Multiple transport proteins involved in the detoxification of endo- and xenobiotics

Transport mechanisms involved in the exclusion of xeno- and endobiotic toxins from the cellular environment play a crucial role in protecting cells from toxicity of these compounds. A transporter designated as dinitrophenyl S-glutathione ATPase (DNP-SG ATPase) present in human erythrocyte membrane has been characterized in our laboratory. The unique functional features of this transporter include its ability to mediate ATP-dependent transmembrane movement of organic anions such as glutathione conjugates, as well as weakly cationic amphiphilic compounds such as doxorubicin and other substrates of P-glycoprotein. The substrate specificity profile of DNP-SG ATPase overlaps with those of the drug efflux pumps, P-glycoprotein, multidrug resistance associated protein (MRP), and the multi-specific organic anion transporters (MOAT) despite its distinct structural properties from these transporters. Possible functional interrelationships among these transporters is discussed in this review and it is proposed that analogous to the phase I and phase II drug metabolizing enzymes the xeno- and endobiotic transporters may belong to several distinct gene families members of which share overlapping catalytic properties. Their functional diversity covering a wide range of substrate affinities provides protection from structurally diverse xeno- and endobiotic toxicants.