Naunyn-Schmiedeberg's Archives of Pharmacology

, Volume 372, Issue 6, pp 432–443

Pharmacogenomics of human OATP transporters

Authors

    • Institute for Experimental and Clinical Pharmacology and ToxicologyFriedrich-Alexander-University Erlangen-Nuremberg
  • Annick Seithel
    • Institute for Experimental and Clinical Pharmacology and ToxicologyFriedrich-Alexander-University Erlangen-Nuremberg
  • Ulrike Gradhand
    • Institute for Experimental and Clinical Pharmacology and ToxicologyFriedrich-Alexander-University Erlangen-Nuremberg
  • Martin F. Fromm
    • Institute for Experimental and Clinical Pharmacology and ToxicologyFriedrich-Alexander-University Erlangen-Nuremberg
Review

DOI: 10.1007/s00210-006-0040-y

Cite this article as:
König, J., Seithel, A., Gradhand, U. et al. Naunyn Schmied Arch Pharmacol (2006) 372: 432. doi:10.1007/s00210-006-0040-y

Abstract

Organic anion transporting polypeptides (OATPs) mediate the uptake of a broad range of compounds into cells. Substrates for members of the OATP family include bile salts, hormones, and steroid conjugates as well as drugs like the HMG-CoA-reductase inhibitors (statins), cardiac glycosides, anticancer agents like methotrexate, and antibiotics like rifampicin. OATPs are expressed in a variety of different tissues, including intestine, liver, kidney, and brain, suggesting that they play a critical role in drug absorption, distribution, and excretion. The identification and functional characterisation of naturally occurring variations in genes encoding human OATP (SLCO) family members is in the focus of transporter research. As a result of their broad substrate spectrum and their wide tissue distribution, altered transport characteristics or protein localisation can contribute significantly to interindividual variations of drug effects. The analysis of the consequences of genetic variations in genes encoding transport proteins may, therefore, contribute to a better understanding of interindividual differences in drug effects and to individualise treatment regimens with drugs that are substrates for human OATP proteins. In this review, we summarise the current knowledge on genetic variations in transporter genes encoding human OATP family members and their functional consequences analysed by in vitro and in vivo studies.

Keywords

Drug transportHaplotypesOATPsPharmacogenomicsPolymorphisms

The OATP family of uptake transporters

Uptake transporters belonging to the superfamily of solute carriers (SLC) (Hagenbuch and Meier 2004; Hediger et al. 2004), and efflux pumps belonging to the ATP-binding cassette transporter (ABC transporter) superfamily (Borst and Elferink 2002; Fromm 2004; König et al. 1999; Kruh and Belinsky 2003), have an impact on the absorption, distribution and elimination of drugs. Genes encoding organic anion transporting polypeptides form a large family within this superfamily of solute carriers. Their genes are classified within the solute carrier family SLCO (Hagenbuch and Meier 2004). OATP1A2 (formerly termed OATP or OATP-A) was described in 1995 (Kullak-Ublick et al. 1995) and followed by the discovery of the second member OATP1B1 (formerly termed OATP2, OATP-C, or LST1) (Abe et al. 1999; Hsiang et al. 1999; König et al. 2000a). Today, the human OATP family consists of 11 members (Hagenbuch and Meier 2003; Mikkaichi et al. 2004a) including 10 OATPs and the prostaglandin transporter OATP2A1 (formerly termed PGT). Due to the fact that trivial names for individual proteins do not correspond to the continuous numbering based on the chronology of protein identification, and because many mouse/rat Oatps have no direct human orthologue, Hagenbuch and Meier (Hagenbuch and Meier 2004) introduced a new nomenclature for the OATP family. In this review, we will follow this new nomenclature and designate all proteins and genes according to this denomination.

According to computer based hydropathy analysis, all OATPs share a very similar transmembrane domain organisation, with 12 predicted transmembrane domains and a large 5th extracellular loop (Hagenbuch and Meier 2003). Additional conserved features of all OATP proteins are N-glycosylation sites in the extracellular loops 2 and 5 and the OATP ‘superfamily signature’ at the border between the extracellular loop 3 and transmembrane domain 6 (Hagenbuch and Meier 2003). While most of the OATP proteins are expressed in multiple tissues, OATP1B1 (OATP2 / OATP-C) and OATP1B3 (OATP8) are predominantly if not exclusively expressed in liver (Hsiang et al. 1999; König et al. 2000a,b). OATP1A2 shows highest expression in brain and testis (Kullak-Ublick et al. 1995), whereas OATP2B1 (OATP-B) and OATP4A1 (OATP-E) are ubiquitously expressed in all tissues investigated so far (Hagenbuch and Meier 2003). Almost all OATP family members are localised to the basolateral membrane of polarised cells. OATP1B1, OATP1B3 and OATP2B1 have been localised to the basolateral membrane of human hepatocytes (Hsiang et al. 1999; König et al. 2000a,b), whereas OATP2A1 has been localised to the basolateral membrane of brain endothelial cells (Lee et al. 2005a). Interestingly, in addition to its basolateral localisation in liver and placenta (St-Pierre et al. 2002), OATP2B1 has been detected in the apical membrane of enterocytes (Kobayashi et al. 2003). OATP4A1 (formerly termed OATP-E) is predominantly expressed at the apical surface of the syncytiotrophoblast in placenta (Sato et al. 2003) and, together with OATP1C1 (formerly termed OATP-F) and OATP3A1 (formerly termed OATP-D), in the basolateral plasma membrane of the non-pigmented human ciliary body epithelium (Gao et al. 2005). OATP4C1 has been found to be highly expressed at mRNA level in human kidney (Mikkaichi et al. 2004b) and the rat Oatp4c1 protein has been localised to the basolateral membrane of kidney proximal tubular cells (Mikkaichi et al. 2004b). The expression and subcellular localisation of human OATP5A1 and OATP6A1 remains to be clarified.

