The Organic Anion Transporter (OAT) Family: A Systems Biology Perspective

Abstract

The organic anion transporter (OAT) subfamily, which constitutes roughly half of the SLC22 (solute carrier 22) transporter family, has received a great deal of attention because of its role in handling of common drugs (antibiotics, antivirals, diuretics, nonsteroidal anti-inflammatory drugs), toxins (mercury, aristolochic acid), and nutrients (vitamins, flavonoids). Oats are expressed in many tissues, including kidney, liver, choroid plexus, olfactory mucosa, brain, retina, and placenta. Recent metabolomics and microarray data from Oat1 [Slc22a6, originally identified as NKT (novel kidney transporter)] and Oat3 (Slc22a8) knockouts, as well as systems biology studies, indicate that this pathway plays a central role in the metabolism and handling of gut microbiome metabolites as well as putative uremic toxins of kidney disease. Nuclear receptors and other transcription factors, such as Hnf4α and Hnf1α, appear to regulate the expression of certain Oats in conjunction with phase I and phase II drug metabolizing enzymes. Some Oats have a strong selectivity for particular signaling molecules, including cyclic nucleotides, conjugated sex steroids, odorants, uric acid, and prostaglandins and/or their metabolites. According to the "Remote Sensing and Signaling Hypothesis," which is elaborated in detail here, Oats may function in remote interorgan communication by regulating levels of signaling molecules and key metabolites in tissues and body fluids. Oats may also play a major role in interorganismal communication (via movement of small molecules across the intestine, placental barrier, into breast milk, and volatile odorants into the urine). The role of various Oat isoforms in systems physiology appears quite complex, and their ramifications are discussed in the context of remote sensing and signaling.

Handling of Drugs, Metabolites, and Uremic Toxins by Kidney Proximal Tubule Drug Transporters

“…Since the mid-to-late 1990s, many of these transporters have been cloned (1,7,15,19,20) and a great deal of knowledge has accumulated as a result of transport studies in microinjected frog oocytes, transfected cells, and in vivo as well as ex vivo analysis of wild-type and knockout tissues (5,21,22). These data may help explain drug-drug interactions (DDIs) but also may explain differences in pharmacokinetics in different patients, some of whom may have transporter single-nucleotide polymorphisms (SNPs) that lead to more rapid or relatively delayed transport.…”

“…These include drugs (e.g., antibiotics, antivirals, diuretics, nonsteroidal anti-inflammatory drugs, and antidiabetic agents), physiologically important metabolites (e.g., folate, a-ketoglutarate, urate, and carnitine), nutrients (e.g., vitamins and flavonoids), signaling molecules (e.g., odorants, cyclic nucleotides, and prostaglandins), exogenous toxins (e.g., mercurial conjugates and aristolochic acid), gut microbiome products (e.g., kynurenine), and endogenous toxins (socalled uremic toxins, such as indoxyl sulfate) (1)(2)(3)(4)(5)(6)(7). Apart from excreting unmodified small molecule drugs, the kidney handles many conjugated metabolites, most of which are produced by phase 1 and phase 2 metabolism in the liver (e.g., products of hydroxylation, sulfation, and glucuronidation reactions) (8).…”

Cardiotoxicity testing of diglycolic acid using In Vitro and In Vivo models

“…Reports demonstrating the expression of organic anion transporters on cardiac cells have emerged [11,12] and support the idea that DGA could exert a direct effect on heart cells in addition to possibly affecting heart tissue through secondary mechanisms following renal insufficiency and liver injury. The concordance between the data collected from our in vitro model with our in vivo rat model reflects the potential strength of in vitro systems to forecast in vivo animal model results.…”

“…These preliminary findings may suggest the possibility that the heart is vulnerable to the primary or secondary effects of DGA. Furthermore, the possibility of DGA-induced cardiotoxicity is also supported by recent findings that human cardiomyocytes express molecular transporters of organic anions including dicarboxylic acids [11,12]. As a dicarboxylic acid, DGA has the ability to chelate divalent cations [13], which could be a mechanism to behave as a possible toxin.…”

Uric acid transporters hiding in the intestine

“…Nine OATs were functionally identified (OAT1-7, Oatv1 and URAT1). Some OATs have a strong selectivity for uric acid (Nigam et al 2015). Human organic anion transporter (hOAT10) is highly expressed in the kidney and to a weaker extent in the intestine.…”