Disposition, Metabolism and Histone Deacetylase and Acetyltransferase Inhibition Activity of Tetrahydrocurcumin and Other Curcuminoids
Pharmaceutics.2017 Oct 12;9(4).pii: E45
Curcuminoids, curcumin, calebin-A and Tetrahydrocurcumin (THC), found in turmeric (Curcuma longa) have multitude pharmacological activities and are used as health supplements. They have been explored to establish their anticancer properties also. By virtue of P-glycoprotein inhibitory activity curcumioinds are used as adjuvant drugs in cancer therapy. Further, studies have found that curcumin and calebin-A act at the genetic level to inhibit histone acetyltransferase (HAT) and modulate mitogen-activated protein-kinase (MAPK) pathway, respectively. Despite being effective, both curcumin and calebin-A suffer from poor oral bioavailability. THC is an active metabolite of curcumin that has greater stability at the physiological condition and improved aqueous solubility than curcumin. With improved benefits over curcumin, THC is also being explored for its anticancer potential.
To describe the pharmacokinetic characteristics of THC in vivo and anticancer effects along with curcumin and calebin-A, in vitro.
Drug disposition for THC (500 mg/kg) was characterized using surgically-modified, exposed jugular vein-catheterized, adult male CD Sprague-Dawley rats (250–300 g) fasted 12 hours prior to single oral dose. The blood and urine sample were collected at certain intervals until 72 hours post-dosing. The drug was quantified in serum and urine samples obtained from rats administered with THC using ultra-high-performance liquid chromatography–mass spectrometry (UHPLC–MS/MS) to characterize its pharmacokinetics in rats after oral administration. Curcuminoids (THC, curcumin and calebin-A) were assessed for pharmacological potential in vitro, including antioxidant, anti-inflammatory (cyclooxygenase (COX), lipooxygenase (LOX) and tumour necrosis factor (TNF)-alpha inhibition, HDAC1 and PCAF inhibition as well as cellular growth inhibition. Curcuminoids (THC, curcumin and calebin-A) used in this study were by Sabinsa Corporation.
The study results indicate that
- Un-optimized formulations of THC will be poorly absorbed after oral administration and are primarily excreted via non-renal routes; as glucuronide conjugates in bile
- All the curcuminoids tested had 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
- Curcuminoids show a marginal COX inhibition; with curcumin being highly selective to COX-2 than COX-1 isoenzyme, while the calebin-A and THC had an equal propensity to both the isoenzymes
- Both curcumin and calebin-A show direct inhibition of HDAC1 and PCAF as well as displayed a weaker growth inhibition activity against T-cell lymphoblastic lymphoma Sup-T1 cells
This study concludes that both curcumin and calebin-A has anticancer potential by direct inhibition of HDAC1 and HAT PCAF mechanisms, while the THC has different anticancer mechanism maybe by virtue of its anti-inflammatory and antioxidant activities.