PERIODICUM BIOLOGORUM UDC 57:61

VOL. 113, No 1, 7–16, 2011 CODEN PDBIAD

ISSN 0031-5362

Leading article

Are mice, rats, and rabbits good models for

physiological, pharmacological and toxicological
studies in humans?

Abstract
IVAN SABOLI]
DAVORKA BRELJAK In the mammalian kidneys, handling of various organic compounds is
MARIJA LJUBOJEVI] mediated by multispecific organic anion and cation transporters localized
HRVOJE BRZICA in the luminal and contraluminal cell membrane domains of specific
nephron segments, largely in proximal tubules. These transporters are re-
Unit of Molecular Toxicology
Institute for Medical Research and sponsible for cellular uptake and/or elimination of endogenous and xeno-
Occupational Health, Ksaverska cesta 2, biotic organic compounds, including various anionic and cationic drugs,
10001 Zagreb, Croatia thus contributing to their reabsorption and/or secretion along the nephron.
Recent studies have indicated a pivotal role of these transporters in drug re-
Correspondence:
Ivan Saboli}
sistance, drug-drug interactions, and drug-induced nephrotoxicity, whereas
Unit of Molecular Toxicology the presence of disfunctional transporters due to truncated isoforms or point
Institute for Medical Research and mutations can cause genetic diseases. In rat, mouse and rabbit nephrons, a
Occupational Health, Ksaverska cesta 2, number of these transporters exhibit sex differences in their protein and/or
10001 Zagreb,Croatia mRNA expression. In comparison with the expression in rodents and rab-
E-mail: [email protected] bits, in the human nephrons some transporters are absent, some exhibit dif-
Abbreviations: ferent localization in the cell membrane domains, and none exhibit the
BBM – brush-border membrane sex-dependent expression. Species differences in some transporters have been
BLM – basolateral membrane further demonstrated concerning substrate selectivity, distribution in cells
PT – proximal tubules along the nephron, levels of mRNA and/or protein expression, sensitivity to
OA – organic anions inhibitors, and regulation. Overall these differences in the mammalian kid-
OC – organic cations
neys indicate that: a) data on the membrane transporters-related functions
Key words: experimental animals, in one species can not simply be regarded as relevant for other species, and b)
gender differences, mammalian kidney, many physiological, pharmacological, and toxicological findings related to
nephrotoxicity, organic anions, organic organic anion and cation transport and transporters in rodents and rabbits
cations, proximal tubule do not reflect the situation in humans.

INTRODUCTION

A lthough 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
Received February 21, 2011. toxicological studies, especially when testing drugs, mice and rats are
the most common animals used. The 3R-alternatives (Reduction, Re-
I. Saboli} et al. Sex and species differences in renal drug transporters

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

8 Period biol, Vol 113, No 1, 2011.

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.

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I. Saboli} et al. Sex and species differences in renal drug transporters

bers of the ATP-binding casette (Abc in animals/ABC in etc...), which operate as anion exchangers (23), whereas
humans) family of transporters (23, 24). The number of the ATP-driven efflux pumps Mrp1, 3, 5, and 6, and
newly discovered, cloned, and characterized transporters Mrp2 and 4 belong to the subfamily Abcc/ABCC (24).
from both families increases every year. In the nephron, Recent studies have shown that in the rodent and rabbit
these transporters mediate: a) transport (net secretion) of kidneys, some members of both transporter families ex-
various endogenous organic compounds that are gener- hibit species and/or sex differences in the expression of
ated in normal metabolism in the kidneys and other or- mRNA and/or protein, and in their localization along
gans, b) transport (net secretion) of exogenous (xenobio- the nephron, and that these differences influence secre-
tic) organic compounds that enter the body for iatrogen tory functions of the organ. These differences are related
(medicaments/drugs) or alimentary (food constituents) to the sex hormone-regulated expression of specific trans-
reasons, or as the enviromental toxins, c) drug-drug in- porters in one of the membrane domains of (largely) PT
teractions, d) drug resistance, e) development of drug- cells. From the available data for a limited number of re-
-induced nephrotoxicity, and f) specific genetic diseases, nal OA transporters in rats, mice, rabbits, and humans,
caused by malfunctional transporters due to truncated collected and shown in Table 2, one can conclude the fol-
isoforms or point mutations. The convoluted (S1/S2) lowing: (a) Oat1/OAT1 is always expressed in the PT
and straight (S3) proximal tubule (PT) segments are the BLM, but the male (M)-dominant sex differences in its
principal nephron parts in which handling of OA and expression are present in rats and mice, but not in rabbits
OC takes place. In the PT epithelial cells, the relevant and humans, (b) Oat2/OAT2 in rats and mice is locali-
transporters are differently distributed in the luminal zed to the PT BBM, where it exhibits the female (F)-do-
(brush-border, BBM) and contraluminal (basolateral, minant sex differences; its localization in rabbits is not
BLM) membrane domains. A polar distribution of some, known (at the level of mRNA, M = F), whereas in hu-
well characterized transporters of OA and OC in the rat mans, this transporter is localized to the PT BLM and
PT cells is illustrated in Fig. 1C (OA transporters) and exhibits no sex differences, (c) Oat3/OAT3 in rodents
Fig. 1D (OC transporters). 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 AND SPECIES DIFFERENCES sex-independent in rabbits and humans, (d) OAT4 is the
IN THE EXPRESSION OF RENAL human-specific transporter (not detected in rodents and
ORGANIC ANION TRANSPORTERS
rabbits) in the PT BBM, similarly expressed in M and F,
Majority of the cloned and well-characterized OA (e) Oat5 is the rodent-specific transporter (not present in
transporters belong to the subfamily Slc22/SLC22 (Oat1/ humans) in the PT BBM (and in intracellular organelles
OAT1, Oat2/OAT2, Oat3/OAT3, OAT4, Oat5/OAT5, in mice), with F-dominant expression in both rats and

