BREAST CANCER RESISTANCE PROTEIN - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 334

by Suzuki et al. are ABCG2 substrates. 89 However, given its high expression in
the syncytiotrophoblast near the apical surface at the chorionic villus, ABCG2 may
help form the barrier between the maternal and fetal circulation systems and thus
protect the fetus from endogenous and exogenous toxins. Jonker et al. investigated
this possibility by exposing Abcb1 -deficient mice to the known ABCG2 substrate
topotecan. 131 When pregnant mice were given topotecan with the ABCG2 inhibitor
GF120918, fetal plasma levels of topotecan were twice as high as that measured in
maternal plasma. ABCG2 expression is relatively higher in human placental tissue
compared to murine indicating that the protein may play an even more important role
in protecting human fetal exposure to endogenous and exogenous toxins present in the
maternal circulation.
12.8.3. Mammary Gland
As opposed to the role that ABCG2 may play in the placenta, and despite the absence of
expression in adult breast epithelial cells, ABCG2 expression in lactating mammary
tissue has been found to concentrate substrates, including toxins, into breast milk.
Jonker et al. reported that ABCG2 expression is strongly induced in the mammary
glands of lactating mice, cows, and humans. 132 Further, levels of the carcinogen and
toxin PhIP, as well as topotecan, were highly concentrated in the milk of Abcg2 wild-
type mice, whereas these substances were not present in the milk of Abcg2 -deficient
mice. In addition, the administration of GF120918 reversed the active secretion of
topotecan into milk in the wild-type mice. By determining high ratios of substance
concentration in breast milk versus maternal plasma, these researchers confirmed that
cimetidine and acyclovir were Abcg2 substrates. This same group later verified the
role of Abcg2 in concentrating potential substrates in breast milk when they found
that the concentrations of heterocyclic amines as well as aflatoxin were over threefold
higher in breast milk than in maternal plasma in lactating wild-type versus Abcg2 -
deficient mice. 133
This functional role in concentrating substrates in lactating mammary epithelium
is in contrast to the low expression level of ABCG2 observed in nonlactating breast
epithelium. It remains unclear why ABCG2 would be induced in the lactating mam-
mary gland and therefore concentrate potential toxins in breast milk, increasing the
potential harm to feeding infants. The physiologic role of an up-regulated ABCG2,
as well as the identification of endogenous substrates that might be conveyed from
mother to infant by this transporter still need to be discovered.
12.8.4. Testis
High expression of ABCG2 has been reported in normal testis tissue as determined
by Northern blot and localized to the Sertoli-Leydig cells by immunohistochemical
analysis. 123 Bart et al. found ABCG2 as well as Pgp expressed in the myoid cell
layer as well as in endothelial cells of the normal testis. 134 These transporters are
expressed on the luminal side of the endothelium as well as the apical side of myoid