Originally, human OATP1A2 was cloned based on its homology to rat Oatp1a1 (Jacquemin et al. 1994) as a sodium-independent transporter for bile salts and bromosulfophthalein in human liver (Kullak-Ublick et al. 1995). Further studies investigating the substrate spectrum in more detail have shown that OATP1A2 is capable of transporting a wide range of amphipathic organic anions (Table 1), including bile salts (Kullak-Ublick et al. 1995; Meier et al. 1997), thyroid hormones (Friesema et al. 1999), steroid hormones and their conjugates (Bossuyt et al. 1996a), as well as organic cations like N-methyl-quinidine and others (van Montfoort et al. 1999).
Table 1

Substrates for human OATP family members

Substrate

Km value (μM)

References

OATP1A2 (OATP-A)

APD-ajmalinium

 

Bossuyt et al. (1996b)

BQ123

 

Kullak-Ublick et al. (2001)

Bromosulfophthalein

20

Kullak-Ublick et al. (2001)

Chlorambuciltaurocholate

 

Kullak-Ublick et al. (1997)

Cholate

93

Kullak-Ublick et al. (1995)

Bamet-UD

14

Briz et al. (2002)

Bamet-R2

24

Briz et al. (2002)

Dehydroepiandrosterone-3-sulfate

7

Kullak-Ublick et al. (1998)

Deltorphin II

330

Gao et al. (2000)

DPDPE

202

Briz et al. (2003)

Estradiol-17β-glucuronide

 

Briz et al. (2003)

Estrone-3-sulfate

59

Bossuyt et al. (1996b)

Fexofenadine

6

Cvetkovic et al. (1999)

Gd-B20790

92

Pascolo et al. (1999)

Glycocholate

 

Kullak-Ublick et al. (1995)

Microcystin-LR

20

Fischer et al. (2005)

N-Methyl-quinidine

26

van Montfoort et al. (1999)

N-Methyl-quinidine

5

van Montfoort et al. (1999

Ouabain

5.5

Bossuyt et al. (1996b)

Prostaglandin E2

 

Kullak-Ublick et al. (2001)

Reverse Triiodothyronine (rT3)

 

van Montfoort et al. (1999)

Rocuronium

 

van Montfoort et al. (1999)

Taurocholate

60

Kullak-Ublick et al. (1995)

Taurochenodeoxycholate

 

Kullak-Ublick et al. (1995)

Thyroxin (T4)

8

Fujiwara et al. (2001)

Triiodothyronine (T3)

7

Fujiwara et al. (2001)

Tauroursodeoxycholate

19

Kullak-Ublick et al. (1995)

OATP1B1 (OATP-C/OATP2)

DADLE

 

Nozawa et al. (2003)

ACU-154

 

Takada et al. (2004)

Atorvastatin

 

Kameyama et al. (2005)

Benzylpenicillin

 

Tamai et al. (2000)

Bilirubin

8

Cui et al. (2001)

Bisglucuronosyl bilirubin

0.3

Cui et al. (2001)

BQ-123

 

Kullak-Ublick et al. (2001)

Bromosulfophthalein

0.1

Cui et al. (2001)

Capsofungin

 

Sandhu et al. (2005)

Cerivastatin

 

Shitara et al. (2004)

Cholate

11

Cui et al. (2001)

Bamet-UD2

10

Briz et al. (2002)

Bamet-R2

10

Briz et al. (2002)

Dehydroepiandrosterone-3-sulfate

22

Cui et al. (2001)

Demethylphalloin

17

Meier–Abt et al. (2004)

DPDPE

 

Abe et al. (2001)

Estradiol-17β-glucuronide

8

König et al. (2000a)

Estrone-3-sulfate

0.2

Tamai et al. (2000)

13

Cui et al. (2001)

Fluvastatin

 

Kopplow et al. (2005)

Glycocholate

 

Kullak-Ublick et al. (2001)

Leukotriene C4

 

Abe et al. (1999)

Leukotriene E4

 

Abe et al. (1999)

Methotrexate

 

Abe et al. (1999)

Microcystein-LR

7

Fischer et al. (2005)

Monoglucuronosyl bilirubin

0.1

Cui et al. (2001)

Phalloidin

39

Fehrenbach et al. (2003)

Pitavastatin

3

Hirano et al. (2004)

Pravastatin

35

Hsiang et al. (1999)

Prostaglandin E2

 

Tamai et al. (2000)

Repaglinide

 

Niemi et al. (2005a)

Rifampicin

2

Tirona et al. (2003)

13

Vavricka et al. (2002)

Rosuvastatin

 

Schneck et al. (2004)

SN-38

 

Nozawa et al. (2005)

