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1.
Expert Opin Drug Metab Toxicol. 2018 Jun;14(6):561-570. doi: 10.1080/17425255.2018.1473376. Epub 2018 Jun 4.

Developmental regulation of kidney and liver solute carrier and ATP-binding cassette drug transporters and drug metabolizing enzymes: the role of remote organ communication.

Author information

1
a Division of Pharmaceutical Scieinces, Skaggs School of Pharmacy and Pharmaceutical Sciences , University of California , San Diego , USA.
2
b Departments of Pediatrics and Medicine , University of California , San Diego , USA.

Abstract

The ontogeny of drug transport and metabolism is generally studied independently in tissues, yet in the immediate postnatal period the developmental regulation of SLC and ABC transporters and metabolizing enzymes must be coordinated. Using the Remote Sensing and Signaling Hypothesis as a framework, we describe how a systems physiology view helps to make sense of how inter-organ communication via hepatic, renal, and intestinal transporters and drug metabolizing enzymes (DMEs) is regulated from the immediate postnatal period through adulthood. Areas covered: This review examines patterns of developmental expression and function of transporters and DMEs with a focus on how cross-talk between these proteins in the kidney, liver and other organs (e.g., intestine) may be coordinated postnatally to optimize levels of metabolites and endogenous signaling molecules as well as gut-microbiome products. Expert opinion/commentary: Developmental expression is considered in terms of the Remote Sensing and Signaling Hypothesis, which addresses how transporters and DMEs participate in inter-organ and inter-organism small molecule communication in health, development, and disease. This hypothesis, for which there is growing support, is particularly relevant to the 'birth transition' and post-natal developmental physiology when organs must deal with critical physiological tasks distinct from the fetal period and where remote inter-organ and possibly inter-organismal (e.g. infant-gut microbiome) communication is likely to be critical to maintain homeostasis.

KEYWORDS:

Drug metabolism; development; ontogeny; transport

PMID:
29746174
PMCID:
PMC6277044
DOI:
10.1080/17425255.2018.1473376
[Indexed for MEDLINE]
Free PMC Article
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2.
Annu Rev Pharmacol Toxicol. 2018 Jan 6;58:663-687. doi: 10.1146/annurev-pharmtox-010617-052713.

The SLC22 Transporter Family: A Paradigm for the Impact of Drug Transporters on Metabolic Pathways, Signaling, and Disease.

Author information

1
Departments of Pediatrics and Medicine, University of California, San Diego, La Jolla, California 92093, USA; email: snigam@ucsd.edu.

Abstract

The SLC22 transporter family consists of more than two dozen members, which are expressed in the kidney, the liver, and other tissues. Evolutionary analysis indicates that SLC22 transporters fall into at least six subfamilies: OAT (organic anion transporter), OAT-like, OAT-related, OCT (organic cation transporter), OCTN (organic cation/carnitine transporter), and OCT/OCTN-related. Some-including OAT1 [SLC22A6 or NKT (novel kidney transporter)] and OAT3 (SLC22A8), as well as OCT1 (SLC22A1) and OCT2 (SLC22A2)-are widely studied drug transporters. Nevertheless, analyses of knockout mice and other data indicate that SLC22 transporters regulate key metabolic pathways and levels of signaling molecules (e.g., gut microbiome products, bile acids, tricarboxylic acid cycle intermediates, dietary flavonoids and other nutrients, prostaglandins, vitamins, short-chain fatty acids, urate, and ergothioneine), as well as uremic toxins associated with chronic kidney disease. Certain SLC22 transporters-such as URAT1 (SLC22A12) and OCTN2 (SLC22A5)-are mutated in inherited metabolic diseases. A new systems biology view of transporters is emerging. As proposed in the remote sensing and signaling hypothesis, SLC22 transporters, together with other SLC and ABC transporters, have key roles in interorgan and interorganism small-molecule communication and, together with the neuroendocrine, growth factor-cytokine, and other homeostatic systems, regulate local and whole-body homeostasis.

