Recent data from knockouts, human disease, and transport studies suggest that solute carrier (SLC) and ATP binding cassette (ABC) multispecific "drug" transporters maintain effective organ and body fluid concentrations of key nutrients, signaling molecules, and antioxidants. These processes involve transcellular movement of solutes across epithelial barriers and fluid compartments (e.g., blood, cerebrospinal fluid, urine, bile) via "matching" or homologous sets of SLC (e.g., SLC21, SLC22, SLC47) and ABC transporters. changes (e.g., substrate imbalance and injury). They function in parallel with (and interact with) the endocrine and autonomic systems. Uric acid (urate), carnitine, prostaglandins, conjugated sex steroids, cGMP, odorants, and enterobiome metabolites are discussed here as examples. Xenobiotics hitchhike on endogenous carrier systems, sometimes leading to toxicity and side effects. By regulation of the expression and/or function of various remote organ multispecific transporters after injury, the overall transport capacity of the remote organ to handle endogenous toxins, metabolites, and signaling molecules may change, aiding in recovery. Moreover, these transporters may play a role in communication between organisms. The specific cellular components involved in sensing and altering transporter abundance or functionality depend upon the metabolite in question and probably involve different types of sensors as well as epigenetic regulation.

The main kidney transporter of many commonly prescribed drugs (e.g. penicillins, diuretics, antivirals, methotrexate, and non-steroidal anti-inflammatory drugs) is organic anion transporter-1 (OAT1), originally identified as NKT (Lopez-Nieto, C. E., You, G., Bush, K. T., Barros, E. J., Beier, D. R., and Nigam, S. K. (1997) J. Biol. Chem. 272, 6471-6478). Targeted metabolomics in knockouts have shown that OAT1 mediates the secretion or reabsorption of many important metabolites, including intermediates in carbohydrate, fatty acid, and amino acid metabolism. This observation raises the possibility that OAT1 helps regulate broader metabolic activities. We therefore examined the potential roles of OAT1 in metabolic pathways using Recon 1, a functionally tested genome-scale reconstruction of human metabolism. A computational approach was used to analyze in vivo metabolomic as well as transcriptomic data from wild-type and OAT1 knock-out animals, resulting in the implication of several metabolic pathways, including the citric acid cycle, polyamine, and fatty acid metabolism. Validation by in vitro and ex vivo analysis using Xenopus oocyte, cell culture, and kidney tissue assays demonstrated interactions between OAT1 and key intermediates in these metabolic pathways, including previously unknown substrates, such as polyamines (e.g. spermine and spermidine). A genome-scale metabolic network reconstruction generated some experimentally supported predictions for metabolic pathways linked to OAT1-related transport. The data support the possibility that the SLC22 and other families of transporters, known to be expressed in many tissues and primarily known for drug and toxin clearance, are integral to a number of endogenous pathways and may be involved in a larger remote sensing and signaling system The kidney is responsible for the elimination of toxic substances and wastes as well as for the reabsorption of 99% of the glomerular ultrafiltrate each day (ϳ60% of which occurs in the proximal tubule) (1). Among the transporters that drive this reabsorption and secretion process are the organic anion transporters (OATs), 3 which transport an extensive range of endogenous metabolites, such as tricarboxylic acid (TCA) cycle intermediates, cyclic nucleotides, and prostaglandins, and also serve as "drug/xenobiotic transporters" (2). Their abundance in a wide range of tissues other than the kidney, including tissues not generally considered to be sites of xenobiotic elimination, as well as their conservation down to fly and worm (3), indicates an important physiological role for these transporters. The OATs have been shown to mediate the transport of numerous endogenous/exogenous solutes, and a role in blood pressure regulation for OAT3 (4) and remote sensing for OAT6 (5) has been suggested. In addition, the highly active metabolic reactions that occur in the proximal tubule in order to fuel its extensive transport processes as well as the fact that the OATs transport many important metabolic intermediates suggest a vital role in th...

