DRUG TRANSPORT IN THE LIVER - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 367

13.3.2. Basolateral Efflux Transport Proteins

Members of the ATP-dependent MRP subfamily represent a major class of export
proteins on the hepatic basolateral membrane. MRP 1, 3, 4, 5, and 6 are involved
in cellular transport of both hydrophobic uncharged molecules and hydrophilic an-
ionic compounds (see Table 13.2). 33 MRP1 ( ABCC1 ) is responsible for efflux of
various organic anions, including glucuronide, glutathione, and sulfate-conjugated
drugs. MRP1 expression is very low on the basolateral membrane in healthy liver, but
is highly inducible during severe liver injury; MRP1 induction is believed to play a
role in liver protection. 306 MRP3 ( ABCC3 ) is involved in the hepatic excretion of glu-
curonide conjugates (e.g., acetaminophen glucuronide), methotrexate, and estradiol-
17 -glucuronide (E 2 17G). The expression level of MRP3 is increased markedly under

cholestatic conditions. 34 MRP4 ( ABCC4 ) and MRP5 ( ABCC5 ) transport the cyclic
nucleotides cAMP and cGMP as well as the purine analogs 6-mercaptopurine and
6-thioguanine. 35 MRP4 has been implicated in transport of nucleoside analogs such
as zidovudine, lamivudine, and stavudine as well as nonnucleotide substrates (e.g.,
methotrexate) and reverse transcriptase inhibitors (e.g., azidothymidine). MRP4 is
also involved in the transport of sulfate conjugates of bile acids and steroids. 36 While
the expression level of MRP5 in healthy liver is relatively low, lipopolysaccharide
(LPS) treatment resulted in down-regulation of MRP2 and induction of MRP5, sug-
gesting that MRP5 may participate in hepatic response during cholestasis. 37 MRP6
transports glutathione conjugates and the endothelin receptor antagonist BQ-123. 307
Mutations in ABCC6 cause pseudoxanthoma elasticum (PXE), an inheritable systemic
connective tissue disorder affecting the skin, eyes, and blood vessels. 39
In addition to the MRPs, other transport proteins on the basolateral membrane
may play a role in hepatic basolateral excretion. For example, the OATPs have been
hypothesized to function as basolateral export proteins under certain conditions, al-
though the in vivo role of these transport proteins in basolateral hepatic excretion
remains to be elucidated. 308

13.4. INTRACELLULAR TRAFFICKING OF HEPATIC PROTEINS
AND XENOBIOTICS

As discussed above, transport proteins residing on the basolateral and apical mem-
branes of the hepatocyte play an important role in the uptake and excretion of en-
dogenous and exogenous compounds. Research to date has focused primarily on
characterizing these transport proteins on a functional basis. The mechanism(s) in-
volved in the targeted trafficking of these proteins to the correct plasma membrane
domain and the regulation of transport protein trafficking represent areas of ongo-
ing investigation. Membrane transport regulation may be influenced by alterations in
transport function and changes in the number or disposition of transport molecules
in the membrane. Stimulation by an agonist can increase the number of hepatic
transport proteins expressed on the plasma membrane by (1) rapidly recruiting preex-
isting transport proteins located in intracellular stores (short-term modulation), or (2)
synthesis of new protein via transcription and translation (long-term modulation). 41