*3.2. ABCC6 Is an Efflux Pump*

Transport studies in vesicles isolated from Sf9 cells expressing the rat *Abcc6* identified the anionic cyclopentapeptide and endothelin receptor antagonist BQ-123 as substrates [74]. ATP binding and hydrolysis by rat ABCC6 has been demonstrated in a yeast expression system [75]. Using a similar approach with the human ABCC6, Ilias et al. demonstrated ATP binding and ATP-dependent active transport of the glutathione conjugates leukotriene C<sup>4</sup> and *N*-ethylmaleimide *S*-glutathione and of the cyclopentapeptide BQ-123 [76]. Probenecid, benzbromarone and indomethacin specifically inhibited transport of *N*-ethylmaleimide *S*-glutathione [77]. Another study confirmed ATP-dependent transport of BQ123 and leukotriene C<sup>4</sup> by human ABCC6 and also identified *S*-(2, 4-dinitrophenyl) glutathione as an in vitro substrate. Analysis of the drug sensitivity of ABCC6-transfected cells revealed low levels of resistance to etoposide, teniposide, doxorubicin, and daunorubicin, indicating that ABCC6 is able to confer low levels of resistance to certain anticancer agents [78]. However, this function appears unlikely to play a role in the pathophysiology of PXE and thus has limited bearing on the possible therapeutic solutions. Note that the actual endogenous

substrate(s) and the precise molecular mechanism by which ABCC6 achieves the efflux of ATP and other nucleotides/nucleosides are still unknown.
