Xenobiotic, bile acid, and cholesterol transporters: function and regulation

Abstract

Transporters influence the disposition of chemicals within the body by participating in absorption, distribution, and elimination. Transporters of the solute carrier family (SLC) comprise a variety of proteins, including organic cation transporters (OCT) 1 to 3, organic cation/carnitine transporters (OCTN) 1 to 3, organic anion transporters (OAT) 1 to 7, various organic anion transporting polypeptide isoforms, sodium taurocholate cotransporting polypeptide, apical sodium-dependent bile acid transporter, peptide transporters (PEPT) 1 and 2, concentrative nucleoside transporters (CNT) 1 to 3, equilibrative nucleoside transporter (ENT) 1 to 3, and multidrug and toxin extrusion transporters (MATE) 1 and 2, which mediate the uptake (except MATEs) of organic anions and cations as well as peptides and nucleosides. Efflux transporters of the ATP-binding cassette superfamily, such as ATP-binding cassette transporter A1 (ABCA1), multidrug resistance proteins (MDR) 1 and 2, bile salt export pump, multidrug resistance-associated proteins (MRP) 1 to 9, breast cancer resistance protein, and ATP-binding cassette subfamily G members 5 and 8, are responsible for the unidirectional export of endogenous and exogenous substances. Other efflux transporters [ATPase copper-transporting beta polypeptide (ATP7B) and ATPase class I type 8B member 1 (ATP8B1) as well as organic solute transporters (OST) alpha and beta] also play major roles in the transport of some endogenous chemicals across biological membranes. This review article provides a comprehensive overview of these transporters (both rodent and human) with regard to tissue distribution, subcellular localization, and substrate preferences. Because uptake and efflux transporters are expressed in multiple cell types, the roles of transporters in a variety of tissues, including the liver, kidneys, intestine, brain, heart, placenta, mammary glands, immune cells, and testes are discussed. Attention is also placed upon a variety of regulatory factors that influence transporter expression and function, including transcriptional activation and post-translational modifications as well as subcellular trafficking. Sex differences, ontogeny, and pharmacological and toxicological regulation of transporters are also addressed. Transporters are important transmembrane proteins that mediate the cellular entry and exit of a wide range of substrates throughout the body and thereby play important roles in human physiology, pharmacology, pathology, and toxicology.

Fig. 1.

Tissue distribution of Oatp mRNA in mice and humans. Top, relative mRNA levels of transporters in mouse liver, kidneys, lung, stomach, duodenum, jejunum, ileum, large intestine, brain, gonads (testes and ovaries), and placenta are shown. Male (♂) mRNA is shown on the left, whereas female (♀) mRNA is shown on the right side of each box. References for mouse mRNA expression are included (Cheng et al., 2005a). Bottom, relative mRNA levels of transporters in human liver, kidneys, lung, heart, brain, testes, ovaries, placenta, and uterus are shown. Data for humans were obtained from GNF SymAtlas (http://symatlas.gnf.org/; now located at http://biogps.gnf.org). The GNF1H/MAS5 data set was accessed during September 2008.

Fig. 2.

Tissue distribution of Oct, Octn, Oat, and Urat mRNA in mice and humans. Top, relative mRNA levels of transporters in mouse liver, kidneys, lung, stomach, duodenum, jejunum, ileum, large intestine, heart, brain, gonads (testes and ovaries), placenta, and uterus are shown. Male (♂) mRNA is shown on the left whereas female (♀) mRNA is shown on the right side of each box. References for mouse mRNA expression are included (Buist and Klaassen, 2004; Alnouti et al., 2006). Bottom, relative mRNA levels of transporters in human liver, kidneys, lung, heart, brain, testes, ovaries, placenta, and uterus are shown. Data for humans were obtained from GNF SymAtlas (http://symatlas.gnf.org/; now located at http://biogps.gnf.org). The GNF1H/MAS5 data set was accessed during September 2008.

Fig. 3.

Tissue distribution of Pept, Cnt, Ent, and Mate mRNA in mice and humans. Top, relative mRNA levels of transporters in mouse liver, kidneys, lung, stomach, duodenum, jejunum, ileum, large intestine, heart, brain, gonads (testes and ovaries), placenta, and uterus are shown. Male (♂) mRNA is shown on the left whereas female (♀) mRNA is shown on the right side of each box. References for mouse mRNA expression are included (Lu et al., 2004; Lu and Klaassen, 2006; Lickteig et al., 2008). Bottom, relative mRNA levels of transporters in human liver, kidneys, lung, heart, brain, testes, ovaries, placenta, and uterus are shown. Data for humans were obtained from GNF SymAtlas (http://symatlas.gnf.org/; now located at http://biogps.gnf.org). The GNF1H/MAS5 data set was accessed during September 2008.

