Biomedical Engineering Reference
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male-specific expression of rat Cyp2c11 and female-specific Cyp2c12, respectively.
78
GH-secretion pattern in male mice is similar to that in male rats.
79
In female mice, GH
is secreted at regular intervals with a nondetectable baseline between pulses, however,
the pulses are more frequent (1 to 1.5 hours) than those in male mice (2.5 hours).
79
The
GH-secretory pattern in male mice is responsible for induction of male-predominant
Cyp2d9 and repression of female-predominant Cyp2a4 in liver.
80
,
81
Several animal models are used to investigate the effects of hormones on gene
expression. Hypophysectomy (HPX) is surgical removal of the pituitary, which oblit-
erates the production of several hormones, including luteinizing hormone, follicle-
stimulating hormone, adrenocorticotropic hormone, and prolactin. Gonadectomy
(GNX) is the surgical removal of testes or ovaries, the organs primarily responsible for
sex hormone production. A mutant mouse model, the lit/lit mouse, has a spontaneous
mutation in the GH-releasing hormone receptor (GHRH-R), which leads to impaired
GH secretion.
82
-
85
Unlike hypophysectomy, the lit/lit mouse model circumvents the
loss of other pituitary hormones and is still responsive to GH therapy.
81
,
86
Table 20.5 indicates the results of experiments in mice to determine whether sex
hormones or the growth-hormone secretory pattern is responsible for the gender differ-
ences in transporters. The three experimental protocols described above were used:
(1) hypophysectomy, followed by testosterone, estrogen, male-pattern growth hor-
mone, or female-pattern growth hormone; (2) gonadectomy, followed by testosterone
or estrogen; and (3) the lit/lit mouse, followed by male- or female-pattern growth
hormone.
Using these experimental designs, the male-predominant expression of Oatp1a1
in mouse livers is due to the stimulatory effect of male-pattern growth hormone (GH)
secretion, whereas the female-predominant expression of Oatp1a4 in mouse livers
is due to the inhibitory effect of male-pattern GH secretion. In contrast, the male-
predominant expression of Oatp1a1 and 3a1 in mouse kidneys appears to be due to
testosterone. The male-predominant expression of Oatp1a1 in liver and kidney of
mice is due to different mechanisms; in liver it is due to male-pattern GH secretion,
whereas in kidney it is testosterone.
87
The female-predominant expression of the bile acid transporter Ntcp in mouse liv-
ers is due to the inhibitory effect of male-pattern GH secretion. The male-predominant
expression of Bcrp in mouse livers appears to be due to the stimulatory effect of
testosterone,
38
whereas the female-predominant expression of Mrp3 in mouse kid-
neys is due to estrogen stimulation.
88
Whereas the gender difference in expression
of all the transporters above appears to be due to one factor, the female-predominant
expression of Mrp4 in kidney of mice appears to be due to inhibitory effects of both
testosterone and male-pattern growth-hormone secretion.
88
20.9. CONCLUSIONS
The data described in this chapter indicate that many of the transporters involved
in transport of chemicals into and out of cells are observed to have age- and
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