The primary site of mercury-induced injury is the kidney due to uptake of the reactive Hg 2؉ -conjugated organic anions in the proximal tubule. Here, we investigated the in vivo role of Oat1 (organic anion transporter 1; originally NKT (Lopez-Nieto, C. E., You, G., Bush, K. T., Barros, E. J., Beier, D. R., and Nigam, S. K. (1997) J. Biol. Chem. 272, 6471-6478)) in handling of known nephrotoxic doses of HgCl 2 . Oat1 (Slc22a6) is a multispecific organic anion drug transporter that is expressed on the basolateral aspects of renal proximal tubule cells and that mediates the initial steps of elimination of a broad range of endogenous metabolites and commonly prescribed pharmaceuticals. Mercury-induced nephrotoxicity was observed in a wild-type model. We then used the Oat1 knock-out to determine in vivo whether the renal injury effects of mercury are mediated by Oat1. Most of the renal injury (both histologically and biochemically as measured by blood urea nitrogen and creatinine) was abolished following HgCl 2 treatment of Oat1 knock-outs. Thus, acute kidney injury by HgCl 2 was found to be mediated mainly by Oat1. Our findings raise the possibility that pharmacological modulation of the expression and/or function of Oat1 might be an effective therapeutic strategy for reducing renal injury by mercury. This is one of the most striking phenotypes so far identified in the Oat1 knock-out. (Eraly, S. A.,

There is a need for well characterized and economical type 2 diabetic model that mimics the human disease. We have developed a type 2 diabetes rat model that closely resembles the diabetic patients and takes only 24 days to develop robust diabetes. Nonlethal doses of allyl alcohol (35 mg/kg i.p.), CCl 4 (2 ml/kg i.p.), or thioacetamide (300 mg/kg i.p.) yielded 80 to 100% mortality in diabetic rats. The objective of the present study was to investigate two hypotheses: higher CCl 4 bioactivation and/or inhibited compensatory tissue repair were the underlying mechanisms for increased CCl 4 hepatotoxicity in diabetic rats. Diabetes was induced by feeding high fat diet followed by a single dose of streptozotocin on day 14 (45 mg/kg i.p.) and was confirmed on day 24 by hyperglycemia, normoinsulinemia, and oral glucose intolerance. Time course studies (0 -96 h) of CCl 4 (2 ml/kg i.p.) indicated that although initial liver injury was the same in nondiabetic and diabetic rats, it progressed only in the latter, culminating in hepatic failure, and death. Hepatomicrosomal CYP2E1 protein and activity, lipid peroxidation, glutathione, and 14 CCl 4 covalent binding to liver tissue were the same in both groups, suggesting that higher bioactivation-based injury is not the mechanism. Inhibited tissue repair resulted in progression of injury and death in diabetic rats, whereas in the nondiabetic rats robust tissue repair resulted in regression of injury and survival after CCl 4 administration. These studies show high sensitivity of type 2 diabetes to model hepatotoxicants and suggest that CCl 4 hepatotoxicity is potentiated due to inhibited tissue repair.Several animal models resembling type 2 diabetes either occur spontaneously or can be induced experimentally. Most of the commonly used models of type 2 diabetes are genetic and have the disadvantage of prohibitive costs, unavailability, and failure to represent etiology of human disease. Consumption of high fat diet leads to insulin resistance and is considered to be a major predisposing factor for type 2 diabetes (Kraegen et al., 1986). Models based on high fat diet take 3 months or longer to develop diabetes and yield only moderate hyperglycemia (Surwit et al., 1988;Pascoe et al., 1992;Reed et al., 2000). Thus, there is a need for a robust type 2 diabetes model.To address this need, we have refined and characterized an existing model based on high fat diet and a single dose of streptozotocin (STZ, 45 mg/kg i.p.). The principle behind the development of type 2 diabetes is simple. High fat diet elicits insulin resistance, and the rats maintain normoglycemia due to compensatory hyperinsulinemia. Administration of STZ (45 mg/kg i.p.) decreases insulin levels, destroying a population of pancreatic ␤-cells such that the insulin-resistant rats are now unable to maintain normal glucose levels and develop hyperglycemia, even though insulin levels in these rats are comparable with normal diet-fed normoglycemic rats. This is exactly what is seen in human diabetes where insulin res...

No abstract