Taurocholate

10

Cui et al. (2001)

14

Abe et al. (1999)

34

Hsiang et al. (1999)

Thromboxane B2

 

Abe et al. (1999)

Thyroxine (T4)

3

Abe et al. (1999)

Triiodothyronine (T3)

3

Abe et al. (1999)

Troglitazone metabolite M1

 

Nozawa et al. (2004c)

OATP1B3 (OATP8)

Bilirubin

39

Briz et al. (2003)

BQ-123

 

Kullak-Ublick et al. (2001)

Bromosulfophthalein

3.3

König et al. (2000b)

6

Letschert et al. (2004)

CCK-8

11

Ismair et al. (2001)

Dehydroepiandrosterone-3-sulfate

>30

Cui et al. (2001)

Deltorphin II

 

Kullak-Ublick et al. (2001)

Demethlyphalloin

8

Meier–Abt et al. (2004)

Digoxin

 

Kullak-Ublick et al. (2001)

Docetaxel

 

Smith et al. (2005)

DPDPE

 

Abe et al. (2001)

Estradiol-17β-glucuronide

5.4

König et al. (2000b)

Estrone-3-sulfate

 

Nozawa et al. (2004c)

Fexofenadine

108

Shimizu et al. (2005)

Fluvastatin

 

Kopplow et al. (2005)

Fluo-3

 

Cui et al. (2001)

Glycocholate

 

Kullak-Ublick et al. (2001)

Leukotriene C4

 

Kullak-Ublick et al. (2001)

Methotrexate

25

Abe et al. (2001)

Microcystin-LR

9

Fischer et al. (2005)

Monoglucuronosyl bilirubin

0.5

Cui et al. (2001)

Ouabain

 

Kullak-Ublick et al. (2001)

Paclitaxel

7

Smith et al. (2005)

Pitavastatin

 

Hirano et al. (2004)

Rifampicin

2

Vavricka et al. (2002)

Taurocholate

6

Abe et al. (2001)

112

Letschert et al. (2004)

Thyroxine (T4)

 

Kullak-Ublick et al. (2001)

Triiodothyronine (T3)

6

Abe et al. (2001)

OATP1C1 (OATP-F)

Bromosulfophthalein

 

Pizzagalli et al. (2002)

Estradiol-17β-glucuronide

 

Pizzagalli et al. (2002)

Estrone-3-sulfate

 

Pizzagalli et al. (2002)

reverse Triiodothyronine (rT3)

0.1

Fujiwara et al. (2001)

Thyroxin (T4)

0.1

Pizzagalli et al. (2002)

Triiodothyronin (T3)

 

Pizzagalli et al. (2002)

OATP2B1 (OATP-B)

Benzylpenicillin

 

Tamai et al. (2000)

Bromosulfophthalein

0.7

Kullak-Ublick et al. (2001)

Dehydroepiandrosterone-3-sulfate

 

Kullak-Ublick et al. (2001)

Estrone-3-sulfate

5

Tamai et al. (2000)

Fexofenadine

 

Nozawa et al. (2003)

Fluvastatin

 

Kopplow et al. (2005)

Prostaglandin E2

 

Tamai et al. (2000)

OATP3A1 (OATP-D)

Benzylpenicillin

 

Tamai et al. (2000)

Estrone-3-sulfate

 

Tamai et al. (2000)

Prostaglandin E2

 

Tamai et al. (2000)

OATP4A1 (OATP-E)

Benzylpenicillin

 

Tamai et al. (2000)

Estradiol-17β-glucuronide

 

Tamai et al. (2000)

Estrone-3-sulfate

 

Tamai et al. (2000)

Prostaglandin E2

 

Tamai et al. (2000)

Reverse Triiodothyronine (rT3)

 

Fujiwara et al. (2001)

Taurocholate

15

Fujiwara et al. (2001)

Thyroxin (T4)

 

Fujiwara et al. (2001)

Triiodothyronine (T3)

1

Fujiwara et al. (2001)

OATP4C1 (OATP-H)

cAMP

 

Mikkaichi et al. (2004b)

Digoxin

8

Mikkaichi et al. (2004b)

Methotrexate

 

Mikkaichi et al. (2004b)

Ouabain

0.4

Mikkaichi et al. (2004b)

Thyroxine (T4)

 

Mikkaichi et al. (2004b)

Triidothyronine (T3)

6

Mikkaichi et al. (2004b)

OATP5A1 (OATP-J) and OATP6A1 (OATP-I)

