Organic anion transporter (Slc22a) family members as mediators of toxicity

https://doi.org/10.1016/j.taap.2004.10.016Get rights and content

Abstract

Exposure of the body to toxic organic anions is unavoidable and occurs from both intentional and unintentional sources. Many hormones, neurotransmitters, and waste products of cellular metabolism, or their metabolites, are organic anions. The same is true for a wide variety of medications, herbicides, pesticides, plant and animal toxins, and industrial chemicals and solvents. Rapid and efficient elimination of these substances is often the body's best defense for limiting both systemic exposure and the duration of their pharmacological or toxicological effects. For organic anions, active transepithelial transport across the renal proximal tubule followed by elimination via the urine is a major pathway in this detoxification process. Accordingly, a large number of organic anion transport proteins belonging to several different gene families have been identified and found to be expressed in the proximal nephron. The function of these transporters, in combination with the high volume of renal blood flow, predisposes the kidney to increased toxic susceptibility. Understanding how the kidney mediates the transport of organic anions is integral to achieving desired therapeutic outcomes in response to drug interactions and chemical exposures, to understanding the progression of some disease states, and to predicting the influence of genetic variation upon these processes. This review will focus on the organic anion transporter (OAT) family and discuss the known members, their mechanisms of action, subcellular localization, and current evidence implicating their function as a determinant of the toxicity of certain endogenous and xenobiotic agents.

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

References (200)

  • S.A. Eraly et al.

    Organic anion and cation transporters occur in pairs of similar and similarly expressed genes

    Biochem. Biophys. Res. Commun.

    (2003)
  • J. Forn

    Active transport of 5-hydroxyindoleacetic acid by the rabbit choroid plexus in vitro. Blockade by probenecid and metabolic inhibitors

    Biochem. Pharmacol.

    (1972)
  • T.H. Gieske et al.

    Acute effects of cadmium on proximal tubular function in rabbits

    Toxicol. Appl. Pharmacol.

    (1974)
  • S.J. Gorzinski et al.

    Acute, pharmacokinetic, and subchronic toxicological studies of 2,4-dichlorophenoxyacetic acid

    Fundam. Appl. Toxicol.

    (1987)
  • Y. Hirouchi et al.

    Preventive effect of betamipron on nephrotoxicity and uptake of carbapenems in rabbit renal cortex

    Jpn. J. Pharmacol.

    (1994)
  • K.Y. Jung et al.

    Characterization of ochratoxin A transport by human organic anion transporters

    Life Sci.

    (2001)
  • K.Y. Jung et al.

    Involvement of rat organic anion transporter 3 (rOAT3) in cephaloridine-induced nephrotoxicity: in comparison with rOAT1

    Life Sci.

    (2002)
  • T. Kamenosono et al.

    Structure–effect relationship in the mobilization of cadmium in mice by several dithiocarbamates

    Comp. Biochem. Physiol.: C Toxicol. Pharmacol.

    (2002)
  • S. Khamdang et al.

    Interaction of human and rat organic anion transporter 2 with various cephalosporin antibiotics

    Eur. J. Pharmacol.

    (2003)
  • K.R. Kim et al.

    Renal transport systems for organic anions and cations in cadmium-exposed rats

    Toxicol. Appl. Pharmacol.

    (1998)
  • Y. Kobayashi et al.

    Differential gene expression of organic anion transporters in male and female rats

    Biochem. Biophys. Res. Commun.

    (2002)
  • S. Kojima et al.

    Comparative effects of three chelating agents on distribution and excretion of cadmium in rats

    Toxicol. Appl. Pharmacol.

    (1986)
  • S. Kojima et al.

    Mechanism of mobilization of renal and hepatic cadmium by dithiocarbamates in mice

    Toxicology

    (1994)
  • H. Kusuhara et al.

    Molecular cloning and characterization of a new multispecific organic anion transporter from rat brain

    J. Biol. Chem.

    (1999)
  • K. Kuze et al.

    Heterologous expression and functional characterization of a mouse renal organic anion transporter in mammalian cells

    J. Biol. Chem.

    (1999)
  • S.A. Lacy et al.

    Effect of oral probenecid coadministration on the chronic toxicity and pharmacokinetics of intravenous cidofovir in cynomolgus monkeys

    Toxicol. Sci.

    (1998)
  • L.H. Lash et al.

    Cytotoxicity of S-(1,2-dichlorovinyl)glutathione and S-(1,2-dichlorovinyl)-l-cysteine in isolated rat kidney cells

    J. Biol. Chem.

    (1986)
  • E.A. Lock et al.

    Effect of the organic acid transport inhibitor probenecid on renal cortical uptake and proximal tubular toxicity of hexachloro-1,3-butadiene and its conjugates

    Toxicol. Appl. Pharmacol.

    (1985)
  • G.W. Aherne et al.

    Prolongation and enhancement of serum methotrexate concentrations by probenecid

    Br. Med. J.

    (1978)
  • N. Apiwattanakul et al.

    Transport properties of nonsteroidal anti-inflammatory drugs by organic anion transporter 1 expressed in Xenopus laevis oocytes

    Mol. Pharmacol.

    (1999)
  • A.G. Aslamkhan et al.

    Human renal organic anion transporter 1-dependent uptake and toxicity of mercuric-thiol conjugates in Madin–Darby Canine kidney cells

    Mol. Pharmacol.

