Are mice, rats, and rabbits good models for physiological, pharmacological and toxicological studies in humans?

Abstract

In the mammalian kidneys, handling of various organic compounds is mediated by multispecific organic anion and cation transporters localized in the luminal and contraluminal cell membrane domains of specific nephron segments, largely in proximal tubules. These transporters are responsible for cellular uptake and/or elimination of endogenous and xenobiotic organic compounds, including various anionic and cationic drugs, thus contributing to their reabsorption and/or secretion along the nephron. Recent studies have indicated a pivotal role of these transporters in drug resistance, drug-drug interactions, and drug-induced nephrotoxicity, whereas the presence of disfunctional transporters due to truncated isoforms or point mutations can cause genetic diseases. In rat, mouse and rabbit nephrons, a number of these transporters exhibit sex differences in their protein and/or mRNA expression. In comparison with the expression in rodents and rabbits, in the human nephrons some transporters are absent, some exhibit different localization in the cell membrane domains, and none exhibit the sex-dependent expression. Species differences in some transporters have been further demonstrated concerning substrate selectivity, distribution in cells along the nephron, levels of mRNA and/or protein expression, sensitivity to inhibitors, and regulation. Overall these differences in the mammalian kidneys indicate that: a) data on the membrane transporters-related functions in one species can not simply be regarded as relevant for other species, and b) many physiological, pharmacological, and toxicological findings related to organic anion and cation transport and transporters in rodents and rabbits do not reflect the situation in humans.

Full text

Are mice, rats, and rabbits good models for
physiological, pharmacological and toxicological
studies in humans?
Abstract
In the mammalian kidneys, handling of various organic compounds is
mediated by multispecific organic anion and cation transporters localized
in the luminal and contraluminal cell membrane domains of specific
nephron segments, largely in proximal tubules. These transporters are re-
sponsible for cellular uptake and/or elimination of endogenous and xeno-
biotic organic compounds, including various anionic and cationic drugs,
thus contributing to their reabsorption and/or secretion along the nephron.
Recent studies have indicated a pivotal role of these transporters in drug re-
sistance, drug-drug interactions, and drug-induced nephrotoxicity, whereas
the presence of disfunctional transporters due to truncated isoforms or point
mutations can cause genetic diseases. In rat, mouse and rabbit nephrons, a
number of these transporters exhibit sex differences in their protein and/or
mRNA expression. In comparison with the expression in rodents and rab-
bits, in the human nephrons some transporters are absent, some exhibit dif-
ferent localization in the cell membrane domains, and none exhibit the
sex-dependent expression. Species differences in some transporters have been
further demonstrated concerning substrate selectivity, distribution in cells
along the nephron, levels of mRNA and/or protein expression, sensitivity to
inhibitors, and regulation. Overall these differences in the mammalian kid-
neys indicate that: a) data on the membrane transporters-related functions
in one species can not simply be regarded as relevant for other species, and b)
many physiological, pharmacological, and toxicological findings related to
organic anion and cation transport and transporters in rodents and rabbits
do not reflect the situation in humans.
INTRODUCTION
Although the exact number of animals used annually for various ex-
perimental purposes worldwide is not known, it has been esti-
mated that between 40 million and 100 million of various animals are
used, most of them (~80%) being the purpose-bread rodents (mainly
mice and rats, but also hamsters, guinea pigs and gerbils) (http://en.wiki-
pedia.org/ wiki/Animal_testing). These animals are used for educa-
tional purposes, in basic research (genetics, physiology, biomedicine,
developmental biology, behavioral studies, basic pharmacology) and in
applied research (surgery, drug development, testing of various toxic
and cosmetic substances, military research). In pharmacological and
toxicological studies, especially when testing drugs, mice and rats are
the most common animals used. The 3R-alternatives (Reduction, Re-
IVAN SABOLI]
DAVORKA BRELJAK
MARIJA LJUBOJEVI]
HRVOJE BRZICA
Unit of Molecular Toxicology
Institute for Medical Research and
Occupational Health, Ksaverska cesta 2,
10001 Zagreb, Croatia
Correspondence:
Ivan Saboli}
Unit of Molecular Toxicology
Institute for Medical Research and
Occupational Health, Ksaverska cesta 2,
10001 Zagreb,Croatia
E-mail: sabolic@imi.hr
Abbreviations:
BBM – brush-border membrane
BLM – basolateral membrane
PT – proximal tubules
OA – organic anions
OC – organic cations
Key words: experimental animals,
gender differences, mammalian kidney,
nephrotoxicity, organic anions, organic
cations, proximal tubule
Received February 21, 2011.