Substrates not yet determined

Abbreviations:ACU-154, O-glucuronide of PKI166 (inhibitor of the tyrosine kinase activity, Novartis Basel); APD ajmalinium, N-(4,4-Azo-n-pentyl)-21-deoxy[21-3H]ajmalinium; Bamet-R2, Cis-diammineplatinum(II)-chlorocholylglycinate; Bamet-UD2, Cis-diamminebisursodeoxycholateplatinum(II); BQ-123, cyclic pentapeptide (cyclo[D-Trp-D-Asp-L-Pro-D-Val-L-Leu]); cAMP, cyclic adenosine monophosphate; CCK-8, L-aspartyl-L-tyrosyl-L-methionylglycyl-L-tryptophyl-L-methionyl-L-aspartyl-L-phenylalaninamide hydrogen sulfate ester); CRC 220, thrombin inhibitor, 4-methoxy-2,3,6-trimethylphenylsulfonyl-L-aspartyl-D-4-amidinophenylalanyl- piperidide; DADLE, (D-Ala[2],D-Leu[5])-enkephalin;DPDPE, [D-penicillamine-2,5] enkephalin; Fluo-3, 1-[2-Amino-5-(2,7-dichloro-6-hydroxy-3-oxo-3H-xanthen-9-yl)]-2-(2′-amino-5′ methyl-phenoxyl)-ethane-N,N,N′,N′-tetraacetic acid penta-ammonium salt; Gd-B20790, MRI contrast agent, gadolinium complex of 18-[[3-(2-carboxybutyl)-2,4,6-triiodophenyl]amino]-3,6,9-tris(carboxymethyl)-11,18-dioxo-3,6,9,12-tetraazaoctadecanoic acid; SN-38, 7-ethyl-10-hydroxycamptothecin

Determining the substrate spectrum of other human OATP family members demonstrated that most of them have a similarly broad substrate spectrum partially overlapping with the substrate spectrum defined for OATP1A2 (Table 1). In addition to endogenous compounds, OATPs are capable of transporting various xenobiotics and drugs and, therefore, play an important role in drug absorption, disposition, and excretion. Especially OATP1B1 and OATP1B3, both highly expressed in human liver and involved in the uptake of endogenous substances and of xenobiotics into hepatocytes, are able to transport various drugs, including HMG-CoA-reductase inhibitors like pravastatin (Hsiang et al. 1999; Nakai et al. 2001) and pitavastatin (Hirano et al. 2004), the endothelin receptor antagonist BQ123 (Kullak-Ublick et al. 2001), and the antibiotic rifampicin (Tirona et al. 2003; Vavricka et al. 2002) (Table 1). Since expression and substrates for all human OATP family members have not been completely characterised, additional functional studies and investigations of protein localisations are required to determine the specific role of each OATP family member in drug disposition.

Pharmacogenomics of OATP1B1

In vitro analysis of polymorphisms and haplotypes

Polymorphisms in genes encoding transport proteins may play an important role in the interindividual variability of drug disposition and drug response. A considerable effort has been made to identify single nucleotide polymorphisms (SNPs) or haplotypes, to determine their frequency, and to establish their potential functional consequences on protein localisation and transport function. A summary of so far reported non-synonymous SLCO polymorphisms, haplotypes, alleles, and their allelic frequencies is shown in Table 2 and the localisation of the respective amino acid exchanges is indicated in Fig. 1.
Table 2

Non-synonymous polymorphisms, alleles, amino acid exchanges, and allelic frequencies in SLCO genes encoding human OATP family members

 

Polymorphism or Haplotype

Alleles

Amino acid exchange

Allellic frequency [%]

Reference

AA

EA

CA

HA

Cau

JP

OATP1A2

NM_134431

OATP1A2*1

        
 

38T>C

OATP1A2*2

Ile13Thr

2.1

11.1

0

5.7

  

Lee et al. (2005a)

 

516A>C

OATP1A2*3

Glu172Asp

2.1

5.3

0

2.1

  

Lee et al. (2005a)

 

559G>A

OATP1A2*4

Ala187Thr

0

0

0

0.5

  

Lee et al. (2005a)

 

382A>T

OATP1A2*5

Asn128Tyr

1

0

0

0

  

Lee et al. (2005a)

 

404A>T

OATP1A2*6

Asn135Ile

0*

0*

0*

0*

  

Lee et al. (2005a)

 

2003C>G

OATP1A2*7

Thr668Ser

3.7

0

0

1

  

Lee et al. (2005a)

OATP1B1

AB026257; AJ132573

OATP1B1*1a

      

35.2

König et al. (2000a); Nozawa et al. (2002)

388A>G

OATP1B1*1b

Asn130Asp

74

30

   

53.7

Hsiang et al. (1999); Tirona et al. (2001); Nozawa et al. (2002)

 

388A>G + 1007C>G

OATP1B1*1b+1007C>G

Asn130Asp + Pro336Arg

      

Kameyama et al. (2005)

 

455G>A + 721G>A

OATP1B1*1c

Arg152Lys + Asp241Asn

     

0

Abe et al. (1999); Nozawa et al. (2002)

 

−11110T>G

OATP1B1*1e

Promoter

      

Niemi et al. (2004)

 

217T>C

OATP1B1*2

Phe73Leu

0

2

   

0

Tirona et al. (2001); Nishizato et al. (2003)

 

245T>C + 467A>G

OATP1B1*3

Val82Ala + Glu156Gly

      

Tirona et al. (2001)

 

463C>A

OATP1B1*4

Pro155Thr

2

16

   

0

Tirona et al. (2001); Nishizato et al. (2003)

 

521T>C

OATP1B1*5

Val174Ala

2

14

   

0.7

Tamai et al. (2000); Tirona et al. (2001); Nozawa et al. (2002)

 

521T>C + 1007C>G

OATP1B1*5+1007C>G

Val174Ala + Pro336Arg

      

Kameyama et al. (2005)

 

1058T>C

OATP1B1*6

Ile353Thr

0

2

    

Tirona et al. (2001)

 