Fig. 4.

Tissue distribution of Mdr, Mrp, and Bcrp mRNA in mice and humans. Top, relative mRNA levels of transporters in mouse liver, kidneys, lung, stomach, duodenum, jejunum, ileum, large intestine, brain, gonads (testes and ovaries), and placenta are shown. Male (♂) mRNA is shown on the left whereas female (♀) mRNA is shown on the right side of each box. References for mouse mRNA expression are included (Maher et al., 2005b; Cui et al., 2009c). Bottom, relative mRNA levels of transporters in human liver, kidneys, lung, heart, brain, testes, ovaries, placenta, and uterus are shown. Data for humans were obtained from GNF SymAtlas (http://symatlas.gnf.org/; now located at http://biogps.gnf.org). The GNF1H/MAS5 data set was accessed during September 2008.

Fig. 5.

Tissue distribution of Ntcp, Asbt, Bsep, Ost, Abca, and Abcg mRNA in mice and humans. Top, relative mRNA levels of transporters in mouse liver, kidneys, lung, stomach, duodenum, jejunum, ileum, large intestine, brain, gonads (testes and ovaries), and placenta are shown. Male (♂) mRNA is shown on the left, whereas female (♀) mRNA is shown on the right side of each box. References for mouse mRNA expression are included (Dieter et al., 2004; Cheng et al., 2007). Bottom, relative mRNA levels of transporters in human liver, kidneys, lung, heart, brain, testes, ovaries, placenta, and uterus are shown. Data for humans were obtained from GNF SymAtlas (http://symatlas.gnf.org/; now located at http://biogps.gnf.org). The GNF1H/MAS5 data set was accessed during September 2008.

Fig. 6.

Subcellular localization of uptake and efflux transport proteins in hepatocytes and cholangiocytes. The localization and orientation of uptake and efflux transporters in liver cells (primarily rodents) are shown.

Fig. 7.

Subcellular localization of uptake and efflux transport proteins in renal proximal tubules. The localization and orientation of uptake and efflux transporters in the kidneys (primarily rodents) are shown.

Fig. 8.

Subcellular localization of uptake and efflux transport proteins in enterocytes. The localization and orientation of uptake and efflux transporters in the intestine (primarily rodents) are shown.

Fig. 9.

Subcellular localization of uptake and efflux transport proteins in brain capillary endothelial cells and choroid plexus epithelial cells. The localization and orientation of uptake and efflux transporters in the brain (primarily rodents) are shown.

Fig. 10.

Subcellular localization of uptake and efflux transport proteins in syncytiotrophoblasts and fetal membranes. The localization and orientation of uptake and efflux transporters in placenta and fetal membranes (primarily rodents) are shown.

Fig. 11.

Subcellular localization of uptake and efflux transport proteins in Sertoli and epididymal cells. The localization and orientation of uptake and efflux transporters in testes (primarily rodents) are shown.

Fig. 12.

Ontogeny of mouse basolateral uptake transporter mRNA expression in liver. Tissues from C57BL/6 mice were obtained at −2, 0, 5, 10, 15, 22, 30, and 45 days. Day −2 represents gestational day 17. Male (♂) mRNA is shown on the left, whereas female (♀) mRNA is shown on the right side of each box. Data are summarized from unpublished observations (C. Klaassen) and previous publications (Cheng et al., 2005a, 2007; Alnouti et al., 2006).

Fig. 13.

Ontogeny of mouse canalicular efflux transporter mRNA expression in liver. Tissues from C57BL/6 mice were obtained at −2, 0, 5, 10, 15, 22, 30, and 45 days. Day −2 represents gestational day 17. Male (♂) mRNA is shown on the left, whereas female (♀) mRNA is shown on the right side of each box. Data are summarized from unpublished observations (C. Klaassen) and previous publications (Maher et al., 2005b; Cheng et al., 2007; Cui et al., 2009c).

Fig. 14.

Ontogeny of mouse basolateral efflux transporter mRNA expression in liver. Tissues from C57BL/6 mice were obtained at −2, 0, 5, 10, 15, 22, 30, and 45 days. Day −2 represents gestational day 17. Male (♂) mRNA is shown on the left, whereas female (♀) mRNA is shown on the right side of each box. Data are summarized from unpublished observations (C. Klaassen) and previous publications (Maher et al., 2005b).

