Abstract 4426: Metabolism and tissue distribution of curcumin in mouse GI tract.
2013
Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC
Purpose: Curcuminoids have shown pronounced preventive activities on gastrointestinal (GI) cancers in preclinical settings and have now advanced to clinical evaluation. However, their tissue distribution and metabolism in the GI tissues remain largely unknown. The objective of this study is to establish an LC-MS/MS method to profile curcumin (CUR), demethoxycurcumin (DMC), bisdemethoxycurcumin (BDMC) and CUR Metabolites: CUR O-glucuronide (COG), CUR O-sulfate (COS), and tetrahydrocurcumin (THC) in plasma, and to study their disposition and kinetics in the GI tissues and lumens.
Methods: The following ion transitions at m/z: 367.4/149.1, 337.3/216.9, 307.5/186.8, 543.7/216.9, 447.4/216.9, and 371.2/235.1, and 301.5/163.9 were used for monitoring CUR, DMC, BDMC, COG, COS, THC and hesperetin (internal standard), respectively, on an API mass spectrometer. Nano-emulsion CUR (50 mg/kg) was orally administered to CD2F1 mice. Plasma, stomach tissues (ST) and lumens (SL), intestine tissue (IT) and lumens (IL), and colon tissue (CT) and feces (F) were collected up to 6 h after the dose and analyzed using an LC-MS/MS method.
Results: CUR and its metabolites were simultaneously quantified in mouse plasma, GI tissue homogenates, and GI lumens using the LC-MS/MS method with a linear range of 2 to 1000 ng/mL. COG was found to be the most abundant circulating CUR metabolite with a peak concentration of 3.99 μM in plasma at 30 min, which is approximately 8 and 36 fold higher than that of CUR and COS, respectively. In contrast, CUR was the most abundant transient species in ST, IT and CT, and reached pharmacological effective peak concentrations (μM) of 118, 55, and 142 in ST, IT and CT at 20, 60 and 30 min, respectively. The concentrations of CUR were 8261, 923 and 9.74 μM in SL, IL and F at 30, 60 and 30 min, respectively. COG and COS were two main metabolites of CUR with relative lower peak concentrations of 6.46 and 8.79 μM in IT and 30.4 and 80.1 μM in IL at 60 min, respectively, while COG and COS concentrations were much lower in ST, CT and F, and they were not detectable in SL. Notably, THC was the main metabolite of CUR with peak concentrations of 24 and 1.89 μM in ST and CT at 10 and 360 min, respectively, while no THC was detected in SL, IT, IL and F. In addition, DMC, BDMC, and THC, and their glucuronide and sulfate adducts were also profiled using these ion transition channels.
Conclusions: The LC-MS/MS method provides a critical analytic method to study the metabolism, tissue distribution, and pharmacokinetics (PK) of CUR in mice. These results demonstrated that orally ingested CUR could deliver pharmacological effective level of CUR to GI tissues and lumens, which is completely different from that in plasma. Therefore, further investigation of curcuminoids as a preventive or therapeutic agent for GI cancers is warranted. Supported by R21CA135478 (Liu), CA159077-01 (Liu & Xu) and Biomedical Mass Spectrometric Laboratory (Chan & Liu).
Citation Format: Yu Cao, Ming Chiu, Kenneth K. Chan, Ronald Xu, Zhongfa Liu. Metabolism and tissue distribution of curcumin in mouse GI tract. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4426. doi:10.1158/1538-7445.AM2013-4426
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