1294A>G

OATP1B1*7

Asn432Asp

0

1

    

Tirona et al. (2001)

 

1385A>G

OATP1B1*8

Asp462Gly

0

1

    

Tirona et al. (2001)

 

1463G>C

OATP1B1*9

Gly488Ala

9

0

    

Tirona et al. (2001)

 

1964A>G

OATP1B1*10

Asp655Gly

0

2

    

Tirona et al. (2001)

 

2000A>G

OATP1B1*11

Glu667Gly

34

2

    

Tirona et al. (2001)

 

217T>C + 1964A>G

OATP1B1*12

Phe73Leu + Asp655Gly

      

Tirona et al. (2001)

 

245T>C + 467A>G + 2000A>G

OATP1B1*13

Val82Ala + Glu156Gly + Glu667Gly

      

Tirona et al. (2001)

 

388A>G + 463C>A

OATP1B1*14

Asn130Asp + Pro155Thr

      

Tirona et al. (2001)

 

388A>G + 512T>C

OATP1B1*15

Asn130Asp + Val174Ala

     

10.3

Nozawa et al. (2002)

 

388A>G + 521T>C + 1007C>G

OATP1B1*15+1007C>G

Asn130Asp + Val174Ala + Pro336Arg

      

Kameyama et al. (2005)

 

452A>G

OATP1B1*16

Asn151Ser

     

3.7

Iida et al. (2001); Nishizato et al. (2003)

 

−11187G>A + 388A>G + 521T>C

OATP1B1*17

Asn130Asp + Val174Ala

      

Niemi et al. (2004)

 

388A>G + (411G>A) + 463C>A + (571T>C) + 578T>G

OATP1B1*18

Asn130Asp + Pro155Thr + Leu193Arg

      

Niemi et al. (2004)

 

(571T>C) + 1929A>C

OATP1B1*19

Leu643Phe

      

Niemi et al. (2004)

 

388A>G + (597C>T) + 1929A>C

OATP1B1*20

Asn130Asp + Leu643Phe

      

Niemi et al. (2004)

 

−11187G>A + 388A>G + (597C>T) + 1929A>C

OATP1B1*21

Asn130Asp + Leu643Phe

      

Niemi et al. (2004)

 

245T>C

 

Val82Ala

0

2

   

0

Tirona et al. (2001); Nishizato et al. (2003)

 

467A>G

 

Glu156Gly

0

2

   

0

Tirona et al. (2001); Nishizato et al. (2003)

 

578T>G

 

Leu193Arg

      

Michalski et al. (2002)

 

1007C>G

 

Pro336Arg

     

1.2

Nishizato et al. (2003)

 

1454G>T

 

Cys485Phe

     

0.8

Nishizato et al. (2003)

 

1628T>G

 

Leu543Trp

      

Morimoto et al. (2004)

 

1929A>C

 

Leu643Phe

      

Niemi et al. (2004)

 

−11187G>A

 

promoter

    

7.1

 

Niemi et al. (2004)

OATP1B3

NM_019844

        

König et al. (2000b)

 

334T>G

 

Ser112Ala

    

74

 

Iida et al. (2001); Letschert et al. (2004)

 

699G>A

 

Met233Ile

    

71

 

Letschert et al. (2004)

 

1564G>T

 

Gly522Cys

    

1.9

 

Letschert et al. (2004)

OATP2B1

NM_007256

OATP2B1*1

      

69.1

Tamai et al. (2000); Nozawa et al. (2002)

 

1175C>T

OATP2B1*2

Thr392Ile

    

0*

0*

Nozawa et al. (2002); Niemi et al. (2004)

 

1457C>T

OATP2B1*3

Ser486Phe

    

1.2

30.9

Tamai et al. (2000); Nozawa et al. (2002); Niemi et al. (2004)

( ): synonymous mutation; AA: African-American; EA: European-American; CA: Chinese-American; HA: Hispanic-American; Cau: Caucasian; JP: Japanese; * found only in SNP-database

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Fig. 1

Localisation of amino acid exchanges caused by mutations and polymorphisms in genes encoding human members of the OATP family. A two-dimensional model of human OATP proteins is shown based on several transmembrane analysis programs. Amino acid exchanges caused by mutations in the SLCO1A2 gene encoding human OATP1A2 are shown in grey, by mutations in the SLCO1B1 gene encoding human OATP1B1 are shown in red, by mutations in the SLCO1B3 gene encoding human OATP1B3 are shown in blue, and by mutations in the SLCO2B1 geneencoding human OATP2B1 are shown in green

Tirona et al. (2001) investigated 14 non-synonymous polymorphisms in the SLCO1B1 gene identified in a population of African and European Americans and discovered that some polymorphisms or haplotypes can affect localisation or transport function of the respective protein. In particular, the exchange 217T>C (OATP1B1*2; see Table 2), alone or together with the exchange 1964A>G (haplotype OATP1B1*12), increased the Km value for [3H]estrone-3-sulfate from 0.54 μM to 5.9 and 8.1 μM, respectively. Furthermore, reduced transport of the substrates estrone-3-sulfate, rifampicin, and estradiol-17β-glucuronide was observed for the variants OATP1B1*3, *5, *6, *9, and *13. Interestingly, many of these amino acid exchanges are located within the transmembrane-spanning domains or in the 2nd and 5th extracellular loop (Fig. 1). These results suggest that these protein regions are involved in substrate recognition and transport.