KEYWORDS:

OAT1; OAT3; OCT1; OCT2; drug metabolizing enzyme; drug transporter; homeostasis

3.
Drug Metab Dispos. 2016 Jul;44(7):1050-60. doi: 10.1124/dmd.115.068254. Epub 2016 Apr 4.

Kidney versus Liver Specification of SLC and ABC Drug Transporters, Tight Junction Molecules, and Biomarkers.

Author information

1
Department of Pediatrics (G.M., K.T.B., S.K.N.), Department of Medicine, Division of Nephrology and Hypertension, (S.K.N.), and Department of Cellular and Molecular Medicine (S.K.N.), University of California, San Diego, La Jolla, California.
2
Department of Pediatrics (G.M., K.T.B., S.K.N.), Department of Medicine, Division of Nephrology and Hypertension, (S.K.N.), and Department of Cellular and Molecular Medicine (S.K.N.), University of California, San Diego, La Jolla, California snigam@ucsd.edu.

Abstract

The hepatocyte nuclear factors, Hnf1a and Hnf4a, in addition to playing key roles in determining hepatocyte fate, have been implicated as candidate lineage-determining transcription factors in the kidney proximal tubule (PT) [Martovetsky et. al., (2012) Mol Pharmacol 84:808], implying an additional level of regulation that is potentially important in developmental and/or tissue-engineering contexts. Mouse embryonic fibroblasts (MEFs) transduced with Hnf1a and Hnf4a form tight junctions and express multiple PT drug transporters (e.g., Slc22a6/Oat1, Slc47a1/Mate1, Slc22a12/Urat1, Abcg2/Bcrp, Abcc2/Mrp2, Abcc4/Mrp4), nutrient transporters (e.g., Slc34a1/NaPi-2, Slco1a6), and tight junction proteins (occludin, claudin 6, ZO-1/Tjp1, ZO-2/Tjp2). In contrast, the coexpression (with Hnf1a and Hnf4a) of GATA binding protein 4 (Gata4), as well as the forkhead box transcription factors, Foxa2 and Foxa3, in MEFs not only downregulates PT markers but also leads to upregulation of several hepatocyte markers, including albumin, apolipoprotein, and transferrin. A similar result was obtained with primary mouse PT cells. Thus, the presence of Gata4 and Foxa2/Foxa3 appears to alter the effect of Hnf1a and Hnf4a by an as-yet unidentified mechanism, leading toward the generation of more hepatocyte-like cells as opposed to cells exhibiting PT characteristics. The different roles of Hnf4a in the kidney and liver was further supported by reanalysis of ChIP-seq data, which revealed Hnf4a colocalization in the kidney near PT-enriched genes compared with those genes enriched in the liver. These findings provide valuable insight, not only into the developmental, and perhaps organotypic, regulation of drug transporters, drug-metabolizing enzymes, and tight junctions, but also for regenerative medicine strategies aimed at restoring the function of the liver and/or kidney (acute kidney injury, AKI; chronic kidney disease, CKD).

PMID:
27044799
PMCID:
PMC4931883
DOI:
10.1124/dmd.115.068254
[Indexed for MEDLINE]
Free PMC Article
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4.
Clin J Am Soc Nephrol. 2015 Nov 6;10(11):2039-49. doi: 10.2215/CJN.02440314. Epub 2015 Oct 21.

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

Author information

1
Department of Medicine, Department of Pediatrics, Department of Cell & Molecular Medicine, snigam@ucsd.edu.
2
Department of Medicine.
3
Department of Pediatrics.
4
Division of Nephrology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts.
5
Division of Nephrology-Hypertension, and Veterans Affairs San Diego Healthcare System, San Diego, California; and.
6
Division of Family & Preventative Medicine, University of California-San Diego, La Jolla, California;

