Drug and toxicant handling by the OAT organic anion transporters in the kidney and other tissues

Abstract

Organic anion transporters (OATs) translocate drugs as well as endogenous substances and toxins. The prototype, OAT1 (SLC22A6), first identified as NKT in 1996, is the best-studied member of the OAT subgroup of the SLC22 transporter family, which also includes OCTs (organic cation transporters), OCTNs (organic cation transporters of carnitine) and Flipts (fly-like putative transporters). The SLC22 family is evolutionarily conserved, with members expressed in fly and worm. An unusual feature of many SLC22A genes is a tendency to exist in pairs or clusters in the genome. Much of the early research in the field focused on the role of OATs and other SLC22 family members in renal drug transport. OATs have now been localized to other epithelial tissues, including placenta (OAT4) and mouse olfactory mucosa (Oat6). Although findings from in vivo physiological studies in mice lacking OATs (e.g. Oat1 and Oat3) have generally been consistent with in vitro transport data from Xenopus oocytes and transfected cells, these in vivo data are helping to clarify the relative contributions of individual OATs to the renal excretion of particular organic anions and drugs. Moreover, in mutant mice, certain endogenous anions accumulate, suggesting the physiological roles of the proteins encoded by the mutant genes. It has been proposed that the presence of OATs and other SLC22-family members in multiple tissue compartments might enable a 'remote sensing' mechanism by allowing communication between organs, and possibly individuals, through organic ions. Variability of human drug responses and susceptibility to drug toxicity might, in part, be explained by variations in the coding and promoter regions of these genes. Computational biological studies are likely to not only shed light on molecular mechanisms of transport for compounds of clinical and toxicological interest, but also aid in drug design.