Michalski et al. (2002) analysed 81 human liver samples originating from Caucasians and identified one haplotype containing 5 base pair exchanges resulting in 3 amino acid substitutions. Two of them corresponded to the previously analysed, frequent polymorphisms OATP1B1*1b and OATP1B1*4 (Tirona et al. 2001). The third exchange could be analysed as the first naturally occurring, rare mutation (OATP1B1-Leu193Arg) within the SLCO1B1 gene with a frequency below 0.3%. Using stably transfected MDCKII cells and bromosulfophthalein, estradiol-17β-glucuronide, and taurocholate as substrates, the functional consequences of these 3 exchanges have been analysed (Michalski et al. 2002). Whereas bromosulfophthalein was transported from OATP1B1*1b and OATP1B1*4 according to transport rates determined for the OATP1B1 protein, transport of estradiol-17β-glucuronide was significantly reduced by OATP1B1*4. Using taurocholate as substrate, the transport by OATP1B1*1b was reduced and totally abolished by OATP1B1*4. Furthermore, none of the tested substrates was transported by a protein containing the mutation Leu193Arg. In addition, a pronounced change in protein localisation was observed after expression of the mutant OATP1B1-Leu193Arg protein, which was hardly detectable in the lateral membrane of MDCKII cells and mainly retained intracellularly. These investigations demonstrated that alterations in the extracellular loop 2, where the polymorphisms OATP1B1*1b and OATP1B1*4 are localised (Fig. 1), could influence the substrate spectrum whereas the mutation OATP1B1-Leu193Arg totally abolishes the transport function of the protein.

Nozawa et al. (2002) investigated several polymorphisms in the Japanese population and found that the previously identified OATP1B1*1c allele could not be detected in 267 healthy Japanese subjects, whereas OATP1B1*1b and OATP1B1*5 were present with 54% and 0.7%, respectively. In addition, they identified a novel allele, termed OATP1B1*15 (Table 2), possessing the two SNPs Asn130Asp and Val174Ala simultaneously. The allelic frequency of OATP1B1*15 in the investigated population was 3.0%. Using transfected HEK293 cells, they also investigated the functional consequences of these polymorphisms and found no significant alteration in Km or Vmaxvalues of the [3H]estrone-3-sulfate uptake. These results were confirmed in a second study investigating the same haplotypes (Iwai et al. 2004) and estradiol-17ß-glucuronide as substrate. Interestingly, the authors did not find a change in Km values for any of the three haplotypes. However, the Vmax value for OATP1B1*15 was decreased to less than 30% compared with OATP1B1*1a. Furthermore, Nozawa et al. (2004b) demonstrated that this haplotype exhibits decreased transport activities for SN-38, the active metabolite of the topoisomerase inhibitor topotecan as well as for the HMG-CoA-reductase inhibitor pravastatin. Therefore, the haplotype OATP1B1*15 could contribute to the known interindividual variability in disposition of these two drugs.

OATP1B1 polymorphisms and drug disposition and effects in humans

Based on the in vitro findings described above, various groups tested the hypothesis whether polymorphisms in the SLCO1B1 gene have an impact on pharmacokinetics and the effects of drugs in humans. The data currently available on this issue are summarised in Table 3. In spite of the fact that the HMG-CoA-reductase inhibitor pravastatin is not significantly metabolised in humans, pharmacokinetic studies in humans reported a large interindividual variability in pravastatin plasma concentrations (Neuvonen et al. 1998). Kobayashi et al. (2003) reported a pH-dependent OATP2B1-mediated transport of pravastatin. In addition, in vitro data indicate that pravastatin is also a substrate of OATP1B1 (Hsiang et al. 1999; Nakai et al. 2001), thereby mediating pravastatin uptake into hepatocytes. One would expect that genetic variations or haplotypes associated with a reduced OATP1B1 function would limit the access of pravastatin into the hepatocytes and thereby result in increased systemic exposure to pravastatin. Indeed, several publications highlight the relevance of genetic variations in the SLCO1B1 gene for pravastatin disposition (Table 3, Fig. 2) (Mwinyi et al. 2004; Niemi et al. 2004; Nishizato et al. 2003). For example, Niemi et al. (2004) reported that individuals with the 521TC genotype have on average a 106% higher pravastatin plasma concentration compared to the 521TT group (Fig. 2a), which is in accordance with previous in vitro studies showing reduced transport activity for 521T>C (OATP1B1*5; see Table 2) (Tirona et al. 2001, 2003). Based on these pharmacokinetic findings, it was tempting to speculate whether the pravastatin effect on hepatic HMG-CoA-reductase is reduced in individuals with the 521C genotype. In accordance with the underlying hypothesis, Niemi et al. (2005c) reported significantly smaller effects of pravastatin on cholesterol synthesis (determined by plasma lathosterol concentration and lathosterol to cholesterol concentration ratio) in heterozygous carriers of the SCLO1B1*17 (containing -11187G, 388A and 521C) haplotype compared with non-carriers (Fig. 2a) (Niemi et al. 2005c).
Table 3

Impact of SLCO1B1 polymorphisms on drug disposition and effects in humans

Drug

Subjects / study design

Result

Reference

Pravastatin

41 healthy Caucasians / 1×40 mg p.o.