PERIODICUM BIOLOGORUM UDC 57:61
VOL. 113, No 1, 7–16, 2011 CODEN PDBIAD
ISSN 0031-5362
Leading article

finement, Replacement), including non-animal alterna-
tives, have been widely accepted as the way to diminish
the use of experimental animals in research and testing,
but when studying interactions among cells, tissues and
organs, or when testing pharmacology and toxicology of
various substances, including drugs to be used in human
and veterinary medicine, in most cases there is no plausi-
ble substitute for the living animal. Moreover, the current
legislation requires that all new drugs, before being li-
cenced for human and animal use, have to be rigorously
tested in at least two mammalian species (rodents AND
non-rodents) for metabolism, pharmacokinetics, acute
and chronic toxicology in adult species, efficasy regard-
ing the expected actions, effects on reproduction, embry-
onic toxicity, and potential carcinogenicity. However, the
increasing evidence indicate that rodents and some other
common experimental animals, such as rabbits, may not
be good models for such studies relevant to humans due
to sex and species differences in various properties. Par-
ticularly relevant to this problem are the data on the role
and expression of various membrane transporters that
mediate transport of organic anions (OA) and cations
(OC) in the mammalian kidneys and other organs. In re-
cent years, a number of these transporters from different
protein families and species have been cloned and char-
acterized, and their localization, mainly in the liver and
kidneys, but also in the intestine, brain and placenta,
have been studied. Their kinetic and functional charac-
teristics, sex and species differences in their expression,
and their relevance for drug transport, drug-drug inter-
actions and drug toxicity, have been extensively studied
in normal and specific gene-inactivated (knock-out) ani-
mals, as well as in humans, and discussed in numerous
recent reviewes (1–22).
ORGANIC ANION AND CATION
TRANSPORTERS IN THE MAMMALIAN
KIDNEY
Humans and animals are constantly exposed to vari-
ous organic compounds that are either produced during
normal metabolism (endogenous substances) or enter
the body via food, air, or medication (exogenous com-
pounds, xenobiotics), and are potentially harmful to their
health. In the body, these compounds are either biotrans-
formed into more or less active metabolites, largely in
liver and kidneys, or remain unchanged. Dependent on
their physico-chemical characteristics, at the physiologi-
cal pH these organic compounds behave as OA (nega-
tively-charged) or OC (positively-charged), whereas so-
me compounds may be both (zwitter-ions). The unchan-
ged or biotransformed organic compounds are elimi-
nated from the body partially by the liver and largely by
the kidneys via secretory processes that are mediated by
various transporters localized in the cell membrane. The
representative groups of endogenous and xenobiotic OA
and OC, which are handled by the mammalian liver and
kidneys, are listed in Table 1. The cell membrane is not
freely permeable to these compounds; they are trans-
ported by various specialized proteins localized in the
membrane, collectively named as »drug transporters«.
Detailed lists of these compounds associated with rel-
evant transporters in the animal and human kidneys
have been reviewed elsewhere (1, 2, 4, 5, 8, 10, 11, 13, 16,
17, 22).
In the mammalian kidneys, transport of OA and OC
is maintained by numerous, largely multispecific trans-
porters that are localized in the apical (luminal) and/or
basolateral membrane domains in the epithelial cells
along the nephron. To drive vectorial transport of their
substrates in direction of secretion or reabsorption, most
OA transporters operate as bidirectional anion exchan-
gers, and use transmembrane ion gradients (secondary-
or tertiary-active transporters) generated by the activity
of primary-active Na/K-ATPase and/or secondary-active
ion exchangers (for example, Na+/H+antiporter), whe-
reas most OC transporters operate as the bidirectional fa-
cilitators, while some OA and OC transporters use ATP
(primary-active transporters). The characteristics and the
nomenclature of all these transporters have been recently
collected and published; most of them belong to the large
family of solute carriers (Slc in animals/SLC in hu-
mans), whereas the ATP-driven transporters are mem-
8Period biol, Vol 113, No 1, 2011.
I. Saboli} et al. Sex and species differences in renal drug transporters
TABLE 1
Representative endogenous and exogenous (xenobiotic)
OA and OC that are handled by various membrane
transporters in the mammalian kidneys.
Organic anions
Endogenous: cyclic nucleotides, dicarboxylates, urate, folate,
some prostaglandins, neurotransmitter metabolites, steroid
hormones conjugated with sulfate, cysteine, glycine, and glu-
curonide.
