Biomedical Engineering Reference
In-Depth Information
2.6.2. Oct2 Knockout Mice
Similar to
Oct
-
/
- mice,
Oct2
-
/
- mice were viable and fertile, showing no apparent
1
physiological defects.
67
However, unlike the
Oct
-
/
- mice, pharmacokinetics of
1
intravenous [
14
C]TEA were quite similar in
Oct2
-
- mice and wild-type mice, with
the exception of a slight decrease in distribution of TEA into brain in Oct2-deficient
mice. Renal clearance of TEA in
Oct2
-
/
- mice was not different from that in
wild-type mice, with active secretion being the primary mechanism of clearance. The
explanation for these findings is that in mouse kidney, Oct1 expression is sufficient
to maintain the capacity for active secretion of organic cations even in the absence of
Oct2. Thus, to develop a mouse model of renal disposition of organic cations, it was
necessary to generate an
Oct
/
1
/
2
-
/
- double-knockout mouse.
2.6.3. Oct1/Oct2 Knockout Mice
Generation of
Oct
- double-knockout mice revealed that the absence of both
genes, as with each of the single knockouts, was compatible with normal physi-
ology (i.e., normal viability, fertility, and life span were observed, with no appar-
ent physiological abnormalities).
67
1
/
2
-
/
However, unlike the single knockouts,
Oct
1
/
2
-
- mice show significant impairment in the active tubular secretion of organic
cations in the kidney. Specifically, renal tubular secretion of TEA was effectively
abolished in
Oct
/
- mice, with renal clearance approximating glomerular
filtration. This resulted in significantly elevated plasma levels of TEA in these
mice compared with wild-type or
Oct
1
/
2
-
/
- single-knockout mice. After steady-
state infusion of TEA, plasma levels were elevated approximately sixfold in the
Oct
-
/
1
1
/
2
-
/
- double-knockout mice compared to
Oct
-/-,
Oct2
-/-, or wild-type
1
mice.
2.6.4. Oct3 Knockout Mice
As mentioned earlier, OCT3 is believed to be primarily responsible for the transport
of endogenous monoamines in extraneuronal tissues, also known as the
uptake-2
transport system
. Zwart et al. generated an Oct3-deficient mouse in order to deter-
mine the importance of this transporter in the peripheral disposition of monoamine
neurotransmitters.
68
Although the
Oct3
-
- mice were viable and fertile and showed
no deficiency in dopamine or norepinephrine metabolism, they did show impaired
uptake-2 activity as evidenced by a
/
>
70% reduced uptake of the synthetic monoamine
MPP
+
into heart in
Oct3
-
/
- mice compared to wild-type mice. Additionally, it was
shown that in
Oct3
heterozygous females impregnated in a heterozygous cross,
intravenous injection of MPP
+
+
/
−
resulted in a threefold reduction of MPP
+
uptake in
- embryos versus wild-type embryos, whereas the accumulation of MPP
+
in
the placenta was not different between groups. These results suggest that OCT3 acts
as an uptake transporter for monoamines at the fetoplacental interface. Apart from
the distribution of MPP
+
into heart and placental transfer of MPP
+
, no significant
phenotypic differences have been observed in
Oct3
-
Oct3
-
/
/
- mice.
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