Abstract
Demethoxycurcumin (DMC) is a safe and natural food-coloring additive, as well as an agent with several therapeutic properties. However, extensive glucuronidation in vivo has resulted in its poor bioavailability. In this study, we aimed to investigate the formation of DMC-O-glucuronides by uridine 5'-diphospho-glucuronosyltransferase 1A1 (UGT1A1) and its transport by breast cancer resistance protein (BCRP) and multidrug resistance-associated proteins (MRPs) in HeLa cells stably transfected with UGT1A1 (named HeLa1A1 cells). The chemical inhibitors Ko143 (a selective BCRP inhibitor) and MK571 (a pan-MRP inhibitor) both induced an obvious decrease in the excretion rate of DMC-O-glucuronides and a significant increase in intracellular DMC-O-glucuronide concentrations. Furthermore, BCRP knock-down resulted in a marked reduction in the level of excreted DMC-O-glucuronides (maximal 55.6%), whereas MRP1 and MRP4 silencing significantly decreased the levels of excreted DMC-O-glucuronides (a maximum of 42.9% for MRP1 and a maximum of 29.9% for MRP3), respectively. In contrast, neither the levels of excreted DMC-O-glucuronides nor the accumulation of DMC-O-glucuronides were significantly altered in the MRP4 knock-down HeLa cells. The BCRP, MRP1 and MRP3 transporters were identified as the most important contributors to the excretion of DMC-O-glucuronides. These results may significantly contribute to improving our understanding of mechanisms underlying the cellular disposition of DMC via UGT-mediated metabolism.
Highlights
Β-estradiol-3-O-glucuronide was excreted into the extracellular medium after the incubation of β-estradiol (5 and 20 μM) with HeLa1A1 cells and displayed a linear increase within 60 min, with excretion rates of 0.74 and 1.66 pmol/min after an incubation with 5 μM and 20 μM β-estradiol, respectively [30]
These established HeLa1A1 cells were rather active in generating the glucuronides after incubations with wushanicaritin, chrysin, genistein, apigenin and other compounds [20,21,22]
After an incubation of HeLa1A1 cells or wild-type HeLa cells with DMC (4 μM), two obvious additional metabolites were detected in the HeLa1A1 cell incubation medium, whereas no metabolites were detected in the medium of the wild-type HeLa cells (Fig 1A)
Summary
We aimed to investigate the formation of DMC-O-glucuronides by uridine 5’-diphospho-glucuronosyltransferase 1A1 (UGT1A1) and its transport by breast cancer resistance protein (BCRP) and multidrug resistance-associated proteins (MRPs) in HeLa cells stably transfected with UGT1A1. We aimed to investigate the mechanisms of DMC disposition via glucuronide formation and excretion
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