DRUG TRANSPORT IN THE BRAIN - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 433

Both peptide histidine transporter 1 (Pht1, Slc15a4) and peptide histidine trans-
porter 2 (Pht2, Slc15a3) have been cloned from the rat brain cDNA library. 310 , 311
In situ hybridization studies have also revealed Pht1 localization in several regions
of the rat brain, including the hippocampus, cerebellum, and pontine nucleus, and
in lower levels of the cerebral cortex, brain stem, thalamus, and hypothalamus. 310
When expressed in Xenopus oocytes, rat Pht1 transports histidine and histidine-
containing dipeptide, carnosine, in a pH-dependent manner and is inhibited by
other di- and tripeptides. 310 On the other hand, in transfected cells, Pht2 acts as
a lysosomal histidine and histidylleucine transporter and may play a role in the
intracellular trafficking of small peptides. 311 Unfortunately, information on tissue
distribution and cellular localization and transport properties of Pht1 and Pht2 is
limited.
14.4. RELEVANCE OF DRUG TRANSPORTERS IN DISEASES
OF THE CNS
The expression of many different drug transport proteins in the brain implies a highly
complex system that regulates the permeation of xenobiotics into the CNS. Many
diseases remain refractory to pharmacotherapy, which may be directly related to the
expression of drug efflux transporters at the brain barriers and in brain parenchyma.
In addition, factors related to the neurological disease and pathological conditions of
the CNS may lead to altered drug transporter functional expression. This suggests
that drug permeation and distribution in the brain during various disease conditions
may be much different than expected. The relationship of drug transport proteins
to the pharmacotherapy of neurological disorders such as brain neoplasia, HIV-1
encephalitis, epilepsy, Alzheimer's disease, and Parkinson's disease is discussed in
the following section.
14.4.1. Brain Neoplasia
Pharmacological treatment of brain cancer is extremely difficult, possibly due to
the limited brain accumulation of chemotherapeutic agents. Many tumors, especially
those of neuroepithelial origin (i.e., involving astrocytes, oligodendrocytes, ependy-
mal cells, and the choroid plexus), have been shown to express drug transporters
known to regulate the cellular accumulation of antineoplastic drugs. Most current re-
search has focused on the expression and functional activity of ABC superfamily drug
efflux transporters in tumor cells and the consequent development of MDR. Tumor
cells rapidly develop MDR, which may be either intrinsic or acquired. Intrinsic (also
known as de novo) resistance is present prior to chemotherapy exposure and leads to
initial treatment failure. Resistance developed during the course of chemotherapy is
known as acquired MDR , and these patients often display disease progression even
though initially, they responded to treatment. 95 Several lines of evidence support the
expression of ABC transporters in brain tumors, although the relationship of trans-
porter expression to tumor grade and cellular origin remains unclear. Pgp expression