AUC: −11187GG<GA; AUC: 521TT<TC; AUC: *15B non-carriers<carriers; AUC: *17 non-carriers<carriers

Niemi et al. (2004)

Pravastatin

30 healthy Caucasians / 1×40 mg p.o.

AUC: *1a/*1b or *1b/1b<*1a/*1a<*1a/*5

Mwinyi et al. (2004)

Pravastatin

23 healthy Japanese / 1×10 mg p.o.

CLnr: *1b/*15<*1b/*1b

Nishizato et al. (2003)

Pravastatin

41 healthy Caucasians / 1×40 mg p.o.

effect of pravastatin on rate of cholesterol synthesis: *17 carriers<non-carriers

Niemi et al. (2005c)

Pravastatin/ atorvastatin

10 Japanese patients with plasma creatinine kinase elevation or severe muscle complaints vs control patients, who received statins

risk for pravastatin- or atrovastatin induced myopathy: *15 non-carriers<carriers

Morimoto et al. (2004)

Fexofenadine

20 healthy Caucasians / 1×180 mg p.o.

AUC: 521TT<TC< CC

Niemi et al. (2005b)

Repaglinide

56 healthy volunteers / 1×0.25 mg p.o.

AUC: 521TT<TC< CC (+ CYP2C8 genotype) change in blood glucose concentration: −11187GG<GA

Niemi et al. (2005a)

Repaglinide

12 healthy volunteers / 1×0.25 mg p.o.

Increase in repeglinide AUC caused by cyclosporine: 521TT>TC

Kajosaari et al. (2005)

Pitavastatin

24 healthy Koreans / 1×1–8 mg p.o.

AUC: *1b/*1b<*1a/*1a or *1a/*1b<*1a/*15 or *1b/*15

Chung et al. (2005)

Rosuvastatin

36 white, 36 Chinese, 35 Malay and 35 Asian-Indians / 1×40 mg p.o

Whites AUC: 521TT<TC<CC; other ethnic groups AUC: no effect of 521 polymorphism

Lee et al. (2005b)

AUC: area under the plasma-concentration-time curve; CLnr: non-renal clearance

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Fig. 2

Impact of SLCO1B1 polymorphisms and haplotypes on the disposition and effects of pravastatin and repaglinide. aLeft panels: effect of SLCO1B1 polymorphism 521 and of haplotype OATP1B1*17 on pharmacokinetics of orally administered prava-statin (1×40 mg) to healthy volunteers of both genders (with permission from Niemi et al. 2004); right panel: reduced pravastatin effect on cholesterol synthesis in carriers with haplotype OATP1B1*17 (with permission from Niemi et al. 2005c). b Effect of SLCO1B1 polymorphisms 521 and -11187 on repaglinide pharmacokinetics and effects on blood glucose studied in healthy volunteers of both genders (1×0.25 mg p. o.). (With permission from Niemi et al. 2005a; American Society for Clinical Pharmacology and Therapeutics)

Recently, the effect of OATP variant alleles on the pharmacokinetic of pitavastatin, another HMG-CoA-reductase inhibitor, has been analysed in healthy Korean subjects (Chung et al. 2005). This group characterised the effect of the alleles OATP1B1*1a, *1b, and *15 (Table 2) and found that the OATP1B1*15 allele is associated with increased pitavastatin plasma concentrations. Similar to pravastatin, the H1-receptor antagonist fexofenadine is not metabolised in humans and is excreted mainly via the biliary route. In a study with healthy volunteers, fexofenadine plasma concentrations were (similar to the observations with pravastatin) highest in individuals with the 521CC genotype, intermediate in the 521TC group and lowest in the 521TT group (Table 3) (Niemi et al. 2005b). Interestingly, fexofenadine has been established to be a substrate for P-glycoprotein and several OATP transporters (OATP1A2, OATP1B3, OATP2B1) (Cvetkovic et al. 1999; Nozawa et al. 2004a; Shimizu et al. 2005). However, one recent in vitro study reported no significant fexofenadine transport by OATP1B1 (Shimizu et al. 2005). This discrepancy between in vivo and in vitro findings deserves further studies.

Finally, there are recently published data indicating a relevance of polymorphisms in the SLCO1B1 gene for pharmacokinetics and effects of a drug which is eliminated completely by metabolism, namely for the antidiabetic drug repaglinide. Similar to the in vivo findings with pravastatin and fexofenadine, the AUC for repaglinide in subjects with the 521CC genotype was 107% and 188% higher, respectively, than in individuals with 521TC and 521CC genotype (Table 3, Fig. 2b) (Niemi et al. 2005a). Accordingly, the 521CC group had the largest changes in blood glucose levels, which were, however, not statistically significant (Niemi et al. 2005a). In addition, the effect of repaglinide on blood glucose was significantly associated with the SCLO1B1 polymorphism - 11187G>A (Fig. 2b).

In addition to this data on the influence of OATP1B1 polymorphisms on drug disposition and effects, Huang et al. (2005) reported an increased risk for unconjugated hyperbilirubinemia in Taiwanese patients with the two frequent polymorphisms at nucleotide position 388 and 521.