Fig. 15.

Ontogeny of human uptake transporter mRNA expression in liver. Human liver specimens are from various time periods: perinatal (prenatal to postnatal day 30, n = 6), 0 to 4 years (n = 8), and more than 7 years old (n = 6). Data from male and female human livers are combined (C. Klaassen, unpublished observations).

Fig. 16.

Ontogeny of human efflux transporter mRNA expression in liver. Human liver specimens are from various time periods: perinatal (prenatal to postnatal day 30, n = 6), 0 to 4 years (n = 8), and more than 7 years old (n = 6). Data from male and female human livers are combined (C. Klaassen, unpublished observations).

Fig. 17.

Ontogeny of mouse basolateral uptake transporter mRNA expression in kidneys. Tissues from C57BL/6 mice were obtained at −2, 0, 5, 10, 15, 22, 30, and 45 days. Day −2 represents gestational day 17. Male (♂) mRNA is shown on the left, whereas female (♀) mRNA is shown on the right side of each box. It is noteworthy that Oat1 and Oat3 mRNA expression was not quantified at day −2. Data are summarized from previous publications (Buist and Klaassen, 2004; Cheng et al., 2005a; Alnouti et al., 2006; Cheng and Klaassen, 2009).

Fig. 18.

Ontogeny of mouse apical uptake transporter mRNA expression in kidneys. Tissues from C57BL/6 mice were obtained at −2, 0, 5, 10, 15, 22, 30, and 45 days. Day −2 represents gestational day 17. Male (♂) mRNA is shown on the left, whereas female (♀) mRNA is shown on the right side of each box. Data are summarized from unpublished observations (C. Klaassen) and previous publications (Cheng et al., 2005a; Alnouti et al., 2006; Cheng and Klaassen, 2009).

Fig. 19.

Ontogeny of mouse apical efflux transporter mRNA expression in kidneys. Tissues from C57BL/6 mice were obtained at −2, 0, 5, 10, 15, 22, 30, and 45 days. Day −2 represents gestational day 17. Male (♂) mRNA is shown on the left, whereas female (♀) mRNA is shown on the right side of each box. Data are summarized from unpublished observations (C. Klaassen) and previous publications (Maher et al., 2005b; Lickteig et al., 2008; Cheng and Klaassen, 2009; Cui et al., 2009c).

Fig. 20.

Ontogeny of mouse basolateral efflux transporter mRNA expression in kidneys. Tissues from C57BL/6 mice were obtained at −2, 0, 5, 10, 15, 22, 30, and 45 days. Day −2 represents gestational day 17. Male (♂) mRNA is shown on the left, whereas female (♀) mRNA is shown on the right side of each box. Data are summarized from unpublished observations (C. Klaassen) and previous publications (Maher et al., 2005b; Cheng and Klaassen, 2009).

Fig. 21.

Hepatic transporter mRNA expression in male transcription factor-null mice after chemical inducer treatment. Wild-type (WT) and knockout (KO) mice lacking AhR, CAR, PXR, PPARα, and Nrf2 were treated for 4 days with prototypical inducers (or corn oil vehicle) for each transcription factor. WT and AhR-null mice were administered TCDD (40 μg/kg i.p.). WT and CAR-null mice were administered TCPOBOP (300 μg/kg i.p.). WT and Nrf2-null mice were administered oltipraz (150 mg/kg i.p.). WT and PPARα-null mice were administered clofibrate (500 mg/kg i.p.). WT and PXR-null mice were administered PCN (200 mg/kg i.p.). Livers were removed 24 h after the final chemical inducer treatment. Transporter mRNA expression was quantified using multiplex mRNA expression analysis.

Fig. 22.

Transporter regulation by the AhR, CAR, PXR, PPARα, and FXR transcription factors. Hepatic mRNA and/or protein expression of rodent (in vivo studies) and human (in vitro studies) transporters is increased (↑) or decreased (↓) in response to transcription factor activation.

Fig. 23.

Transporter regulation by the HNF1α, HNF4α, and Nrf2 transcription factors. Hepatic mRNA and/or protein expression of rodent (in vivo studies) and human (in vitro studies) transporters is increased (↑) or decreased (↓) in response to transcription factor activation.

Fig. 24.

Pathophysiological regulation of hepatic transporters. Hepatic mRNA and/or protein expression of rodent uptake and efflux transporters is increased (↑), decreased (↓), and/or unchanged (↔) in response to various toxicants and pathological conditions. The time points at which mRNA and protein transporter changes are observed vary among experimental models.