Regulation of ATP‐binding cassette (Abc) transporters by organoselenium compounds

Abstract

Selenium‐containing compounds have demonstrated chemopreventive activity in a variety of chemically‐induced tumor models, but a unifying mechanism for this effect remains elusive. Altered disposition of chemicals and toxic metabolites may be contributing factors. Following dietary ingestion of selenocysteine pro‐drugs and selenocystine (15 ppm Se) for 1 month, mouse hepatic glutathione transferase, quinone oxidoreductase and microsomal epoxide hydrolase activities were elevated by 2‐butyl‐ and 2‐oxoselenazolidine‐4‐carboxylic acids (SCAs) and selenocystine, but not by 2‐cyclohexyl‐, 2‐phenyl‐, and 2‐(2′‐hydroxyphenyl)‐ SCAs. Expression of multidrug resistance‐associated proteins and other Abc transporters were evaluated by qPCR. Of 10 transporters examined, none responded in a pattern similar to the activities of the enzymes capable of being regulated via the Nrf2/ARE mechanism. Abcc3 (Mrp3) was increased only by 2‐butylSCA and no transporters were induced by 2‐oxoSCA or selenocystine. 2‐(2′‐Hydroxyphenyl)SCA was the only compound that induced expression of Abcc2 (Mrp2) and Abcb6. All the selenocompounds reduced the expression of Abcb11. Expression of Abcc1, Abcc4, Abcc5, Abcc6, and Abcg2 and Abca3, was not altered by any compound. Selenocompound regulation of Abc transporter expression appears to be compound dependent and unrelated to the Nrf2/ARE pathway.Support: GM 058913