BILE ACID TRANSPORTERS - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 206

Mutations in the SLC10A2 gene encoding ASBT have been identified that can
cause primary bile acid malabsorption, a rare disorder of the intestine characterized
by congenital diarrhoea, steatorrhea and reduced plasma cholesterol levels. 38 The
ASBT variants carrying these mutations exhibit severely reduced bile acid transport
activity in vitro.
No mutations in the SLC10A1 gene encoding NTCP leading to clinically manifest
defects in hepatic bile acid uptake have been characterized thus far. However, a
recent study identified ethnicity-dependent single-nucleotide polymorphisms in the
SLC10A1 gene that were associated with a considerable decrease in transport function
in vitro. 39 Thus, genetic heterogeneity in the SLC10A1 gene may play a role in the
etiology of hypercholanemia. Furthermore, certain human diseases, such as advanced
stage primary biliary cirrhosis 40 and cholestatic alcoholic hepatitis, 41 are associated
with reduced NTCP expression. However, this change in NTCP expression may be a
consequence of cholestatic liver injury rather than a cause of it.
9.4. CONTROL OF BILE ACID TRANSPORT AND METABOLISM
In addition to their role as physiological detergents, bile acids possess crucial reg-
ulatory properties which allow them to control their own transport and metabolism
within the enterohepatic circulation through multiple feedforward and feedback mech-
anisms. Hepatocytes and enterocytes possess numerous signaling pathways that are
activated or modulated by bile acids, and ultimately serve to maintain intracellular
concentrations of potentially toxic bile acids at a constant level.
An important mechanism toward controlling bile acid levels within cells is to
adjust the cellular uptake or efflux of bile acids by regulating the expression and/or
activity of uptake and efflux proteins, as discussed in detail below. It should be noted,
however, that additional mechanisms are also operational in preventing intracellular
bile acid concentrations from reaching toxic levels. One such mechanism is to regu-
late the de novo synthesis of bile acids according to the existing intracellular bile acid
content. To reduce bile acid synthesis, the expression levels of the key CYP enzymes
involved in de novo bile acid synthesis (i.e., CYP7A1, CYP8B1, and CYP27A1)
are suppressed. 42 Furthermore, expression levels of several phase II enzymes that in
addition to their role in drug detoxification may convert bile acids into less toxic and
more hydrophilic derivatives are induced in response to elevated levels of bile acids. 43
These metabolizing enzymes include uridine 5 -diphosphate-glucuronosyltransferase
2B4 (UGT2B4) and dehydroepiandrosterone sulfotransferase (SULT2A1).
In this review we focus on the mechanisms that regulate the expression of bile acid
transporters at the transcriptional level. However, it should be remembered that the ac-
tivity of bile acid transporters is also known to be regulated at other levels, particularly
through posttranslational protein modification and protein-protein interactions. 44 , 45
The relative importance of transcriptional and posttranslational events in controlling
bile acid transport activity in either normal physiology or pathophysiology remains
largely unelucidated. Both are likely to be highly important. It seems likely that the
mechanisms involving modification at the protein level could elicit the most rapid