Organic anion transporter (Slc22a) family members as mediators of toxicity
Introduction
Proper renal function is essential to the maintenance of total body homeostasis. The kidney actively senses and regulates fluid volume, acid–base balance, electrolyte concentration, and hormone levels, in addition to ridding the body of metabolic waste products. In order to accomplish these tasks efficiently, the kidney receives roughly 25% of the resting cardiac output. However, as a consequence of this physiological relationship, the kidney is continuously bathed in potentially toxic substances, many of which are actively accumulated to very high levels within the cells of the proximal tubules. Toxic exposures can be environmental, drug, or disease state in nature (i.e., both endogenous and xenobiotic in origin). The role of the kidney in the pathophysiology of toxic organic anions has been the subject of intense study for over a hundred years. This extensive scrutiny resulted in a precise model detailing the physiological properties of the cellular entry and exit of organic anions (OAs), which are unable to freely diffuse through the lipid bilayer. This latter property led to the postulation that specific membrane associated transport proteins must exist to mediate these processes and connect them to cellular energy.
In the past decade, hundreds of transporter proteins have been cloned and characterized resulting in the identification of a multitude of gene families responsible for the transepithelial flux of charged organic compounds. Subsequently, renal expression of many of these transporters was detected and their role as ‘doorways’ through which charged organic molecules cross the plasma membrane of renal proximal tubule cells (RPTCs) was demonstrated. In RPTCs one such family is the organic anion transporter (OAT) family, which constitutes a subfamily within the Amphiphilic Solute Transporter branch (Slc22a) of the Major Facilitator Superfamily (Eraly et al., 2003, Sweet and Pritchard, 1999, Sweet et al., 2001). The OAT family plays a critical role in the renal excretion and detoxification of a wide variety of compounds including drugs, toxins, hormones, and neurotransmitter metabolites (See Table 1). Thus, a thorough understanding of OAT function, as well as that of substrate “cross-over” with members of other transporter families (e.g., the multidrug resistance associated proteins (Mrp) or the organic anion transporting polypeptides (Oatp)), is crucial if we are to accurately assess their impact on the efficacy and extent of exposures to toxic organic anions.
Section snippets
Renal organic anion transport
The mechanisms and driving forces governing the renal uptake and efflux of small (300–500 Da) OAs via the ‘classical’ renal organic anion transport system, of which the OATs are an integral part, are well defined (Sweet and Pritchard, 1999, Sweet et al., 2001). As their name implies, OAs carry a negative charge and as such their entry into the negatively charged interior of RPTCs requires energy. To accomplish this, entry across the basolateral membrane of RPTCs involves the concerted action of
OAT expression in extrarenal tissues
Every OAT identified thus far is expressed in the kidney where their function is a major determinant of toxicity and the therapeutic action of drugs. In addition to the kidney, active OA transport is also an important function of other barrier epithelia including liver, placenta, brain capillaries, and choroid plexus. Accordingly, OAT expression has been detected in these tissues (Table 2). Oat2 is the only OAT that is highly expressed in the liver; however, its function in hepatic OA transport
The organic anion transporter (OAT) family
The purpose of this review is to highlight recent evidence that implicates members of the OAT (Slc22a) family as playing a role in mediating the toxicity of a variety of substances. A brief synopsis of each member of the OAT family is presented followed by a discussion of their potential involvement in the toxicity of example endogenous compounds, drugs, chemicals, heavy metals, and environmental toxins. However, it is important to note that as our molecular understanding of the renal organic
OATs as mediators of toxicity
Examination of cloned transporters expressed in isolation has revealed that the OATs are capable of handling an enormous variety of structurally diverse OAs as substrates. Evidence indicates they are intimately involved in the distribution and elimination of many potentially toxic endogenous and exogenous organic anions. Indeed, the nature of these substrates suggests that proper OAT function is essential to maintaining total body homeostasis and that altered OAT function (and/or expression)
Future perspectives
In the last decade, a large number of genes encoding transporter proteins have been cloned and characterized, greatly increasing our understanding of the organic anion transport process (Sweet and Pritchard, 1999, Sweet et al., 2001, Van Aubel et al., 2000, Wright and Dantzler, 2004). Although this review has focused on the potential involvement of the OAT (Slc22a) family of transporters in mediating the systemic disposition and elimination of various toxicants, it is increasingly clear that
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