Biomedical Engineering Reference
In-Depth Information
5.5.2. Physiological and Pathophysiological Roles
Bilirubin Homeostasis
The liver serves to remove albumin-bound bilirubin from
the circulation for further metabolism through glucuronidation and eventual excre-
tion of conjugates in bile. The uptake of bilirubin from blood into hepatocytes ap-
pears to occur via OATP-mediated facilitated transport. In different experimental sys-
tems, unconjugated and conjugated bilirubin was transported by OATP1B1
96
,
97
and
OATP1B3.
97
It has also been well known that administration of organic anions that are
OATP substrates such as rifampin can cause unconjugated hyperbilirubinemia.
98
,
99
However, there is contradicting evidence to suggest that OATP1B1 alone does not
transport unconjugated bilirubin
100
and that other unrelated proteins are involved in
hepatic bilirubin uptake.
101
In any case, what has become increasingly apparent is the
link between hyperbilirubinemia and
SLCO1B1
genotype. An increased risk (odds
ratio of 3) of neonatal jaundice was observed in newborns carrying the
SLCO1B1
388G genotype but not the 521C gentoype.
102
This result suggests that OATP1B1
variants with the aspartate in codon 130 (388G) are defective in bilirubin uptake in
neonates. However, in adults, higher unconjugated bilirubin levels are observed in
persons with the
SLCO1B1
521C but not the 388G genotype,
103
underscoring that the
effect of
SLCO1B1
genotype is age dependent. In patients with the benign form of
mild unconjugated hyperbilirubinemia, Gilbert's syndrome, there was a greater like-
lihood for carrying either
SLCO1B1
388G or 521C polymorphism.
104
These findings
are consistent with the observation that people with Gilbert's syndrome have a hepatic
organic anion transport defect.
105
Although there seems ample evidence to support a
role for OATPs in bilirubin homeostasis, further research is required to clarify some
of the issues and to determine mechanisms.
Other Physiological Roles
Overall, there is a poor understanding of the physiologi-
cal roles of OATPs. It is only possible to speculate the molecular physiology based on
the respective tissue distributions and the spectrum of endogenous substrates. Hence,
high affinity transport of T
3
and T
4
by OATP1C1 coupled with selective expression
in brain and testes suggests an organ-specific role of this transporter in thyroid hor-
mone physiology.
9
Similarly, a testicular-specific expression OATP6A1, along with
substrate selectivity toward androgen conjugates and thyroid hormones, suggests a
role in male reproductive physiology.
106
For OATP2A1, a transport specificity for
prostaglandins together with broad tissue distribution indicates a role in the autocrine
and paracrine regulation of eicosanoid signaling.
107
Finally, there is compelling ev-
idence to support a role for OATP1B1 and OATP1B3 in bile acid homeostasis and
enterohepatic recirculation based on several clues: direct transcriptional regulation
by FXR
51
and down-regulation in expression during cholestatic disease.
108
Molecular Pathophysiology
The role of OATPs in the pathogenesis of disease has
been considered and requires further study. For instance, OATP1B3 is highly ex-
pressed in certain colon cancers,
55
which draws an intriguing relationship between
bile acids and disease risk and progression with bile acid transport. In breast cancer,
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