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

  • Pharmaceutics. 2017 Oct 12;9(4):45. doi: 10.3390/pharmaceutics9040045.
Júlia T Novaes  1 ,  Ryan Lillico  2 ,  Casey L Sayre  3 ,  Kalyanam Nagabushnam  4 ,  Muhammed Majeed  5 ,  Yufei Chen  6 ,  Emmanuel A Ho  7 ,  Ana Luísa de P Oliveira  8 ,  Stephanie E Martinez  9 ,  Samaa Alrushaid  10 ,  Neal M Davies  11 ,  Ted M Lakowski  12
Affiliations
  • 1. The Rady Faculty of Health Sciences, College of Pharmacy, Pharmaceutical Analysis Laboratory, University of Manitoba, Winnipeg, MB R3E 0T5, Canada. [email protected].
  • 2. The Rady Faculty of Health Sciences, College of Pharmacy, Pharmaceutical Analysis Laboratory, University of Manitoba, Winnipeg, MB R3E 0T5, Canada. [email protected].
  • 3. College of Pharmacy, Roseman University of Health Sciences, South Jordan, UT 84096, USA. [email protected].
  • 4. Sabinsa Corporation, 20 Lake Drive, East Windsor, NJ 08520, USA. [email protected].
  • 5. Sabinsa Corporation, 20 Lake Drive, East Windsor, NJ 08520, USA. [email protected].
  • 6. The Rady Faculty of Health Sciences, College of Pharmacy, Pharmaceutical Analysis Laboratory, University of Manitoba, Winnipeg, MB R3E 0T5, Canada. [email protected].
  • 7. Faculty of Science, School of Pharmacy, University of Waterloo, Kitchener, ON N2G 1C5, Canada. [email protected].
  • 8. The Rady Faculty of Health Sciences, College of Pharmacy, Pharmaceutical Analysis Laboratory, University of Manitoba, Winnipeg, MB R3E 0T5, Canada. [email protected].
  • 9. Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Washington State University, Pullman, WA 99164-6610, USA. [email protected].
  • 10. The Rady Faculty of Health Sciences, College of Pharmacy, Pharmaceutical Analysis Laboratory, University of Manitoba, Winnipeg, MB R3E 0T5, Canada. [email protected].
  • 11. Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB T6G 2R3, Canada. [email protected].
  • 12. The Rady Faculty of Health Sciences, College of Pharmacy, Pharmaceutical Analysis Laboratory, University of Manitoba, Winnipeg, MB R3E 0T5, Canada. [email protected].
PMID: 29023392 DOI: 10.3390/pharmaceutics9040045
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.

Keywords
HAT; HDAC; UHPLC–MS/MS; anti-inflammatory; anticancer; antioxidant; calebin-A; curcumin; pharmacokinetics; tetrahydrocurcumin.
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