The Regional-Specific Relative and Absolute Expression of Gut Transporters in Adult Caucasians: A Meta-Analysis

Matthew D. Harwood; Mian Zhang; Shriram M. Pathak; Sibylle Neuhoff

doi:10.1124/dmd.119.086959

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Fig. 1.
Exclusion criteria applied to the complete database for the absolute (left) and relative (right) abundance data. Percentages for each exclusion criterion refer to the fraction of the samples in the complete database that were excluded on its basis.
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Fig. 2.
Absolute abundance quantification of ATP-binding cassette (ABC) transporters normalized to the jejunum I segment (A) and solute carrier (SLC) family transporters (B) in all intestinal segments representing the ADAM model (C, colon; D, duodenum; I1–I4, ileum I1–I4 segments; J1 and J2, jejunum I and II segments). Relative abundance quantification of ABC transporters normalized to the jejunum I (C) and SLC transporters (D) in all intestinal segments representing the ADAM and M-ADAM models. The bars represent the weighted mean normalized abundance of each transporter. Representative values depicted in this figure are provided in Supplemental Table 3. Where no abundance data were available a zero value was assigned. This is represented in histogram B for SLC51A/B in all segments except jejunum II and ileum IV and in histogram D for SLC2A2 in all segments except duodenum, SLCO4C1 duodenum, and jejunum I and II. The values provided above the bars for SLC10A2 in histogram B represent the scaled up expression relative to the break point [(//), i.e., 5] executed for these values.
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Fig. 3.
Intestinal drug transporter pies. Proximal jejunum (jejunum I) ATP-binding cassette (ABC) (A) and solute carrier (SLC) and OATP (SLCO) (B). Distal ileum (ileum IV) ABC (C) and SLC and OATP (SLCO) (D). Protein abundance in the final subdatabase for each transporter family transporters as a percentage of the total abundance (in picomoles) of the region shown after performing a simulation with 2000 North European Caucasians.

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TABLE 1

The 16 transporters selected for inclusion into the meta-analysis after exclusion criteria were applied to determine region-specific transporter expression in the ADAM and M-ADAM models

Protein	Membrane Localization	Functionality	Quantification (Relative/Absolute)^{^a}
SLC10A2 (IBAT)	Apical	Uptake	Relative and absolute
SLC15A1 (PEPT1)	Apical	Uptake	Relative and absolute
SLC16A1 (MCT1)	Apical	Uptake	Relative
SLCO2B1 (OATP2B1)	Apical	Uptake	Relative and absolute
SLC22A1 (OCT1)	Apical	Uptake	Relative and absolute
SLC22A3 (OCT3)	Apical	Uptake	Relative and absolute
SLC22A4 (OCTN1)	Apical	Uptake	Relative
ABCB1 (P-gp)	Apical	Efflux	Relative and absolute^{^b}
ABCC2 (MRP2)	Apical	Efflux	Relative and absolute^{^b}
ABCG2 (BCRP)	Apical	Efflux	Relative and absolute^{^b}
SLC2A2 (GLUT2)	Basolateral^{^c}	Uptake	Relative
SLCO4C1 (OATP4C1)	Basolateral^{^c}	Uptake	Relative
SLC51A/B (OST-α/β)	Basolateral^{^c}	Efflux	Relative and absolute^{^d}
ABCC1 (MRP1)	Basolateral^{^c}	Efflux	Relative
ABCC3 (MRP3)	Basolateral^{^c}	Efflux	Relative and absolute
ABCC4 (MRP4)	Basolateral^{^c}	Efflux	Relative

BCRP, breast cancer resistance protein; MCT1, monocarboxylate transporter 1; PEPT1, peptide transporter 1.
↵^a Relates to data available and collated in the final database (i.e., without exclusion criteria applied) (see Fig. 1) for a transporter.
↵^b A substantial meta-analysis for relative expression of P-gp, MRP2, and BCRP had already been performed, and the results are published in Harwood et al. (2013).
↵^c Note that the M-ADAM model requires selection to enable activation of the basolateral membrane localized transporters.
↵^d Data collated distinctly for α (SLC51A) and β (SLC51B) subunits, hence counted as individual transporters in the Fig. 1 count of transporter data collated.