Exogenous (xenobiotics): Medicaments (antibiotics, anti-vi-
ral drugs, nonsteroid anti-inflammatory drugs, diuretics, an-
giotensin-converting enzyme inhibitors, angiotensin II an-
tagonists, anti-neoplastics, anti-epileptics, histamine-H2-re-
ceptor antagonists); Conjugates (steroid hormones conju-
gated with sulfate, cysteine, glycine, and glucuronide); Diag-
nostic and experimental drugs (p-aminohippuric acid (PAH));
Food constituents (flavonoids); Environmental toxins (my-
cotoxins, herbicides, pesticides, some toxic metals).
Organic cations
Endogenous: choline, corticosterone, progesterone, endoge-
nous cardiac glycosides, bioactive monoamines (dopamine,
histamine, epinephrin, norepinephrin, serotonin), some pro-
staglandins.
Exogenous (xenobiotics): Medicaments ((ant)agonists of va-
rious receptors, ion channel blockers, transporter blockers,
psychoactive drugs, some antiviral drugs, antidiabetics, ane-
stetics, antimalarics, muscle relaxants, cardiac glycosides);
Toxins and experimental drugs (tetraethylammonium (TEA),
tetramethylammonium (TMA), nicotine).
Zwitter ion – L-carnitine
Detailed lists of these compounds associated with relevant
transporters in the animal and human kidneys have been re-
viewed elsewhere (1, 2, 4, 5, 8, 10, 11, 13, 16, 17, 22).

Period biol, Vol 113, No 1, 2011. 9
Sex and species differences in renal drug transporters I. Saboli} et al.
Figure 1. Polar distribution of the common drug transporters in the rat PT cells. A. Definition of various nephron segments in relation to specific tissue
zones. C, cortex; OS, outer stripe; IS, inner stripe; IM, inner medulla; PAP, papilla; UR, ureter; CG, cortical glomerulus; JMG, juxtamedullary
glomerulus; PCT, proximal convoluted tubule; S3, PT straight segment; DT, distal tubule; CD, collecting duct; TALH, thick ascending limb of
Henle; HL, Henle loop. B. Transmission electron micrograph of a PCT (cross section). BLM, basolateral (contraluminal) membrane; V, vacuole;
BBM, brush-border (luminal, apical) membrane; M, mitochondria; N, nucleus). C. Membrane domain-specific distribution of various OA trans-
porters (OA-Ts) in the PT cell. Slc (solute carriers) are secondary- or terciary-active transporters: sodium-dicarboxylate cotransporter NaDC3 and so-
dium-independent OA exchanger Oat1 and 3 are located in the BLM, whereas NaDC1, Oat2 and 5, and Oatp1 and 2 are located in the BBM. The
driving force for all these transporters provides the ATP-driven (primary-active) Na/K-ATPase in the BLM, which generates ion gradients and the
transmembrane (inside-negative) membrane potential. Abc (ATP-binding casette) are all ATP-driven (primary-active) transporters, located in ei-
ther BLM (multidrug resistance associated proteins Mrp1, 3, 5, and 6) or BBM (Mrp2 and 4), which predominantly accept OC as substrates, and sev-
eral multidrug resistance proteins from the Mdr1 (P-gp) subfamily in BBM, which predominantly accept OA, but also some OC as substrates. At the
BBM, some OA from the glomerular filtrate (GF) can be reabsorbed, whereas at the BLM, most OA (drugs) are transported and accumulated in the
cell, and then secreted across the BBM into the tubule luminal fluid. D. Membrane domain-specific distribution of various OC transporters (OC-Ts)
in the PT cell. Slc: The OC transporters Oct1-3 in the BLM operate as facilitators that transport OC into the cell using the inside-negative membrane
potential (generated by the Na/K-ATPase and ion gradients) as a driving force. Thus accumulated OC can exit the cell partially via the Abc trans-
porters (Mrp1, 3, 5, 6) in the BLM, and predominantly via the BBM transporters, e.g., H+/OC exchangers Octn1 (organic cation novel membrane
transporter) and MATE1 (multidrug and toxin extruder), Mdr1 (P-gp) proteins, and (less with) Mrp2 and 4. Some OC and the zwitterion
L-carnitine can be reabsorbed from the glomerular filtrate by the action of Na+(or H+)-OC cotransporter Octn2. The non-reabsorbed and secreted
OA or OC finish in urine. E-L, Representative pictures, obtained in immunocytochemical studies using specific antibodies (26–28, and our unpub-
lished results), showing localization of a few OA and OC transporters in the PT BLM (E-I) and BBM (J-L). E, Na/K-ATPase; F, Oat1; G, Oat3; H,
Oct1; I, Oct2; J, Oat2; K, Oat5; L, Mdr1.