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 = Fb M=F
PT, BBM PT, BBM ? PT, BLM
Oat3/OAT3 M>F M < Fb M=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.

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Sex and species differences in renal drug transporters I. Saboli} et al.

TABLE 3 ent metabolism of anionic (and other) drugs catalized by

In rats, sex differences in the expression of some renal drug-metabolizing enzymes, not the transporters-medi-
OA transporters correlate well with the excretion of rele- ated active secretion in the renal tubules (3, 15).
vant OA in urine.

Oat Protein Organic anion Urine excretion SEX AND SPECIES DIFFERENCES
Expression IN THE EXPRESSION OF RENAL
Oat1 M>F PAH, Furosemide M>F ORGANIC CATION TRANSPORTERS
Oat2 M<F PFOA M<F A number of OC transporters from different protein
Oat3 M>F PAH, Taurocholate M>F
families and species have been cloned and characterized,
and their functional roles have been studied mainly in
Data have been collected from the available literature and the liver and kidneys (8). The most important OC trans-
from own publications (for references see (15)). M, males; F, porters are grupped into the families Slc22/SLC22 (Oct1/
females; PAH, p-aminohippurate; PFOA, perfluorooctanoic OCT1, Oct2/OCT2, Oct3/OCT3, Octn1/OCTN1, Octn2/
acid. OCTN2), Slc47/SLC47 (MATE1, MATE2, MATE2-
-K), and Abcb/ABCB (Mdr1/MDR1 (P-glycoprotein, P-gp)).
Oct1-3/OCT1-3 represent polyspecific bidirectional trans-
mice, and (f) the expression of Mrp4 in the PT BBM is porters that mediate electrogenic, sodium- and pH-inde-
M-dominant in rats and F-dominant in mice; the data pendent intracellular uptake of OC via facilitated diffu-
for rabbits and humans are not available. A number of sion. In the rat PT, these transporter are predominantly
other renal OATs in adult rats, mice, and in few other localized to the BLM, where they mediate the first step of
species, also exhibit sex differences in their expression at the renal OC excretion. The second, exit step across the
the level of protein and/or mRNA, whereas in prepube- BBM is largely mediated by the electroneutral H+-OC
rtal animals, the expression of thus far tested OA trans- exchangers MATE1 (in rodents, rabbits and humans),
porters was low and sex-independent (15, 25). MATE2 (in mice, not known for rats, not present in rab-
As has been tested in rats, mice and rabbits, the urine bits and humans), and MATE2-K (in rabbits and hu-
excretion of relevant OA correlates well with the renal mans, not present in rats and mice), and by the ATP-
expression of Oats. Thus, sex differences in the renal ex- -driven efflux pump Mdr1/MDR1. Besides in expression
pression of Oat1, Oat2, and Oat3 in adult rats clearly cor- and localization, OC transporters in various species dif-
relate with similar differences in the urine excretion of fer in substrate specificity, inhibitor sensitivity, transport
their substrates (Table 3), whereas in the adult rabbits, in mechanism, and regulation (8, 33).
which the expression of these Oats is similar in both The renal OC transporters have been extensively stu-
sexes, the excretion of relevant OA is also similar (30). died recent years, but most of this research showed their
Furthermore, the prepubertal M and F rats excrete expression at the level of mRNA, whereas only a few
OA with similar and much lower rate than the adults, transporters were described also at the protein level. As
which is in good correlation with the sex-independent listed in Table 4, the mRNA expression of various renal
and much lower expression of renal Oats (for references OC transporters in different species exhibits different
see (15)). In addition, in mice with the knocked-out Oat1 pattern of sex dependency. Thus, in the rat, mouse, rabbit
and Oat3 genes, the urine excretion of p-aminohippurate and human kidneys: (a) mRNA expression of various
(PAH) and a few other OA is strongly impaired (29, 31, OC transporters is species-dependent, but sex differences
32). Since the localization and the level of protein expres- are present only in some cases, (b) expression of both
sion in the cell membrane is one of the major determi- mRNA and protein have been thus far studied and corre-
nants (next to the substrate specificity and kinetic charac- lated only in a few cases, (c) in the Oct/OCT subfamily,
teristics) of the transporter function, the observations in rats and mice express the Oct1 mRNA in similar abun-
humans that: a) none of the indicated transporters shows dance in M and F, whereas the protein is localized to the
sex differences in the expression, b) OAT2 is localized in proximal tubule BLM with (largely) M-dominant ex-
the membrane domain (BLM) which is opposite from pression. However, rabbits do not express the Oct1 mRNA
that in rodents (BBM), and c) OAT4 is present only in and protein at all, whereas in humans, OCT1 is localized
humans, whereas Oat5 is rodent-specific, indicate that to the apical membrane of proximal and distal tubules
the renal handling of OA with the all possible conse- with similar expression in M and F. (d) The expression of
quences, such as interactions and nephrotoxicity of an- renal Oct2/OCT2 in different species has been studied in
ionic drugs, may be in humans different from that in ro- more detail at both mRNA and protein level. The expres-
dents and rabbits. Moreover, different sex-related expres- sion of Oct2 mRNA in rats, mice and rabbits exhibits the
sion of Oat3 in rats, mice, and rabbits, and of Mrp4 in rats M-dominant pattern, but at the protein level this ba-
and mice, indicates that the overall handling and secre- solateral transporter in PT is clearly stronger in M than F
tion of many OA may be different among these species. rats and mice, but sex-independent in rabbits and hu-
The respective transport studies in humans are scarce; mans. (e) In the Octn/OCTN subfamily, the mRNA ex-
only a few of them have shown that the renal clearance of pression of the indicated transporters is either sex-inde-
some drugs and/or their metabolites may be sex-related, pendent or still controversial, whereas the Octn2 protein
but these differences may rather reflect the sex-depend- in rats and mice is localized to the PT BBM. (f) In the

