats formed more octahydro than tetrahydro metabolites and female rats more tetrahydro- than octahydrocurcuminoids. Tetrahydro, hexahydro, and octahydro metabolites were predominantly present as glucuronides, but a significant proportion of sulfate conjugates was also observed. The lack of formation of oxidative metabolites of curcumin and the ready generation of reductive metabolites were confirmed using rat liver microsomes and cytosol, respectively. Results of enzymatic hydrolysis studies conducted under various conditions revealed that curcumin and demethoxycurcumin are chemically less stable than bis-demethoxycurcumin, whereas the reductive metabolites of all three curcuminoids are stable compounds. This is the first report on the metabolism of demethoxycurcumin and bis-demethoxycurcumin. In view of the chemical instability of the parent curcuminoids, it is proposed to use their major phase I metabolites, that is, the stable hexahydro products, as biomarkers for exposure in clinical studies.

Animals↗

PubMed2001

Potential role of antioxidants during ethanol-induced changes in the fatty acid composition and arachidonic acid metabolites in male Wistar rats.

Biochemical assessment of liver damage during ethanol-induced stress was done by measuring the activities of serum enzymes, viz., aspartate transaminase (AST) and alkaline phosphatase (ALP), which were significantly elevated in rats fed ethanol. Ethanol administration for a period of 60 days modifies the fatty acid composition, and the analysis of fatty acids showed that there was a significant increase in the concentrations of palmitic acid (16:0), stearic acid (18:0), and oleic acid (18:1) in liver, kidney, and brain, whereas the concentrations of palmitoleic (16:1) and arachidonic acid (20:4) were significantly decreased. The breakdown products of arachidonic acids (20:4), prostaglandins, were elevated. The antioxidants curcumin and N-acetylcysteine (NAC) decreased the activities of serum AST and ALP. Curcumin and NAC decreased the concentrations of fatty acids, viz., palmitic, stearic, and oleic acid, whereas arachidonic acid and palmitoleic acid were elevated. The prostaglandin concentrations were also decreased after curcumin and N-acetylcysteine treatment. Thus the present investigation shows that curcumin and N-acetylcysteine prevent the fatty acid changes produced by ethanol and also reduce the inflammatory response of ethanol by reducing the level of prostaglandins.

Acetylcysteine↗

PubMed1999

Choleretic effects of curcuminoids on an acute cyclosporin-induced cholestasis in the rat.

Former studies have shown that curcumin, which can be extracted from different Curcuma species, is able to stimulate bile flow in rats, whereas bisdemethoxycurcumin, which is mainly found in rhizomes of Curcuma longa, is believed to inhibit bile flow. To reevaluate this observation we investigated the influence of both curcuminoids on bile flow, bile acid concentration and excretion over a time period of 180 min in the bile fistula model in rats. Furthermore, we tested the ability of both curcuminoids to reduce cyclosporin-induced cholestasis. 30 min after intravenous injection of 25 mg/kg of curcumin and bisdemethoxycurcumin bile flow was enhanced from 500 microliters/kg/15 min (100%) to 180% and to 220%, respectively. The choleretic effect of bisdemethoxycurcumin lasted longer than that of curcumin. Following intravenous injection of 30 mg/kg of cyclosporin, which reduced bile flow, bile acid concentration (15 mmol/l) and excretion (12.5 mumol/kg/15 min) to 40% of the initial value, administration of curcumin and bisdemethoxycurcumin transiently increased bile flow to 100% and to 125% of the starting value, respectively. However, only bisdemethoxycurcumin statistically significantly attenuated cyclosporin-induced reduction of bile acid excretion. We conclude that the beneficial properties of curcuminoids for the therapy of cyclosporin-induced cholestasis still remain to be proven.

Animals↗

PubMed1991

Suppression of c-Jun/AP-1 activation by an inhibitor of tumor promotion in mouse fibroblast cells.

Curcumin, a dietary pigment responsible for the yellow color of curry, is a potent inhibitor of tumor promotion by phorbol esters. Functional activation of transcriptional factor c-Jun/AP-1 is believed to play an important role in signal transduction of phorbol 12-myristate 13-acetate-induced tumor promotion. Suppression of the c-Jun/AP-1 activation by curcumin is observed in mouse fibroblast cells. In vitro experiments indicate that inhibition of c-Jun/AP-1 binding to its cognate motif by curcumin may be responsible for the inhibition of c-Jun/AP-1-mediated gene expression. These findings show that the effect of curcumin on phorbol 12-myristate 13-acetate-induced inflammation/tumor promotion could be studied at the molecular level.

Animals↗