Abstract

The proximal tubule of the kidney plays a crucial role in the renal handling of drugs (e.g., diuretics), uremic toxins (e.g., indoxyl sulfate), environmental toxins (e.g., mercury, aristolochic acid), metabolites (e.g., uric acid), dietary compounds, and signaling molecules. This process is dependent on many multispecific transporters of the solute carrier (SLC) superfamily, including organic anion transporter (OAT) and organic cation transporter (OCT) subfamilies, and the ATP-binding cassette (ABC) superfamily. We review the basic physiology of these SLC and ABC transporters, many of which are often called drug transporters. With an emphasis on OAT1 (SLC22A6), the closely related OAT3 (SLC22A8), and OCT2 (SLC22A2), we explore the implications of recent in vitro, in vivo, and clinical data pertinent to the kidney. The analysis of murine knockouts has revealed a key role for these transporters in the renal handling not only of drugs and toxins but also of gut microbiome products, as well as liver-derived phase 1 and phase 2 metabolites, including putative uremic toxins (among other molecules of metabolic and clinical importance). Functional activity of these transporters (and polymorphisms affecting it) plays a key role in drug handling and nephrotoxicity. These transporters may also play a role in remote sensing and signaling, as part of a versatile small molecule communication network operative throughout the body in normal and diseased states, such as AKI and CKD.

KEYWORDS:

ATP-Binding Cassette Transporters; Acute Kidney Injury; Anti-Bacterial Agents; Cations; Chronic; Diuretics; Organic Anion Transporters; Renal Insufficiency; drug transporter; nephrotoxicity; renal physiology

PMID:
26490509
PMCID:
PMC4633783
DOI:
10.2215/CJN.02440314
[Indexed for MEDLINE]
Free PMC Article
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5.
Clin Pharmacol Ther. 2015 Sep;98(3):266-87. doi: 10.1002/cpt.176.

Human Ontogeny of Drug Transporters: Review and Recommendations of the Pediatric Transporter Working Group.

Author information

1
Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
2
Department of Pharmacology and Toxicology, Rutgers, the State University of New Jersey, Ernest Mario School of Pharmacy, Piscataway, New Jersey, USA.
3
NIH Library, National Institutes of Health, Bethesda, Maryland, USA.
4
Obstetric and Pediatric Pharmacology and Therapeutics Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Rockville, Maryland, USA.
5
College of Pharmacy, Department of Industrial and Physical Pharmacy, Purdue University, West Lafayette, Indiana, USA.
6
Simulations Plus, lnc., Lancaster, California, USA.
7
University of Tennessee Health Science Center, College of Pharmacy, Memphis, Tennessee, USA.
8
University of California San Diego, La Jolla, California, USA.
9
Department of Pediatrics, University of Western Ontario, London, Ontario, Canada.
10
Erasmus MC Sophia Children's Hospital, Intensive Care and Department of Pediatric Surgery, Rotterdam, the Netherlands.

Abstract

The critical importance of membrane-bound transporters in pharmacotherapy is widely recognized, but little is known about drug transporter activity in children. In this white paper, the Pediatric Transporter Working Group presents a systematic review of the ontogeny of clinically relevant membrane transporters (e.g., SLC, ABC superfamilies) in intestine, liver, and kidney. Different developmental patterns for individual transporters emerge, but much remains unknown. Recommendations to increase our understanding of membrane transporters in pediatric pharmacotherapy are presented.

PMID:
26088472
PMCID:
PMC4731327
DOI:
10.1002/cpt.176
[Indexed for MEDLINE]
Free PMC Article
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6.
Nat Rev Drug Discov. 2015 Jan;14(1):29-44. doi: 10.1038/nrd4461. Epub 2014 Dec 5.

What do drug transporters really do?

Author information

1
Departments of Pediatrics, Medicine, and Cellular and Molecular Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0693, USA.

Abstract

Potential drug-drug interactions mediated by the ATP-binding cassette (ABC) transporter and solute carrier (SLC) transporter families are of clinical and regulatory concern. However, the endogenous functions of these drug transporters are not well understood. Discussed here is evidence for the roles of ABC and SLC transporters in the handling of diverse substrates, including metabolites, antioxidants, signalling molecules, hormones, nutrients and neurotransmitters. It is suggested that these transporters may be part of a larger system of remote communication ('remote sensing and signalling') between cells, organs, body fluid compartments and perhaps even separate organisms. This broader view may help to clarify disease mechanisms, drug-metabolite interactions and drug effects relevant to diabetes, chronic kidney disease, metabolic syndrome, hypertension, gout, liver disease, neuropsychiatric disorders, inflammatory syndromes and organ injury, as well as prenatal and postnatal development.