bers of the ATP-binding casette (Abc in animals/ABC in
humans) family of transporters (23, 24). The number of
newly discovered, cloned, and characterized transporters
from both families increases every year. In the nephron,
these transporters mediate: a) transport (net secretion) of
various endogenous organic compounds that are gener-
ated in normal metabolism in the kidneys and other or-
gans, b) transport (net secretion) of exogenous (xenobio-
tic) organic compounds that enter the body for iatrogen
(medicaments/drugs) or alimentary (food constituents)
reasons, or as the enviromental toxins, c) drug-drug in-
teractions, d) drug resistance, e) development of drug-
-induced nephrotoxicity, and f) specific genetic diseases,
caused by malfunctional transporters due to truncated
isoforms or point mutations. The convoluted (S1/S2)
and straight (S3) proximal tubule (PT) segments are the
principal nephron parts in which handling of OA and
OC takes place. In the PT epithelial cells, the relevant
transporters are differently distributed in the luminal
(brush-border, BBM) and contraluminal (basolateral,
BLM) membrane domains. A polar distribution of some,
well characterized transporters of OA and OC in the rat
PT cells is illustrated in Fig. 1C (OA transporters) and
Fig. 1D (OC transporters).
SEX AND SPECIES DIFFERENCES
IN THE EXPRESSION OF RENAL
ORGANIC ANION TRANSPORTERS
Majority of the cloned and well-characterized OA
transporters belong to the subfamily Slc22/SLC22 (Oat1/
OAT1, Oat2/OAT2, Oat3/OAT3, OAT4, Oat5/OAT5,
etc...), which operate as anion exchangers (23), whereas
the ATP-driven efflux pumps Mrp1, 3, 5, and 6, and
Mrp2 and 4 belong to the subfamily Abcc/ABCC (24).
Recent studies have shown that in the rodent and rabbit
kidneys, some members of both transporter families ex-
hibit species and/or sex differences in the expression of
mRNA and/or protein, and in their localization along
the nephron, and that these differences influence secre-
tory functions of the organ. These differences are related
to the sex hormone-regulated expression of specific trans-
porters in one of the membrane domains of (largely) PT
cells. From the available data for a limited number of re-
nal OA transporters in rats, mice, rabbits, and humans,
collected and shown in Table 2, one can conclude the fol-
lowing: (a) Oat1/OAT1 is always expressed in the PT
BLM, but the male (M)-dominant sex differences in its
expression are present in rats and mice, but not in rabbits
and humans, (b) Oat2/OAT2 in rats and mice is locali-
zed to the PT BBM, where it exhibits the female (F)-do-
minant sex differences; its localization in rabbits is not
known (at the level of mRNA, M = F), whereas in hu-
mans, this transporter is localized to the PT BLM and
exhibits no sex differences, (c) Oat3/OAT3 in rodents
and humans is localized to the PT BLM (in rabbits, the
PT membrane domain has not been defined), but the ex-
pression is M-dominant in rats, F-dominant in mice, and
sex-independent in rabbits and humans, (d) OAT4 is the
human-specific transporter (not detected in rodents and
rabbits) in the PT BBM, similarly expressed in M and F,
(e) Oat5 is the rodent-specific transporter (not present in
humans) in the PT BBM (and in intracellular organelles
in mice), with F-dominant expression in both rats and
10 Period biol, Vol 113, No 1, 2011.
I. Saboli} et al. Sex and species differences in renal drug transporters
TABLE 2
Sex and species differences in the expression of several OA transporters in the mammalian kidneys.
Species and sex differences, localization in the nephron segment, membrane domain
Family Transporter Rats Mice Rabbits Humansa
Slc/SLC Oat1/OAT1 M>F M>F M=F M=F
PT, BLM PT, BLM PT,? PT, BLM
Oat2/OAT2 M<F M<F M=F
bM=F
PT, BBM PT, BBM ? PT, BLM
Oat3/OAT3 M>F M<F
bM=F M=F
PT, BLM PT, BLM PT,? PT, BLM
OAT4 ND ND ND M = F
PT, BBM
Oat5 M<F M<F ? ND
PT, BBM PT, BBM, IO ? ?
Abc/ABC Mrp4 M>F M<F ? ?
