Regulation of biliary drug efflux pump expression by hormones and xenobiotics

Biliary elimination of endogenous compounds and xenobiotics usually require s carrier-mediated systems allowing movement across the canalicular membran e of hepatocytes. The major systems implicated belong to the ATP binding ca ssette transporter family: P-glycoprotein (P-gp) and multidrug resistance-a ssociated protein 2 (MRP2), principally mediate the passage into the bile o f cationic and anionic compounds, respectively, whereas the bile salt expor t pump (BSEP) handles biliary acids and also some anticancer drugs. Express ion of these canalicular proteins can be altered in response to various hor mones and structurally unrelated xenobiotics. Indeed, glucocorticoids up-re gulate expression of both MRP2 and BSEP in rat hepatocytes, whereas insulin induces P-gp. P-gp expression is also up-regulated by numerous chemical ca rcinogens, such as polycyclic aromatic hydrocarbons and 2-acetylaminofluore ne and by some anticancer drugs, such as anthracyclins. 2-Acetylaminofluore ne also induces MRP2; in addition, expression of this transporter in liver cells is increased in response to various drugs, such as the barbiturate ph enobarbital, the chemopreventive agent, oltipraz and the anticancer drug, c isplatin. Most of the chemical inducers acting on canalicular transporter l evels are well-known to up-regulate some hepatic drug metabolizing enzymes, suggesting a coordinate regulation of liver detoxifying proteins in respon se to these compounds. (C) 2001 Elsevier Science Ireland Ltd. All rights re served.