AGE- AND GENDER-RELATED DIFFERENCES IN XENOBIOTIC TRANSPORTER EXPRESSION - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 607

BRAIN

-2 20 5 0 5 3 0 5 RLU 05 10 15 23 30 45 Ref

− RLU

RLU

70 np

Mdr1a Mdr1b

np

55

Mdr1b Mdr1b

48 np

Ent2 Ent2

np

240

Oatp1a4 Oatp1a4

np

390

Oatp1c1 Oatp1c1

np

89

Mrp4 Mrp4

np

660

Mrp5 Mrp5

FIGURE 20.14. Ontogenic expression of transporters Mdr1a, Mdr1b, Ent2, Mrp4, Mrp5,
Oatp1a4, and Oatp1c1 in the brain of male mice. Previous studies showed that there is no gender
difference in mRNA expression of these transporters in the brain of adult mice. Therefore, the
total RNA from male C57BL/6 mouse brain at each age ( n = 5) was analyzed by the bDNA
method. Data are presented as the ratio of mRNA expression at that age to the highest observed
in the brain. RLU (relative light unit) represents the highest mRNA expression observed in the
brain.

This is not known either. Little is known about the transcription factors that regulate
the basal developmental expression of transporters.
The importance of the transcription factor hepatic nuclear factor 1 alpha (HNF1 )

on the constitutive expression of transporters in liver and kidney has been examined in
HNF1 -null mice. 65 HNF1

is a positive regulatory factor for expression of the Oat
family of transporters in both liver and kidney and most of the Oatp family members
in these two organs. In contrast, HNF1 is a negative regulatory factor for most Mdr

and Mrp transporters in mouse liver and kidney. Very little information is available
on other transcription factors that regulate the constitutive expression of transporters
in adult animals, and essentially nothing is known about the transcription factors
responsible for the development pattern of transporters in newborn animals. This is a
fertile research area.

20.7. GENDER DIFFERENCES IN TRANSPORTER EXPRESSION

Over the years we have learned that there are gender differences in the disposition
of xenobiotics, especially in rodents. Some of these differences are due to gender
variations in expression of phase I and II drug-metabolizing enzymes. However,
gender differences in transporters might be equally important.