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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, M vs. F

Membrane domain)
Oct1/OCT1 Rat M£F PT, BLM M³F
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 M³F 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.

12 Period biol, Vol 113, No 1, 2011.

Sex and species differences in renal drug transporters I. Saboli} et al.

MATE subfamily, MATE1 in the rat kidney is localized Several in vivo studies in variously-treated rats and
to the PT BBM and M-dominant in both mRNA and mice, and/or in vitro studies in tissue slices or isolated re-
protein expression. Mice exhibit higher expression of nal BLM vesicles from the same animals, have correlated
mRNA in M, but the protein was detected in the apical the protein expression of some OC transporters and the
membrane of various tubule segments with unknown rates of OC secretion (34, reviewed in (15)). The data
levels of expresssion in M and F. MATE1 is present also have shown that: (a) M rats and mice exhibit higher rate
in the rabbit and human kidneys, but in these species the of OC tetraethylammonium (TEA) clearance than the F
levels of MATE1 mRNA and protein expression in M animals, (b) in rodents, tissue slices from the M kidneys
and F has been poorly investigated. However, clear spe- exhibit higher accumulation of TEA than the slices from
cies differences exist in the expression of MATE2, which the F kidneys, (c) in BLM vesicles isolated from the rat
kidneys, TEA uptake in the vesicles from M kidneys is
is present in mice (not clear in rats), but not in rabbits
greater than in the vesicles from F kidneys, (d) gonade-
and humans, and MATE2-K, which is present in rabbits ctomy of M rodents downregulates, the treatment of
and humans, but not in rodents. (g) In the Mdr/MDR these animals with testosterone strongly upregulates, whe-
subfamily, the Mdr1a mRNA expression in the rat kid- reas the treatment with estradiol slightly downregulates
neys is M > F, whereas in mice, the mRNA expression of the renal expression of Oct2 protein and the accumula-
this transporters may be just opposite, e.g., M < F. Whe- tion of TEA in kidney tissue slices. These data thus indi-
re tested, sex hormones responsible for the observed sex cate the major role of androgens in regulating the Oct2-
differences in the expression of mRNA and/or protein of -mediated OC secretion in rodents. An important role of
the specific OC transporters have been defined, whereas this transporter for OC secretion in the mouse kidneys
in prepubertal animals, the expression of both parame- can be further demonstrated in the animals defficient
ters is low and sex-independent (reviewed in (15)). (knock-out) in Oct1 and Oct2, in which the renal secre-

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
Km value 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 Oct2/OCT2-transfected cells rabbit < human
and famotidine
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, MATE1-transfected cells mouse < human
corticosterone, testosterone and quercetin

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.

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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.

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

14 Period biol, Vol 113, No 1, 2011.

Sex and species differences in renal drug transporters I. Saboli} et al.

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