PMID:
25475361
PMCID:
PMC4750486
DOI:
10.1038/nrd4461
[Indexed for MEDLINE]
Free PMC Article
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7.
Mol Pharmacol. 2013 Dec;84(6):808-23. doi: 10.1124/mol.113.088229. Epub 2013 Sep 13.

Hepatocyte nuclear factors 4α and 1α regulate kidney developmental expression of drug-metabolizing enzymes and drug transporters.

Author information

1
Department of Pediatrics (G.M., S.K.N.), Department of Biomedical Sciences (G.M.), Department of Medicine (S.K.N.), and Department of Cellular and Molecular Medicine (S.K.N.), University of California at San Diego, La Jolla, California; and Department of Pediatrics, Dalhousie University and IWK Health Centre, Halifax, Nova Scotia, Canada (J.B.T.).

Abstract

The transcriptional regulation of drug-metabolizing enzymes and transporters (here collectively referred to as DMEs) in the developing proximal tubule (PT) is not well understood. As in the liver, DME regulation in the PT may be mediated through nuclear receptors, which are thought to "sense" deviations from homeostasis by being activated by ligands, some of which are handled by DMEs, including drug transporters. Systems analysis of transcriptomic data during kidney development predicted a set of upstream transcription factors, including hepatocyte nuclear factor 4α (Hnf4a) and Hnf1a, as well as Nr3c1 (Gr), Nfe2l2 (Nrf2), peroxisome proliferator-activated receptor α (Pparα), and Tp53. Motif analysis of cis-regulatory enhancers further suggested that Hnf4a and Hnf1a are the main transcriptional regulators of DMEs in the PT. Available expression data from tissue-specific Hnf4a knockout tissues revealed that distinct subsets of DMEs were regulated by Hnf4a in a tissue-specific manner. Chromatin immunoprecipitation combined with massively parallel DNA sequencing was performed to characterize the PT-specific binding sites of Hnf4a in rat kidneys at three developmental stages (prenatal, immature, adult), which further supported a major role for Hnf4a in regulating PT gene expression, including DMEs. In ex vivo kidney organ culture, an antagonist of Hnf4a (but not a similar inactive compound) led to predicted changes in DME expression, including among others Fmo1, Cyp2d2, Cyp2d4, Nqo2, as well as organic cation transporters and organic anion transporters Slc22a1 (Oct1), Slc22a2 (Oct2), Slc22a6 (Oat1), Slc22a8 (Oat3), and Slc47a1 (Mate1). Conversely, overexpression of Hnf1a and Hnf4a in primary mouse embryonic fibroblasts, sometimes considered a surrogate for mesenchymal stem cells, induced expression of several of these proximal tubule DMEs, as well as epithelial markers and a PT-enriched brush border marker Ggt1. These cells had organic anion transporter function. Taken together, the data strongly supports a critical role for HNF4a and Hnf1a in the tissue-specific regulation of drug handling and differentiation toward a PT-like cellular identity. We discuss our data in the context of the "remote sensing and signaling hypothesis" (Ahn and Nigam, 2009; Wu et al., 2011).

PMID:
24038112
PMCID:
PMC3834141
DOI:
10.1124/mol.113.088229
[Indexed for MEDLINE]
Free PMC Article
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8.
Clin Pharmacol Ther. 2013 Jul;94(1):27-9. doi: 10.1038/clpt.2013.82.

How much do we know about drug handling by SLC and ABC drug transporters in children?

Author information

1
Department of Pediatrics, University of California-San Diego, La Jolla, California, USA. snigam@ucsd.edu

Abstract

Although solute carrier (SLC) and ATP-binding cassette (ABC) transporters are critical to the absorption, distribution, and elimination of many small-molecule drugs in children, how these transporters regulate pediatric drug handling remains unclear. For proper dosing and to diminish toxicity, we need a better understanding of how organ development and functional maturation, as well as developmental changes in systemic physiology, impact transporter-mediated drug handling at pediatric developmental stages from the preterm infant through adolescence.