    (2003)
  • A. Bahn et al.

    Interaction of the metal chelator 2,3-dimercapto-1-propanesulfonate with the rabbit multispecific organic anion transporter 1 (rbOAT1)

    Mol. Pharmacol.

    (2002)
  • N. Ballatori et al.

    N-acetylcysteine as an antidote in methylmercury poisoning

    Environ. Health Perspect.

    (1998)
  • B. Bannwarth et al.

    Clinical pharmacokinetics of low-dose pulse methotrexate in rheumatoid arthritis

    Clin. Pharmacokinet.

    (1996)
  • E.H. Barany

    Inhibition by hippurate and probenecid of in vitro uptake of iodipamide and o-iodohippurate. A composite uptake system for iodipamide in choroid plexus, kidney cortex and anterior uvea of several species

    Acta Physiol. Scand.

    (1972)
  • A.L. Betz et al.

    Polarity of the blood–brain barrier: neutral amino acid transport into isolated brain capillaries

    Science

    (1978)
  • K.H. Beyer et al.

    ‘Benemid,’ p-(di-n-propylsulfamyl)-benzoic acid; its renal affinity and its elimination

    Am. J. Physiol.

    (1951)
  • G. Birner et al.

    Nephrotoxic and genotoxic N-acetyl-S-dichlorovinyl-l-cysteine is a urinary metabolite after occupational 1,1,2-trichloroethene exposure in humans: implications for the risk of trichloroethene exposure

    Environ. Health Perspect.

    (1993)
  • J.W. Blomstedt et al.

    pH-gradient-stimulated transport of urate and p-aminohippurate in dog renal microvilles membrane vesicles

    J. Clin. Invest.

    (1980)
  • E.F. Boumendil-Podevin et al.

    Uricosuric agents in uremic sera. Identification of indoxyl sulfate and hippuric acid

    J. Clin. Invest.

    (1975)
  • T. Bruning et al.

    Renal toxicity and carcinogenicity of trichloroethylene: key results, mechanisms, and controversies

    Crit. Rev. Toxicol.

    (2000)
  • S.C. Buist et al.

    Rat and mouse differences in gender-predominant expression of organic anion transporter (Oat1–3; Slc22a6–8) mRNA levels

    Drug Metab. Dispos.

    (2004)
  • S.C. Buist et al.

    Gender-specific and developmental influences on the expression of rat organic anion transporters

    J. Pharmacol. Exp. Ther.

    (2002)
  • B.C. Burckhardt et al.

    Electrophysiologic characterization of an organic anion transporter cloned from winter flounder kidney (fROAT)

    J. Am. Soc. Nephrol.

    (2000)
  • N.L.R. Butcher

    Effect of 2,4-dichlorophenoxyacetic acid on experimental animals

    Proc. Soc. Exp. Biol. Med.

    (1946)
  • S.H. Cha et al.

    Identification and characterization of human organic anion transporter 3 expressing predominantly in the kidney

    Mol. Pharmacol.

    (2001)
  • J.Y. Chatton et al.

    Renal secretion of 3′-azido-3′-deoxythymidine by the rat

    J. Pharmacol. Exp. Ther.

    (1990)
  • T. Cihlar et al.

    The antiviral nucleoside phosphonates cidofovir and adefovir are novel substrates for human and rat renal organic anion transporter 1

    Mol. Pharmacol.

    (1999)
  • T.W. Clarkson

    The three modern faces of mercury

    Environ. Health Perspect.

    (2002)
  • T.W. Clarkson et al.

    The toxicology of mercury-current exposures and clinical manifestations

    N. Engl. J. Med.

    (2003)
  • Cited by (141)

    • Investigating the interaction between organic anion transporter 1 and ochratoxin A: An in silico structural study to depict early molecular events of substrate recruitment and the impact of single point mutations

      2022, Toxicology Letters
      Citation Excerpt :

      Substances can be excreted via passive excretion by filtration of the blood through the glomeruli, typically excreting the unbound fraction of chemical to the pre-urine, and by active transport processes from the kidney blood to the pre-urine via the renal proximal tubule cells. For the active transport, kidney proximal tubule cells express several transport proteins, including OATs, regulating the trafficking of molecules from the bloodstream to proximal tubule lumen, and vice versa, eventually determining the excretion of chemicals via urine (Sweet, 2005). Further understanding of the relationships between molecular features of transporters and their functions (transport of substrates) provide important insights into their role in the elimination, internal exposure and the associated toxicity of food-related xenobiotics (Zhang et al., 2021).

    • Effects of rhein and Rheum palmatum L. extract on the pharmacokinetics and tissue distribution of aristolochic acid I and its demethylated metabolite in rats

      2021, Journal of Ethnopharmacology
      Citation Excerpt :

      Furthermore, AAI induced renal injury was reduced by the co-administration with probenecid, a typical OAT inhibitor (Shibutani et al., 2007; Xue et al., 2011; Zeng et al., 2012). As OATs are believed to mediate renal toxicity (Sweet, 2005), it was not surprising that OAT inhibitors protected against renal toxicity caused by certain endogenous and xenobiotic substrates (Wang et al., 2017; Xue et al., 2011). Chinese rhubarb (called Da Huang in China) is the dried root and rhizome of Rheum palmatum L. (RP, http://mpns.kew.org), Rheum tanguticum (Maxim.

    View all citing articles on Scopus
    View full text