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TABLE 2

The weighted mean, coefficient of variation, and geometric mean of total membrane protein abundance of drug transporters in the proximal jejunum (jejunum I) obtained from the meta-analysis of measurements in tissue of healthy Caucasian adults

Transporter	Mean^{^a}	CV	Geometric Mean^{^a}	Number of Samples	Number of Studies	Heterogeneity		Reference
Transporter	Mean^{^a}	CV	Geometric Mean^{^a}	Number of Samples	Number of Studies	P	Yes/No	Reference
		%
ABCB1 (P-gp)	0.4	44	0.37	11	3	0.98	No	Gröer et al. (2013), Oswald et al. (2013), Drozdzik et al. (2014)
ABCC2 (MRP2)	0.86	68	0.71	11	3	0.82	No	Gröer et al. (2013), Oswald et al. (2013), Drozdzik et al. (2014)
ABCC3 (MRP3)	0.58	64	0.49	7	2	N/A^{^b}	N/A^{^b}	Gröer et al. (2013), Drozdzik et al. (2014)
ABCG2 (BCRP)	0.34	62	0.29	11	3	0.93	No	Gröer et al. (2013), Oswald et al. (2013), Drozdzik et al. (2014)
SLC10A2 (ASBT/IBAT)	0.01	43^{^c}	0.01	6	1	N/A^{^b}	N/A^{^b}	Drozdzik et al. (2014)
SLC15A1 (PepT1)	3.69	41	3.41	11	3	0.92	N/A^{^b}	Gröer et al. (2013), Oswald et al. (2013), Drozdzik et al. (2014)
SLCO2B1 (OATP2B1)	0.4	74	0.32	11	3	0.57	No	Gröer et al. (2013), Oswald et al. (2013), Drozdzik et al. (2014)
SLC22A1 (OCT1)	0.65	49	0.58	6	1	N/A^{^b}	N/A^{^b}	Drozdzik et al. (2014)
SLC22A3 (OCT3)	0.06	74	0.05	6	1	N/A^{^b}	N/A^{^b}	Drozdzik et al. (2014)
SLC51A/B (OST-α/β)	0.47^{^d}	99^{^d}	0.47	1	1	N/A^{^b}	N/A^{^b}	Harwood (2015)

ASBT, apical sodium-dependent bile acid transporter; BCRP, breast cancer resistance protein; N/A, not applicable; PepT1, peptide transporter 1.
↵^a Values are given as picomoles per milligram of total membrane protein.
↵^b Heterogeneity reporting is not applicable with only one or two studies, when considering subtracting the degree of freedom component (i.e., n minus one study).
↵^c The final CV value for jejunum I SLC10A2 was taken from Hilgendorf et al. (2007), based on jejunum mRNA data since it was determined that low abundance levels could give rise to inflated interindividual variability due to analytical imprecision at such low levels of expression.
↵^d For OST-α/β, the mean abundance is from a distal jejunum sample and is based on the α-subunit data considering the rate-limiting component for conferring OST-α/β activity (Sun et al., 2007). Also, only a single sample was available; therefore, the CV value was obtained from a combined analysis of jejunum samples from relative and absolute data.

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TABLE 3

Final region-specific abundances along the gastrointestinal tract normalized to jejunum I based on relative abundance quantification or by combining abundance data obtained from relative and absolute quantification methodology