PT, BBM PT, BBM
Species-specific sex differences in the expression of OA transporters were observed at the level of protein and/or mRNA. For Oat1, Oat2,
Oat3, and Oat5 expression in experimental animals, sex differences are determined by either stimulatory effects of androgens or inhibi-
tory effects of estrogens and progesterone, or both, and are absent in prepubertal animals. Most data have been collected from various
publications (15, 26–29). aOur unpublished data. bData from (29, 30), and our unpublished data. M, males; F, females; PT, proximal tu-
bules; BBM, brush-border (luminal) membrane; BLM, basolateral (contraluminal) membrane; IO, intracellular organelles; ND, not de-
tected in the species; ?, unknown.

mice, and (f) the expression of Mrp4 in the PT BBM is
M-dominant in rats and F-dominant in mice; the data
for rabbits and humans are not available. A number of
other renal OATs in adult rats, mice, and in few other
species, also exhibit sex differences in their expression at
the level of protein and/or mRNA, whereas in prepube-
rtal animals, the expression of thus far tested OA trans-
porters was low and sex-independent (15, 25).
As has been tested in rats, mice and rabbits, the urine
excretion of relevant OA correlates well with the renal
expression of Oats. Thus, sex differences in the renal ex-
pression of Oat1, Oat2, and Oat3 in adult rats clearly cor-
relate with similar differences in the urine excretion of
their substrates (Table 3), whereas in the adult rabbits, in
which the expression of these Oats is similar in both
sexes, the excretion of relevant OA is also similar (30).
Furthermore, the prepubertal M and F rats excrete
OA with similar and much lower rate than the adults,
which is in good correlation with the sex-independent
and much lower expression of renal Oats (for references
see (15)). In addition, in mice with the knocked-out Oat1
and Oat3 genes, the urine excretion of p-aminohippurate
(PAH) and a few other OA is strongly impaired (29, 31,
32). Since the localization and the level of protein expres-
sion in the cell membrane is one of the major determi-
nants (next to the substrate specificity and kinetic charac-
teristics) of the transporter function, the observations in
humans that: a) none of the indicated transporters shows
sex differences in the expression, b) OAT2 is localized in
the membrane domain (BLM) which is opposite from
that in rodents (BBM), and c) OAT4 is present only in
humans, whereas Oat5 is rodent-specific, indicate that
the renal handling of OA with the all possible conse-
quences, such as interactions and nephrotoxicity of an-
ionic drugs, may be in humans different from that in ro-
dents and rabbits. Moreover, different sex-related expres-
sion of Oat3 in rats, mice, and rabbits, and of Mrp4 in rats
and mice, indicates that the overall handling and secre-
tion of many OA may be different among these species.
The respective transport studies in humans are scarce;
only a few of them have shown that the renal clearance of
some drugs and/or their metabolites may be sex-related,
but these differences may rather reflect the sex-depend-
ent metabolism of anionic (and other) drugs catalized by
drug-metabolizing enzymes, not the transporters-medi-
ated active secretion in the renal tubules (3, 15).
SEX AND SPECIES DIFFERENCES
IN THE EXPRESSION OF RENAL
ORGANIC CATION TRANSPORTERS
A number of OC transporters from different protein
families and species have been cloned and characterized,
and their functional roles have been studied mainly in
the liver and kidneys (8). The most important OC trans-
porters are grupped into the families Slc22/SLC22 (Oct1/
OCT1, Oct2/OCT2, Oct3/OCT3, Octn1/OCTN1, Octn2/
OCTN2), Slc47/SLC47 (MATE1, MATE2, MATE2-
-K), and Abcb/ABCB (Mdr1/MDR1 (P-glycoprotein, P-gp)).
Oct1-3/OCT1-3 represent polyspecific bidirectional trans-
porters that mediate electrogenic, sodium- and pH-inde-
pendent intracellular uptake of OC via facilitated diffu-
sion. In the rat PT, these transporter are predominantly
localized to the BLM, where they mediate the first step of
the renal OC excretion. The second, exit step across the
BBM is largely mediated by the electroneutral H+-OC
exchangers MATE1 (in rodents, rabbits and humans),
MATE2 (in mice, not known for rats, not present in rab-
bits and humans), and MATE2-K (in rabbits and hu-
mans, not present in rats and mice), and by the ATP-
-driven efflux pump Mdr1/MDR1. Besides in expression
and localization, OC transporters in various species dif-
fer in substrate specificity, inhibitor sensitivity, transport
mechanism, and regulation (8, 33).
