TY - JOUR
T1 - Beta-Glucuronidase Catalyzes Deconjugation and Activation of Curcumin-Glucuronide in Bone
AU - Kunihiro, Andrew G.
AU - Luis, Paula B.
AU - Brickey, Julia A.
AU - Frye, Jen B.
AU - Chow, H. H.Sherry
AU - Schneider, Claus
AU - Funk, Janet L.
N1 - Funding Information:
We kindly thank Dr. J. H. Wolfe (University of Pennsylvania) for providing B6.C-H2bm1/ByBir-Gusmps/J mice. This work was supported by the National Cancer Institute (NCI), the National Center for Complementary and Integrative Health (NCCIH), and the Office of Dietary Supplements (ODS) at the National Institutes of Health (NIH) (R01CA174926 and R34 AT007837 to J.L.F., R01AT006896 to C.S., and F31AT009938 to A.K.); the United States Department of Agriculture (2014-38420-21799 National Needs Fellowship to A.K.); and the American Heart Association (16POST27250138 postdoctoral fellowship to P.B.L.). Mass spectrometric analyses were performed in part through Vanderbilt University Medical Center’s Digestive Disease Research Center supported by NIH grant P30DK058404 Core Scholarship. Pharmacokinetic analyses were performed in part through the University of Arizona Cancer Center’s Analytical Chemistry Shared Resource supported by NCI Cancer Center Support Grant P30CA023074.
Publisher Copyright:
© 2019 American Chemical Society and American Society of Pharmacognosy.
PY - 2019/3/22
Y1 - 2019/3/22
N2 - 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 antiresorptive effects of curcumin require deconjugation within bone to form the bioactive aglycone and that β-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.
AB - 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 antiresorptive effects of curcumin require deconjugation within bone to form the bioactive aglycone and that β-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.
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U2 - 10.1021/acs.jnatprod.8b00873
DO - 10.1021/acs.jnatprod.8b00873
M3 - Article
C2 - 30794412
AN - SCOPUS:85062348337
SN - 0163-3864
VL - 82
SP - 500
EP - 509
JO - Journal Of Natural Products
JF - Journal Of Natural Products
IS - 3
ER -