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Revolving Door Action of BCRP Facilitates or Controls the Efflux of Flavone Glucuronides from UGT1A9-Overexpressing HeLa Cells.

Mol Pharm. 2013 Feb 12;

Authors: Wei Y, Wu B, Jiang W, Yin T, Jia X, Basu S, Yang G, Hu M


Cellular production of flavonoid glucuronides requires the action of both UDP-glucuronosyltransferases (UGT) and efflux transporters since glucuronides are too hydrophilic to diffuse across the cellular membrane. We determined the kinetics of efflux of 13 flavonoid glucuronides using the newly developed HeLa-UGT1A9 cells and correlated them with kinetic parameters derived using expressed UGT1A9. The results indicated that among the seven monohydroxyflavones (HFs), there was moderately good correlation (r2≥0.65) between fraction metabolized (fmet) derived from HeLa-UGT1A9 cells and CLint derived from the UGT1A9-mediated metabolism. However, there was weak or no correlation between these two parameters for six dihyroxylflavones (DHFs). Furthermore, there was weak no correlation between various kinetic parameters (Km, Vmax or CLint) for the efflux and the metabolism regardless if we were using 7 HFs, 6 DHFs or a combination thereof. Instead, cellular excretion of many flavonoids glucuronides appears to be controlled by the efflux transporter, and poor affinity of glucuronide to the efflux transporter resulted in major intracellular accumulation of glucuronides to a level that is above the dosing concentration of its aglycone. Hence, the efflux transporters appear to act as the "Revolving Door" to control the cellular excretion of glucuronides. In conclusion, the determination of a flavonoid's susceptibility to glucuronidation must be based on both its susceptibility to glucuronidation by the enzyme and resulting glucuronide's affinity to the relevant efflux transporters, which act as the "Revolving Door(s)" to facilitate or control its removal from the cells.

PMID: 23402418 [PubMed - as supplied by publisher]