The renal OC transporters have been extensively stu-
died recent years, but most of this research showed their
expression at the level of mRNA, whereas only a few
transporters were described also at the protein level. As
listed in Table 4, the mRNA expression of various renal
OC transporters in different species exhibits different
pattern of sex dependency. Thus, in the rat, mouse, rabbit
and human kidneys: (a) mRNA expression of various
OC transporters is species-dependent, but sex differences
are present only in some cases, (b) expression of both
mRNA and protein have been thus far studied and corre-
lated only in a few cases, (c) in the Oct/OCT subfamily,
rats and mice express the Oct1 mRNA in similar abun-
dance in M and F, whereas the protein is localized to the
proximal tubule BLM with (largely) M-dominant ex-
pression. However, rabbits do not express the Oct1 mRNA
and protein at all, whereas in humans, OCT1 is localized
to the apical membrane of proximal and distal tubules
with similar expression in M and F. (d) The expression of
renal Oct2/OCT2 in different species has been studied in
more detail at both mRNA and protein level. The expres-
sion of Oct2 mRNA in rats, mice and rabbits exhibits the
M-dominant pattern, but at the protein level this ba-
solateral transporter in PT is clearly stronger in M than F
rats and mice, but sex-independent in rabbits and hu-
mans. (e) In the Octn/OCTN subfamily, the mRNA ex-
pression of the indicated transporters is either sex-inde-
pendent or still controversial, whereas the Octn2 protein
in rats and mice is localized to the PT BBM. (f) In the
Period biol, Vol 113, No 1, 2011. 11
Sex and species differences in renal drug transporters I. Saboli} et al.
TABLE 3
In rats, sex differences in the expression of some renal
OA transporters correlate well with the excretion of rele-
vant OA in urine.
Oat Protein
Expression
Organic anion Urine excretion
Oat1 M > F PAH, Furosemide M > F
Oat2 M < F PFOA M < F
Oat3 M > F PAH, Taurocholate M > F
Data have been collected from the available literature and
from own publications (for references see (15)).M, males; F,
females; PAH, p-aminohippurate; PFOA, perfluorooctanoic
acid.

12 Period biol, Vol 113, No 1, 2011.
I. Saboli} et al. Sex and species differences in renal drug transporters
TABLE 4
Sex and species differences in the renal expression of OC transporters at the level of mRNA and/or protein.
OC Transporter Species mRNA M vs. F Protein (Nephron segment,
Membrane domain)
M vs. F
Oct1/OCT1 Rat M £F PT, BLM M ³F
Mouse M = F PT, BLM M > F
Rabbit ND ND ND
Human +/? PT & DT, AM M = F
Oct2/OCT2 Rat M > F PT, BLM M > F
Mouse M > F PT, BLM M > F
Rabbit M > F PT,? M = F
Human +/? PT, BLM M = F
Oct3/OCT3 Rat M = F ?
Mouse M = F ?
Rabbit M = F ?
Human +/? ?
Octn1/OCTN1 Rat M = F ?
Mouse M = F ?
Rabbit +/? ?
Human +/? ?
Octn2/OCTN2 Rat M ³F PT, BBM
Mouse M = F PT, BBM
Rabbit +/? ?
Human +/? ?
MATE1 Rat M > F PT, BBM M > F
Mouse M > F Various segments, AM ?
Rabbit M = F ?
Human +/? PT, BBM ?
MATE2 Rat +/? ?
Mouse M = F
Rabbit ND ND
Human ND ND
MATE2-K Rat ND ND
Mouse ND ND
Rabbit M = F ?
Human +/? PT, BBM ?
Mdr1a Rat M > F ?
Mouse M £F?
Mdr1b Rat +/? ?
Mouse M < F ?
Mdr2 Rat +/? ?
Mouse M = F ?
MDR1 Human +/? ?
Data have been collected from the previously reviewed literature (15), from other studies (34, 36–49), and from own unpublished stud-
ies. The mRNA expression was determined in the kidney cortex or whole kidney tissue, whereas protein expression was determined by
immunocytochemistry in tissue cryosections and/or by Western blotting in cell membranes isolated from various kidney zones. F, fe-
males; M, males; ND, not detected; +/?, mRNA detected, but sex-dependency unknown; ?, unknown data; PT, proximal tubules;
BLM, basolateral membrane; DT, distal tubules; AM, apical membrane.

MATE subfamily, MATE1 in the rat kidney is localized
to the PT BBM and M-dominant in both mRNA and
protein expression. Mice exhibit higher expression of
mRNA in M, but the protein was detected in the apical
membrane of various tubule segments with unknown
levels of expresssion in M and F. MATE1 is present also
in the rabbit and human kidneys, but in these species the
levels of MATE1 mRNA and protein expression in M
and F has been poorly investigated. However, clear spe-
cies differences exist in the expression of MATE2, which
is present in mice (not clear in rats), but not in rabbits
and humans, and MATE2-K, which is present in rabbits
and humans, but not in rodents. (g) In the Mdr/MDR
subfamily, the Mdr1a mRNA expression in the rat kid-
neys isM>F,whereas in mice, the mRNA expression of
this transporters may be just opposite, e.g., M < F. Whe-
re tested, sex hormones responsible for the observed sex
differences in the expression of mRNA and/or protein of
the specific OC transporters have been defined, whereas
in prepubertal animals, the expression of both parame-
ters is low and sex-independent (reviewed in (15)).
