Bone‐Specific Metabolism of Dietary Polyphenols in Resorptive Bone Diseases

Abstract

Scope: Curcumin prevents bone loss in resorptive bone diseases and inhibits osteoclast formation, a key process driving bone loss. Curcumin circulates as an inactive glucuronide that can be deconjugated in situ by bone's high β-glucuronidase (GUSB) content, forming the active aglycone. Because curcumin is a common remedy for musculoskeletal disease, effects of microenvironmental changes consequent to skeletal development and/or disease on bone curcumin metabolism were explored.Methods and Results: Across sexual/skeletal development or between sexes in C57BL/6 mice ingesting curcumin (500 mg/kg), bone curcumin metabolism and GUSB enzyme activity were unchanged, except for >2-fold higher (p < 0.05) bone curcumin-glucuronide substrate levels in immature (4-6-week-old) mice. In ovariectomized (OVX) or bone metastasis-bearing female mice, bone substrate levels were also >2-fold higher. Aglycone curcumin levels tended to increase proportional to substrate such that the majority of glucuronide distributing to bone was deconjugated, including OVX mice where GUSB decreased by 24% (p < 0.01).

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

“…[ 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.…”

Perspective on Improving the Relevance, Rigor, and Reproducibility of Botanical Clinical Trials: Lessons Learned From Turmeric Trials

“…For example, we and others have demonstrated that curcumin and many other plant-derived polyphenols primarily circulate as glucuronide or sulfate conjugates (57-60), with ingested aglycones being near undetectable (Figure 3). Indeed, in the case of curcuminoids, these conjugates can persist in the circulation for over 24 h (e.g., 10% of administered curcuminoids, independent of dose) (61), due in part to enterohepatic recirculation (Figure 4A) (60)(61)(62)(63)(64)(65). For this reason, and because glucuronide conjugates are difficult to analyze (66), serum samples for curcuminoids and other botanicals (A) Circulating curcumin-glucuronide (CG) levels predominate and are sustained for up to 24 h in mice following a single oral curcumin dose (HED 2.5 g), with sustained, albeit lower, levels also documented in bone, where ß-glucuronidase-dependent GC hydrolysis to form aglycone curcumin occurs, resulting in higher aglycone concentrations than those perfusing bone.…”

“…which should be considered in clinical trial design (60,62,(94)(95)(96). Interestingly, separate reports suggest that gender may also be an important determinant of clinical curcumin responses, independent of bioavailability, and that gender may also influence bioavailability, although differences in body weight may have accounted for higher levels documented in women.…”

“…Evidence for this later postulate has come from recent studies in our own laboratories. Following oral curcumin administration to mice, bone has the capacity to deconjugate the majority of circulating curcumin glucuronides distributing this site ( Figure 4B ), which has high levels of glucuronidase due to resident hematopoietic marrow cells ( 60 , 62 , 67 ). This deconjugation process is glucuronidase-dependent and can yield local aglycone curcumin concentrations sufficient to inhibit NF-κB-mediated formation of bone-resorbing osteoclasts ( 60 , 62 , 67 ).…”

“…Interestingly, curcumin concentrations in mouse bones are also highest in trabecular bone compartments where menopausal bone loss is most pronounced. Figures are reproduced with permission from John Wiley and Sons ( 62 ).…”