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Incomplete Hydrolysis of Curcumin Conjugates by ?-Glucuronidase: Detection of Complex Conjugates in Plasma.

ABSTRACT: SCOPE:The diphenol curcumin from turmeric is rapidly metabolized into phase II conjugates following oral administration, resulting in negligible plasma concentration of the free compound, which is considered the bioactive form. Total plasma concentration of curcumin is often quantified after treatment with ?-glucuronidase to hydrolyze curcumin-glucuronide, the most abundant conjugate in vivo. The efficiency of enzymatic hydrolysis has not been tested. METHODS AND RESULTS:Using liquid chromatography-mass spectrometry (LC-MS) analyses the efficiency of ?-glucuronidase and sulfatase from Helix pomatia is compared to hydrolyze curcumin conjugates in human and mouse plasma after oral administration of turmeric. Both ?-glucuronidase and sulfatase completely hydrolyze curcumin-glucuronide. Unexpectedly, ?-glucuronidase hydrolysis is incomplete, affording a large amount of curcumin-sulfate, whereas sulfatase hydrolyzed both glucuronide and sulfate conjugates. With sulfatase, the concentration of free curcumin is doubled in human and increased in mouse plasma compared to ?-glucuronidase treatment. Incomplete hydrolysis by ?-glucuronidase suggests the presence of mixed glucuronide-sulfate conjugates. LC-MS based searches detect diglucuronide, disulfate, and mixed sulfate-glucuronide and sulfate-diglucuronide conjugates in plasma that likely contribute to the increase of free curcumin upon sulfatase treatment. CONCLUSION:?-Glucuronidase incompletely hydrolyzes complex sulfate-containing conjugates that appear to be major metabolites, resulting in an underestimation of the total plasma concentration of curcumin.

SUBMITTER: Luis PB

PROVIDER: S-EPMC7080564 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Incomplete Hydrolysis of Curcumin Conjugates by β-Glucuronidase: Detection of Complex Conjugates in Plasma.

Luis Paula B PB Kunihiro Andrew G AG Funk Janet L JL Schneider Claus C

Molecular nutrition & food research 20200129 6

<h4>Scope</h4>The diphenol curcumin from turmeric is rapidly metabolized into phase II conjugates following oral administration, resulting in negligible plasma concentration of the free compound, which is considered the bioactive form. Total plasma concentration of curcumin is often quantified after treatment with β-glucuronidase to hydrolyze curcumin-glucuronide, the most abundant conjugate in vivo. The efficiency of enzymatic hydrolysis has not been tested.<h4>Methods and results</h4>Using liq ...[more]

PMID: 31962379

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Project description:BACKGROUND:Numerous health benefits have been demonstrated for curcumin which is extracted from turmeric (Curcuma longa L). However, due to its poor absorption in the free form in the gastrointestinal tract and rapid biotransformation, various formulations have been developed to enhance its bioavailability. Previous studies indicate that the free form of curcumin is more bioactive than its conjugated counterparts in target tissues. Most curcumin pharmacokinetics studies in humans designed to assess its absorption and bioavailability have measured and reported total (free plus conjugated) curcumin, but not free, bioactive curcumin in the plasma because enzymatic hydrolysis was employed prior to its extraction and analysis. Therefore, the bioavailability of free curcumin cannot be determined. METHODS:Eight human subjects (4 male, 4 female) consumed a single dose of 400?mg curcumin in an enhanced absorption formulation, and blood samples were collected over 6?h. Plasma was treated either with or without glucuronidase/sulfatase prior to extraction. Curcumin and its major metabolites were analyzed using HPLC-tandem mass spectrometry. In addition, the literature was searched for pharmacokinetic studies involving curcumin using PubMed and Google Scholar, and the reported bioavailability data were compared based on whether hydrolysis of plasma samples was used prior to sample analysis. RESULTS:Hydrolysis of blood plasma samples prior to extraction and reporting the results as "curcumin" obscures the amount of free, bioactive curcumin and total curcuminoids as compared to non-hydrolyzed samples. As a consequence, the data and biological effects reported by most pharmacokinetic studies are not a clear indication of enhanced plasma levels of free bioactive curcumin due to product formulations, leading to a misrepresentation of the results of the studies and the products when enzymatic hydrolysis is employed. CONCLUSIONS:When enzymatic hydrolysis is employed as is the case with most studies involving curcumin products, the amount of free bioactive curcumin is unknown and cannot be determined. Therefore, extreme caution is warranted in interpreting published analytical results from biological samples involving ingestion of curcumin-containing products. TRIAL REGISTRATION:ClinicalTrails.gov, trial identifying number NCT04103788 , September 24, 2019. Retrospectively registered.

Dataset Information

Incomplete Hydrolysis of Curcumin Conjugates by ?-Glucuronidase: Detection of Complex Conjugates in Plasma.

Publications

Incomplete Hydrolysis of Curcumin Conjugates by β-Glucuronidase: Detection of Complex Conjugates in Plasma.

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