Several in vivo studies in variously-treated rats and
mice, and/or in vitro studies in tissue slices or isolated re-
nal BLM vesicles from the same animals, have correlated
the protein expression of some OC transporters and the
rates of OC secretion (34, reviewed in (15)). The data
have shown that: (a) M rats and mice exhibit higher rate
of OC tetraethylammonium (TEA) clearance than the F
animals, (b) in rodents, tissue slices from the M kidneys
exhibit higher accumulation of TEA than the slices from
the F kidneys, (c) in BLM vesicles isolated from the rat
kidneys, TEA uptake in the vesicles from M kidneys is
greater than in the vesicles from F kidneys, (d) gonade-
ctomy of M rodents downregulates, the treatment of
these animals with testosterone strongly upregulates, whe-
reas the treatment with estradiol slightly downregulates
the renal expression of Oct2 protein and the accumula-
tion of TEA in kidney tissue slices. These data thus indi-
cate the major role of androgens in regulating the Oct2-
-mediated OC secretion in rodents. An important role of
this transporter for OC secretion in the mouse kidneys
can be further demonstrated in the animals defficient
(knock-out) in Oct1 and Oct2, in which the renal secre-
Period biol, Vol 113, No 1, 2011. 13
Sex and species differences in renal drug transporters I. Saboli} et al.
TABLE 5
Species differences in the rates of OA transport, affinity for OC substrates, inhibitory constant of OC transport, and inhibition
of an OC transport with other OC in various experimental models.
Parameter Experimental model Species differences
Substrate specificity:
Quinidine transport Oct1/OCT1-transfected XO rat –, human +
Na+-L-carnitine cotransport Octn1/OCTN1-transfected cells rat –, mouse +, human +
Relative rate of transport:
TEA uptake Octn2/OCTN2-transfected cells rat > mouse > human
Na+-L-carnitine cotransport Octn2/OCTN2-transfected cells rat < mouse < human
Kmvalue for:
Choline Oct2/OCT2-transfected XO rat > human
TEA (Octn1-mediated) Renal cortical BBMV rat > rabbit
Ki value for:
Inhibition of MPP uptake by n-TAA Oct1/OCT1-transfected XO rat, mouse, rabbit < human
Inhibition of TEA transport by various OC Oct1/OCT1-transfected cells rat < human
Oct2/OCT2-transfected cells rat > human
IC50 value for:
Inhibition of TEA uptake by TBA, TPA, cimetidine guanidine
and famotidine
Oct2/OCT2-transfected cells rabbit < human
Inhibition of TEA uptake by tyramine, carbachol and choline Oct2/OCT2-transfected cells rabbit > human
Inhibition of OC transport with other OC:
Inhibition of L-carnitine transport by TEA and choline Octn2/OCTN2-transfected cells rat > human
Inhibition of TEA transport by cimetidine and rhodamine 123 MATE1-transfected cells mouse > human
Inhibition of TEA transport by quinidine, verapamil, nicotine,
corticosterone, testosterone and quercetin
MATE1-transfected cells mouse < human
Data have been collected from the literature (7, 42, 50–62). XO, Xenopus oocytes; Transfected cells, various kinds of cultured cells
transfected with the indicated OC transporters; BBMV, isolated brush-border membrane vesicles; (-) Absence or (+) presence of trans-
port. Km, Michaelis constant. MPP, 1-methyl-4-phenylpyridinium; n-TAA, n-tetraalkylammonium compounds; TEA, tetraethyl-
ammonium; TBA, tetrabutylammonium.

tion of OA is nearly abolished (35). However, the studies
in isolated PT from the M and F rabbit kidneys have
shown similar uptake of TEA in both sexes, which com-
pares to similar and sex-independent expression of Oct2
protein in their kidneys (30).
