Beta-Glucuronidase Catalyzes Deconjugation and Activation of Curcumin-Glucuronide in Bone

Abstract

The biological basis for documented in vivo bone-protective effects of turmeric-derived curcumin is unclear since curcumin is barely detectable in serum, being rapidly conjugated to form what is thought to be an inactive glucuronide. Studies were therefore undertaken to test the postulate that anti-resorptive effects of curcumin require deconjugation within bone to form the bioactive aglycone, and that ß-glucuronidase (GUSB), a deconjugating enzyme expressed by hematopoietic marrow cells, facilitates this site-specific transformation. Consistent with this postulate, aglycone, but not glucuronidated, curcumin inhibited RANKL-stimulated osteoclastogenesis, a key curcumin target in bone. Aglycone curcumin, expressed relative to total curcumin, was higher in bone marrow than in serum of curcumin-treated C57BL/6J mice, while remaining a minor component. Ex vivo, under conditions preventing further metabolism of the unstable aglycone, the majority of curcumin-glucuronide delivered to marrow in vivo was hydrolyzed to the aglycone, a process that was inhibited by treatment with saccharolactone, a GUSB inhibitor, or in mice having reduced (C3H/HeJ) or absent (mps/mps) GUSB activity. These findings suggest that curcumin, despite low systemic bioavailability, may be enzymatically activated (deconjugated) within GUSB-enriched bone to exert protective effects, a metabolic process that could also contribute to bone-protective effects of other highly glucuronidated dietary polyphenols.

Disposition of Dietary Polyphenols in Breast Cancer Patients’ Tumors, and Their Associated Anticancer Activity: The Particular Case of Curcumin

“…Since chemical hydrolysis associated with the extraction protocol was discarded, the higher presence of free forms in MT and NT could be due to glucuronidase‐catalyzed deconjugations. [ 35–38 ] It is known that the in situ conjugation/deconjugation might depend on the tissue microenvironment and has been suggested in different contexts and for different metabolites. [ 39 ] For example, Patel et al.…”

“…[ 23 ] Recently, several outstanding studies have revealed that unlike inactive curcumin glucuronide, free bioactive curcumin exerts bone‐protective effects upon deconjugation of curcumin glucuronide by glucuronidase‐catalyzed reactions in animal and cell models. [ 38,44,45 ] Indeed, curcumin glucuronide has been acknowledged as the primary circulating metabolite in rodents and humans. [ 44 ] However, although the LOD values in our present study were in the order of those previously published for curcumin and curcumin glucuronide, [ 38 ] we did not detect curcumin glucuronide in most patients, neither after glucuronidase treatment, despite we observed curcumin glucuronide deconjugation ex vivo and in vitro.…”

“…[ 38,44,45 ] Indeed, curcumin glucuronide has been acknowledged as the primary circulating metabolite in rodents and humans. [ 44 ] However, although the LOD values in our present study were in the order of those previously published for curcumin and curcumin glucuronide, [ 38 ] we did not detect curcumin glucuronide in most patients, neither after glucuronidase treatment, despite we observed curcumin glucuronide deconjugation ex vivo and in vitro. Therefore, our results suggest that curcumin was hardly glucuronidated in the patients, supporting that curcumin glucuronide did not reach MT or NT.…”

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

“…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]. Previous studies on bone diseases using curcumin have reported that the deglucuronidation activity of bone marrow cells has given bone protective effects, despite curcumin having low bioavailability [44,45].…”

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

“…The direct analysis of 22 and 23was not easily attainable due to the low extraction efficiency and high probability of sample loss in LC column. It has been well-documented that curcumin glucuronide and curcumin sulfate can be transformed back into curcumin by the enzymemediated hydrolysis reaction[31]. Accordingly, the treatment of 22 and 23 with enzyme that contains sulfatase and glucuronidase is supposed to produce 2m.…”