Curcumin β-D-Glucuronide Plays an Important Role to Keep High Levels of Free-Form Curcumin in the Blood

Abstract

Curcumin, a polyphenol derived from the rhizome of the naturally occurring plant Curcuma longa, has various pharmacological actions such as antioxidant and anti-inflammatory effects. In this paper, we evaluated the role of its internal metabolite, curcumin β-D-glucuronide (curcumin monoglucuronide, CMG), by investigating curcumin kinetics and metabolism in the blood. Firstly, we orally administered highly bioavailable curcumin to rats to elucidate its kinetics, and observed not only the free-form of curcumin, but also, curcumin in a conjugated form, within the portal vein. We confirmed that curcumin is conjugated when it passes through the intestinal wall. CMG, one of the metabolites, was then orally administered to rats. Despite its high aqueous solubility compared to free-form curcumin, it was not well absorbed. In addition, CMG was injected intravenously into rats in order to assess its metabolic behavior in the blood. Interestingly, high levels of free-form curcumin, thought to be sufficiently high to be pharmacologically active, were observed. The in vivo antitumor effects of CMG following intravenous injection were then evaluated in tumor-bearing mice with the HCT116 human colon cancer cell line. The tumor volume within the CMG group was significantly less than that of the control group. Moreover, there was no significant loss of body weight in the CMG group compared to the control group. These results suggest that CMG could be used as an anticancer agent without the serious side effects that most anticancer agents have.

Synthesis, Anticancer Activity, and Preliminary Pharmacokinetic Evaluation of 4,4-Disubstituted Curcuminoid 2,2-bis(Hydroxymethyl)Propionate Derivatives

“…In Such behavior, extensively studied in the phenolic drugs, was beneficial in maintaining the circulating concentration of free-form curcumin [32] and may extend the pharmacological effect of drug [33]. The hydrolysis metabolite 2m emerged from 10 min and reached its maximum blood content at 120 min, indicating that a medium-to-high esterase-mediated biotransformation proceeded in vivo to yield the efficient absorption of 2m.…”

“…The hydrolysis metabolite 2m emerged from 10 min and reached its maximum blood content at 120 min, indicating that a medium-to-high esterase-mediated biotransformation proceeded in vivo to yield the efficient absorption of 2m. Subsequently, the phase II metabolic process of 2m Such behavior, extensively studied in the phenolic drugs, was beneficial in maintaining the circulating concentration of free-form curcumin [32] and may extend the pharmacological effect of drug [33]. The hydrolysis metabolite 2m emerged from 10 min and reached its maximum blood content at 120 min, indicating that a medium-to-high esterase-mediated biotransformation proceeded in vivo to yield the efficient absorption of 2m.…”

Intense Uptake of Liposomal Curcumin by Multiple Myeloma Cell Lines: Comparison to Normal Lymphocytes, Red Blood Cells and Chronic Lymphocytic Leukemia Cells

“…Curcumin was found to be the most active curcuminoid for suppression of NF-ĸB (28) and inflammatory pathways in Alzheimer's disease (29). With respect to the metabolites of curcumin, THC was observed to have, lesser, similar or greater pharmacological activities depending on the biological system investigated (30) and the conjugated metabolites of curcumin reportedly mediate their antitumor effects through conversion to curcumin (31). Thus, the propensity of cancer cells, in particular myeloma, cells to have strikingly higher levels of curcumin (either due to physical differences in the cell membrane or differences in the metabolism of curcumin compared to normal cells), may offer an advantage for the treatment of myeloma.…”

Periodic Curcumin Monoglucuronide Injections Ameliorate Structural Osteoarthritis Changes in Rats with Destabilized Medial Meniscus

“…It is present at high levels in tumors, and it is released from granulocytes, including neutrophils, and injured cells at sites of in ammation [39][40][41]. Due to this enzyme, the intravenous administration of synthesized TBP1901 in mice showed the presence of freeform curcumin in the blood at a constant level (approximately 4-16% of total curcumin levels), and the tumor growth was signi cantly suppressed [42]. Furthermore, the bone has been shown to contain more aglycone curcumin and curcumin than other tissues when curcumin is ingested, probably because the βglucuronidase expressed in bone marrow cells deconjugates TBP1901 [35,43].…”

“…Therefore, TBP1901 may act as a pro-drug that targets the bone. In addition, because TBP1901 has a higher polarity than curcumin, it is more water-soluble than curcumin [42]. Its water-solubility makes it more suitable for use in injections than curcumin, and it may be also more effective for absorption into the joint tissue, which is composed mostly of water.…”