Species differences in some OC transporters have also
been demonstrated concerning substrate selectivity and
transport rates, sensitivity to inhibitors, and regulation. A
comparison of kinetic characteristics of various OC trans-
porters from different species have been tested largely
following their expression in Xenopus oocytes and cul-
tured cells. The data collected from the current literature
clearly indicate species differences in many characteris-
tics among the comparable OC transporters in rats, mice,
rabbits and humans. As listed in Table 5, the related OC
transporters in rodents, rabbits and humans differ in sub-
strate specificity, relative transport rate with specific sub-
strates, affinity (Km) for specific substrates, and inhibi-
tion of the transporter activity with various substrates (Ki
and IC50 values, inhibition of the OC transport with
other OCs). Overall, these data indicate that the OC
transporters from each subfamily exhibit species differ-
ences in a variety of kinetic characteristics that may result
in different, species-specific functional performance in
the mammalian kidneys and other organs.
Various aspects of long-term (developmental, hormo-
nal and nutritional regulation, regulation under patolo-
gical conditions) and short-term regulation of OC trans-
port and expression and/or activity of various OC trans-
porters in the mammalian kidneys in vivo and in various
experimental models in vitro, have been recently revie-
wed (33). A set of information that point to species differ-
ences in short-term regulation of the activity of some of
these transporters has been collected from the literature
and summarized in Table 6. Most of these information
have been generated in the cell lines transfected with the
defined animal or human OC transporters, and in some
cases the regulation of their activity (transporter-medi-
ated uptake of an OC) in the cells could be correlated
with the relevant transport in PT segments isolated from
the same species. Thus (Table 6), (a) in the cells trans-
fected with the rat Oct1, activation of protein kinases A
(PKA) and C (PKC) resulted in upregulation of the OC
transport, whereas in the same cell line transfected with
the human OCT1, activation of these enzymes caused
downregulation of the OC transport (in one study the ef-
fect was not observed), (b) in the cells transfected with
the rabbit Oct2, activation of PKA activity caused upre-
gulation of the OC uptake, and the same effect was pres-
ent in the isolated rabbit PT segments, whereas (c) in the
cells transfected with the human OCT2, and in isolated
human PT segments, the activation of both kinases down-
regulated the OC transport. These experiments in vitro
indicate that the short-term regulation of OC transporter
activity in the mammalian kidneys may be species-spe-
cific also in vivo.
CONCLUSION
In rodents, various renal transporters of OA and OC
exhibit sex differences in their protein (and mRNA) ex-
pression and functional characteristics. This phenome-
non may be relevant during life in these animals in con-
ditions that are associated with significant changes in
blood levels of sex hormones (female hormonal cycle/
oestrus in rodents, pregnancy, ageing). When compared
in rats, mice, rabbits and humans, some renal OA and
OC transporters also exhibit species differences in their
presence, expression level, sex-dependence, membrane
domain-specific localization in the cells, various kinetic
characteristics, and regulation. Humans exhibit no sex
differences in the expression of thus far tested OA and
OC transporters, and other characteristics related to the-
14 Period biol, Vol 113, No 1, 2011.
I. Saboli} et al. Sex and species differences in renal drug transporters
TABLE 6
Species differences in short term regulation of the mammalian OC transporters.
Species & Experimental model Transport Effector Effect on transport
Rat
Oct1-transfected HEK-293 cells ASP+uptake PKA activation Increase
PKC activation Increase
Rabbit
Oct2-transfected CHO-K1 cells TEA uptake PKA activation Increase
Isolated PT segments TEA uptake PKA activation Increase
Human
OCT1-transfected HEK-293 cells Amiloride & PKA activation Decrease
ASP+uptake PKC activation Decrease/NE
OCT2-transfected HEK-293 cells Amiloride & PKA activation Decrease
ASP+uptake PKC activation Decrease/NE
Isolated PT segments ASP+uptake PKC activation Decrease
Data have been collected from the literature (33, 63–69). ASP+, fluorescent cationic dye 4-(4-dimethylamino)styryl-N-methylpy-
ridinium; TEA, tetraetylammonium; PT, proximal tubules; PKA, protein kinase A; PKC, protein kinase C; NE, no effect.

se transporters are in many respects different from those
in rodents and rabbits. Although in humans sex differ-
ences in pharmacokinetics have been identified for some
drugs, they are small, and their clinical relevance is mi-
nor (70). Therefore, (a) data on OA and OC transport
and transporters in one species can not simply be re-
garded as relevant for other species, and (b) physiologi-
cal, pharmacological and toxicological data in rats, mice,
and rabbits, that are related to the functions of these
transporters in the kidneys, may not be relevant to the sit-
uation in humans.
Acknowledgement: This work was supported by grant
No. 022-0222148-2146 (Mammalian Renal Transporters;
Gender Differences and Effects of Toxic Metals) from the
Ministry of Science, Education and Sports, Republic of
Croatia (I.S.).
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