Pharmacogenomics of OATP1A2, OATP1B3, and OATP2B1

OATP1A2 (also known as OATP-A) was the first human OATP family member to be cloned and characterised (Kullak-Ublick et al. 1995). Substrates for this uptake transporter include endogenous compounds like steroid hormones and bile salts, but also drugs such as fexofenadine (Table 1). SLCO1A2 mRNA has been detected in various tissues with a high expression in brain (Kullak- Ublick et al. 1995). There, the protein has been localised to the capillary endothelium (Lee et al. 2005a) suggesting that OATP1A2 may play a critical role in the constitution of the blood-brain barrier. Thus, genetic variations in the SLCO1A2 gene encoding human OATP1A2 may have significant pharmacological consequences. Lee et al. (2005a) identified and analysed 6 non-synonymous polymorphisms in the SLCO1A2 gene and found that the allelic frequencies appear to be ethnicity-dependent (Table 2). To investigate the functional consequences of these polymorphisms, they used transiently transfected HeLa cells expressing the respective mutant OATP1A2 protein. They found that the two alleles OATP1A2*3 (516A>C; Glu172Asp) and OATP1A2*6 (404A>T; Asn135Ile) had a markedly reduced transport capacity for deltorphin II and for estrone-3-sulfate. The reason for this reduced transport could be due to an altered plasma membrane localisation of mutated OATP1A2 proteins as demonstrated by surface biotinylation experiments. Furthermore, the authors found that the variants OATP1A2*4 (559G>A; Ala185Thr) and OATP1A2*7 (2003C>G; Thr668Ser) exhibit a substrate-dependent change in transport activity as shown by altered Vmax values only for selected substrates.

Besides OATP1B1, OATP1B3 seems to be the second liver-specific member of the human OATP family (König et al. 2000b). OATP1B3 has 80% amino acid identity with OATP1B1 and both have an overlapping substrate spectrum. Interestingly, literature on the pharmacogenetics of OATP1B3 is relatively sparse in comparison with OATP1B1. The first identification of SNPs in the SLCO1B3 gene was published by Iida et al. (2001) without analysing the functional consequences of the base pair alterations. They found several SNPs in the noncoding region of the SLCO1B3 gene and the non-synonymous SNP 334T>G resulting in the amino acid exchange Ser112Ala. This exchange, as well as one additional frequent polymorphism (699G>A; Met233Ile; allelic frequency of 71%), one rare polymorphism (1564C>T; Gly522Cys; allelic frequency of 1.9%) and the artificial mutation 1748G>A (Gly583Glu), have been analysed in detail by Letschert et al. (2004) with respect to functional consequences on protein localisation and transport characteristics. These investigations demonstrated that both frequent polymorphisms showed localisation and transport properties corresponding to the protein encoded by the reference sequence. In contrast, the rare polymorphism and the artificial mutation abolish the transport function of the protein for the bile salt taurocholate, whereas other substrates like estradiol-17β-glucuronide and estrone-3-sulfate were transported with transport rates according to the protein encoded by the reference sequence. These results support the hypothesis that the 5th extracellular loop of the OATP1B3 protein is involved in substrate recognition, as has also been suggested for the OATP1B1 protein (Tirona et al. 2001). Interestingly, depending on the cell system used for analysis, the rare polymorphism and the mutation showed different glycosylation patterns as demonstrated by immunoblot analysis.

Like OATP1B1 and OATP1B3, OATP2B1 is also expressed in human liver and, therefore, may contribute to the hepatic elimination of endogenous substances and drugs. In addition, OATP2B1 is expressed in various other tissues including placenta (St-Pierre et al. 2002) and small intestine (Kobayashi et al. 2003). As for OATP1A2 and OATP1B3, the knowledge of the functional consequences of variations in the SLCO2B1 gene is limited. Nozawa et al. (2002) described the two variants OATP2B1*2 (1175C>T; Thr392Ile) and OATP2B1*3 (1457C>T; Ser486Phe) (Table 2) with an allelic frequency of 30.9% for OATP2B1*3, whereas the OATP2B1*2 allele could not be detected in additional 267 Japanese subjects. The functional consequences of both variations compared to the OATP2B1*1 protein have been analysed in HEK293 cells. These experiments demonstrated that the Km values for estrone-3-sulfate used as model substrate are in a comparable range for all three OATP2B1 proteins. In addition, no change in the cellular distribution of all different OATP2B1 proteins could be detected (Nozawa et al. 2002).

In conclusion, uptake transporters are increasingly recognised as important factors in the absorption of drugs into the body, the distribution of drugs, and the directed elimination out of the body. In addition, modification of transport rates by drug competition is a new, additional mechanism of drug-drug interactions. Variations in genes encoding uptake transporters can cause interindividual variations of drug effects. Studies regarding the detailed analysis of the consequences of genetic variations, not only limited to single polymorphisms but also to frequent haplotypes of allelic variants, may be of importance to further individualise and optimise treatment regimens involving drugs that are substrates for the respective uptake transporter. Many drugs, however, are substrates for drug metabolising enzymes and efflux transporters in addition to uptake transporters, highlighting the need to characterise the importance of each component for overall drug elimination.

Acknowledgement

This work was supported by grant DFG Ko2120/1-3 of the Deutsche Forschungsgemeinschaft.

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© Springer-Verlag 2006