Protein	ADAM Model Segment (Sample Number Quantified Is Given in Parentheses)								Reference
Protein	Duodenum	Jejunum I^{^a}	Jejunum II	Ileum I	Ileum II	Ileum III	Ileum IV	Colon	Reference
ABCB1 (P-gp)^{^b}^,^{^c}	0.51 (31)	1 (9)	1.46 (8)	1.50 (42)	1.51 (42)	1.52 (42)	1.51 (42)	0.57 (27)	See Table 2 in Harwood et al. (2013) for references
ABCC1 (MRP1)^{^b}	0.45 (37)	1 (9)	0.88 (9)	0.86 (37)	0.86 (37)	0.89 (37)	0.89 (37)	0.93 (50)	Fromm et al. (2000), Albermann et al. (2005), Zimmermann et al. (2005), Berggren et al. (2007), Blokzijl et al. (2007), Bourgine et al. (2012), Drozdzik et al. (2014)
ABCC2 (MRP2)^{^b}^,^{^c}	1.41 (71)	1 (4)	1 (4)	0.60 (41)	0.60 (41)	0.60 (41)	0.60 (41)	0.02 (26)	See Table 2 in Harwood et al. (2013) for references
ABCC3 (MRP3)	2.15 (29)	1 (16)	0.89 (16)	1.54 (35)	1.54 (35)	1.60 (35)	1.60 (35)	5.95 (35)	Zimmermann et al. (2005), Englund et al. (2006), Seithel et al. (2006), Bourgine et al. (2012), Gröer et al. (2013), Drozdzik et al. (2014)
ABCC4 (MRP4)^{^b}	1.02 (15)	1 (6)	1.22 (6)	1.71 (19)	1.71 (19)	1.20 (19)	1.20 (19)	1.76 (19)	Zimmermann et al. (2005), Bourgine et al. (2012), Drozdzik et al. (2014)
ABCG2 (BCRP)^{^b}^,^{^c}	0.47 (45)	1 (14)	1 (45)	0.59 (45)	0.59 (45)	0.59 (45)	0.59 (45)	0.13 (35)	See Table 2 in Harwood et al. (2013) for references
SLC2A2 (GLUT2)^{^b}	1 (15)	1 (0)^{^d}	1 (0)^{^d}	1 (0)^{^d}	1 (0)^{^d}	1 (0)^{^d}	1 (0)^{^d}	1 (0)^{^d}	Wilder-Smith et al. (2014)
SLC10A2 (ASBT/IBAT)	16.49 (30)	1 (6)	4 (6)	98.44 (59)	98.44 (59)	109.18 (59)	108.00 (59)	1.10 (56)	Hruz et al. (2006), Meier et al. (2007), Wojtal et al. (2009), Bourgine et al. (2012), Gröer et al. (2013), Drozdzik et al. (2014)
SLC15A1 (PEPT1)	0.94 (35)	1 (20)	1.06 (20)	1.23 (67)	1.23 (67)	1.24 (67)	1.24 (67)	0.03 (63)	Ziegler et al. (2002), Englund et al. (2006), Seithel et al. (2006), Meier et al. (2007) Wojtal et al. (2009), Bourgine et al. (2012), Gröer et al. (2013), Oswald et al. (2013), Drozdzik et al. (2014)
SLC16A1 (MCT1)^{^b}	1.25 (17)	1 (13)	1 (13)	1.29 (20)	1.29 (20)	1.29 (20)	1.29 (20)	4.72 (26)	Gill et al. (2005), Englund et al. (2006), Seithel et al. (2006), Bourgine et al. (2012)
SLCO2B1 (OATP2B1)	0.73 (30)	1 (20)	0.94 (20)	1.28 (76)	1.28 (76)	1.28 (76)	1.28 (76)	1.06 (58)	Englund et al. (2006), Seithel et al. (2006), Meier et al. (2007), Wojtal et al. (2009), Bourgine et al. (2012), Gröer et al. (2013), Oswald et al. (2013), Drozdzik et al. (2014)
SLCO4C1 (OATP4C1)^{^b}	1 (0)^{^d}	1 (0)^{^d}	1 (0)^{^d}	1 (3)^{^e}	1 (3)^{^e}	1 (3)^{^e}	1 (3)^{^e}	1 (3)^{^e}	Bourgine et al. (2012)
SLC22A1 (OCT1)	1.03 (6)	1 (6)	0.87 (6)	1.29 (35)	1.29 (35)	1.30 (35)	1.30 (35)	2.77 (32)	Wojtal et al. (2009), Bourgine et al. (2012), Gröer et al. (2013), Drozdzik et al. (2014)
SLC22A3 (OCT3)	1.19 (6)	1 (6)	1.11 (6)	1.08 (12)	1.08 (12)	1.23 (12)	1.23 (12)	1.88 (9)	Bourgine et al. (2012), Gröer et al. (2013), Drozdzik et al. (2014)
SLC22A4 (OCTN1)^{^b}	0.46 (16)	1 (6)	0.63 (6)	0.78 (51)	0.78 (51)	0.80 (51)	0.80 (51)	0.24 (49)	Meier et al. (2007), Wojtal et al. (2009), Bourgine et al. (2012), Girardin et al. (2012), Drozdzik et al. (2014)
SLC51A/B (OST-α/β)^{^f}	0.56 (6)	1 (6)	1.89 (7)	1.08 (40)	1.08 (40)	0.93 (40)	0.93 (41)	0.71 (6)	Renner et al. (2008), Drozdzik et al. (2014), Harwood (2015)
SLC51B (OST-β)^{^f}	0.6 (6)	1.19 (6)	1.16 (9)	1.01 (40)	1.01 (40)	1 (40)	1 (41)	0.33 (6)	Renner et al. (2008), Drozdzik et al. (2014), Harwood (2015)

ASBT, apical sodium-dependent bile acid transporter; BCRP, breast cancer resistance protein; MCT1, monocarboxylate transporter 1; PEPT1, peptide transporter 1.
↵^a Fixed value of 1: jejunum I was fixed to 1 as the final value; however, prior to normalization a weighted mean relative expression was calculated across samples with the potential for CV generation, hence the sample number provided.
↵^b Where only relative abundance data were available.
↵^c Final values not updated from those previously reported (Harwood et al., 2013) since the region-specific absolute abundance values in Supplemental Table 3 were similar.
↵^d Where samples were not quantified within a given region a relative abundance value of 1 was assumed.
↵^e Since there were no jejunum I values available to normalize the ileum and colon abundances to the relative expression for these segments, the value was set to 1.
↵^f Used OST-α values from relative and absolute combined analysis—for completeness the OST-β segmental relative abundance values are given in the last row of the table.