Disposition, Metabolism and Histone Deacetylase and Acetyltransferase Inhibition Activity of Tetrahydrocurcumin and Other Curcuminoids

Abstract

Tetrahydrocurcumin (THC), curcumin and calebin-A are curcuminoids found in turmeric (Curcuma longa). Curcuminoids have been established to have a variety of pharmacological activities and are used as natural health supplements. The purpose of this study was to identify the metabolism, excretion, antioxidant, anti-inflammatory and anticancer properties of these curcuminoids and to determine disposition of THC in rats after oral administration. We developed a UHPLC–MS/MS assay for THC in rat serum and urine. THC shows multiple redistribution phases with corresponding increases in urinary excretion rate. In-vitro antioxidant activity, histone deacetylase (HDAC) activity, histone acetyltransferase (HAT) activity and anti-inflammatory inhibitory activity were examined using commercial assay kits. Anticancer activity was determined in Sup-T1 lymphoma cells. Our results indicate THC was poorly absorbed after oral administration and primarily excreted via non-renal routes. All curcuminoids exhibited multiple pharmacological effects in vitro, including potent antioxidant activity as well as inhibition of CYP2C9, CYP3A4 and lipoxygenase activity without affecting the release of TNF-α. Unlike curcumin and calebin-A, THC did not inhibit HDAC1 and PCAF and displayed a weaker growth inhibition activity against Sup-T1 cells. We show evidence for the first time that curcumin and calebin-A inhibit HAT and PCAF, possibly through a Michael-addition mechanism.

Evidence That Calebin A, a Component of Curcuma Longa Suppresses NF-κB Mediated Proliferation, Invasion and Metastasis of Human Colorectal Cancer Induced by TNF-β (Lymphotoxin)

“…We could previously show in TNF-β-stimulated CRC cells that NF-κB is a major target for the natural substance resveratrol in suppressing CRC tumor cell malignity [12,13,36,63]. Interestingly, a recent study could show that Calebin A mediates its anti-tumorogenic properties by inhibiting P300/CBP-associated factor (PCAF), which serves as transcriptional co-activator for both p53 and NF-kB [32,65].…”

“…More interestingly, this effect was also observed in chemoresistant cells, underlining the immense potential of Calebin A as a chemopreventive/chemosensitivity agent to improve and enhance standard therapeutic approaches. Recently, it was shown that Calebin A exhibits anti-oxidant activity and inhibits histone acetyltransferase (HAT) activity and further mediates its anti-cancer effects by inhibiting P300/CBP-associated factor (PCAF) [32]. A plethora of nutraceuticals have also been shown to prevent NF-κB activation by the inhibition of IKK activity, phosphorylation and degradation of IκBα, nuclear translocation or binding of p65-NF-κB to the DNA [5].…”

Calebin-A, a Curcuminoid Analog Inhibits α-MSH-Induced Melanogenesis in B16F10 Mouse Melanoma Cells

“…CBA has a Michael acceptor group (C=C double bond) similar to curcumin. A previous study has attributed the group to CBA's capacity to inhibit histone acetyltransferase (HAT), similar to curcumin [40].…”

“…For example, a recent study reported synthesis of liposomes of CBA which showed antiproliferative effects in human colorectal cancer and mouse neuroblastoma cells [44]. has attributed the group to CBA's capacity to inhibit histone acetyltransferase (HAT), similar to curcumin [40].…”

Tetrahydrocurcumin, a major metabolite of curcumin, ameliorates allergic airway inflammation by attenuating Th2 response and suppressing the IL‐4Rα‐Jak1‐STAT6 and Jagged1/Jagged2 ‐Notch1/Notch2 pathways in asthmatic mice

“…Cur and THC in plasma and lung homogenates of mice were analysed by ultra-high-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UHPLC/Q-TOF-MS) as described previously with modification. 24 The details of sample preparation and liquid chromatography/mass spectrometry analysis are described in the Appendix S1. Linearity was acquired using calibration curves between the concentration (X) and peak area (Y).…”