PMID:
23778708
DOI:
10.1038/clpt.2013.82
[Indexed for MEDLINE]
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9.
Mol Pharmacol. 2011 Jul;80(1):147-54. doi: 10.1124/mol.110.070680. Epub 2011 Apr 14.

Functional maturation of drug transporters in the developing, neonatal, and postnatal kidney.

Author information

1
Division of Nephrology & Hypertension, Departments of Medicine, University of California, San Diego, La Jolla, California 92093, USA.

Abstract

Because renal function in newborns is immature, the pharmacokinetics of drugs administered to neonates vary significantly from adult patients. The establishment of drug transport systems is a key process in the functional maturation of the nephron. However, a thorough examination of the expression of the main drug transporters in the kidney throughout all stages of development (embryonic, postnatal, and mature) has yet to be carried out, and the functional (physiological) impact is not well understood. Using time-series microarray data, we analyzed the temporal behavior of mRNA levels for a wide range of SLC and ABC transporters in the rodent kidney throughout a developmental time series. We find dynamic increases between the postnatal and mature stages of development for a number of transporters, including the proximal tubule-specific drug and organic anion transporters (OATs) OAT1 (SLC22a6) and OAT3 (SLC22a8). The OATs are the major multispecific basolateral drug, toxin, and metabolite transporters in the proximal tubule responsible for handling of many drugs, as well as the prototypical OAT substrate para-aminohippurate (PAH). We therefore performed specific in vivo pharmacokinetic analysis of the transport of PAH in postnatal and maturing rodent kidney. We show that there is a 4-fold increase in PAH clearance during this period. Clearance studies in Oat1 and Oat3 knockouts confirm that, as in the adult, Oat1 is the principle transporter of PAH in the postnatal kidney. The substantial differences observed supports the need for better understanding of pharmacokinetics in the newborn and juvenile kidney compared with the adult kidney at the basic and clinical level.

PMID:
21493727
PMCID:
PMC3127534
DOI:
10.1124/mol.110.070680
[Indexed for MEDLINE]
Free PMC Article
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10.
Mol Pharmacol. 2009 Sep;76(3):481-90. doi: 10.1124/mol.109.056564. Epub 2009 Jun 10.

Toward a systems level understanding of organic anion and other multispecific drug transporters: a remote sensing and signaling hypothesis.

Author information

1
Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA.

Abstract

Organic anion transporters (Oats) are located in the barrier epithelia of diverse organs, where they mediate the absorption and excretion of a wide range of metabolites, signaling molecules, and xenobiotics. Although their interactions with a broad group of substrates have been extensively studied and described, the primary physiological role of Oats remains elusive. The presence of overlapping substrate specificities among the different Oat isoforms, together with recent metabolomic data from the Oat1, Oat3, and renal-specific transporter (RST/URAT1) knockout mice, suggests a possible role in remote signaling wherein substrates excreted through one Oat isoform in one organ are taken up by another Oat isoform located in a different organ, thereby mediating communication between different organ systems, or even between different organisms. Here we further develop this "remote sensing and signaling hypothesis" and suggest how the regulation of SLC22 subfamily members (including those of the organic cation, organic carnitine, and unknown substrate transporter subfamilies) can be better understood by considering the organism's broader need to communicate between epithelial and other tissues by simultaneous regulation of transport of metabolites, signaling molecules, drugs, and toxins. This systems biology perspective of remote signaling (sensing) could help reconcile an enormous array of tissue-specific data for various SLC22 family genes and, possibly, other multispecific transporters, such as those of the organic anion transporting polypeptide (OATP, SLC21) and multidrug resistance-associated protein (MRP) families.

PMID:
19515966
PMCID:
PMC2730381
DOI:
10.1124/mol.109.056564
[Indexed for MEDLINE]
Free PMC Article
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11.
Nat Clin Pract Nephrol. 2007 Aug;3(8):443-8.

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

Author information

1
University of California, San Diego, La Jolla, CA 92093-0693, USA. snigam@ucsd.edu

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.

PMID:
17653123
DOI:
10.1038/ncpneph0558
[Indexed for MEDLINE]
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