MULTIDRUG RESISTANCE PROTEIN: P-GLYCOPROTEIN - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 248

An association was reported between the response of epilepsy patients to drug
treatment and the C3435T polymorphism in the MDR1 gene. 228 Patients with seizures
that were not controlled by drugs were more likely to be homozygous for the C-variant
allele, which is associated with higher Pgp transport function, suggesting that the drugs
have a lower efficiency of penetration across the blood-brain barrier in this group.
However, two later studies failed to confirm these results. 229 , 230 The anti-Parkinson
drug budipine is exported actively out of the brain by Pgp in mice, 231 and Parkinson's
disease susceptibility has been linked to Pgp polymorphisms in Chinese populations,
where a MDR1 haplotype containing the SNPs 2677T and 3435T was found to protect
against the disease. 232
10.18. CONCLUSIONS
P-Glycoprotein is a drug transporter of the ABC superfamily that functions as an
ATP-powered drug efflux pump. Rapid progress has been made in recent years in un-
derstanding the three-dimensional structure and ATP hydrolysis cycle of this protein,
and many tools are now available for its study at the molecular level. Although the
transporter can interact with hundreds of nonpolar, weakly amphipathic compounds
with no apparent structural similarity, progress is being made in developing a pharma-
cophore model to describe its binding regions. The protein appears to interact with its
multiple substrates via a large flexible drug-binding pocket, to which drugs gain access
from the bilayer, leading to the suggestion that it is a “vacuum cleaner” for hydropho-
bic compounds that concentrate within the membrane. The drug transport mechanism
of Pgp remains ill defined and may involve “flipping” of substrates from the inner to
the outer membrane leaflet. The primary physiological role of the protein appears to be
protection of sensitive organs and tissues from xenobiotic toxicity. Many drugs used in
clinical therapy are P-glycoprotein substrates, and the transporter is now increasingly
recognized to play a central role in the absorption and disposition of many drugs, in-
cluding chemotherapeutic agents. Other compounds, known as modulators, that block
the drug efflux function of Pgp are under development and may have clinical applica-
tions in the future. Nucleotide polymorphisms in the Pgp gene that may affect its reg-
ulation and expression have been identified in human populations. The effect of these
variants on drug response and disease susceptibility is an important focus of future
research.
REFERENCES
1. Croop JM. 1993. P-glycoprotein structure and evolutionary homologies. Cytotechnology
12:1-32.
2. Lincke CR, Broeks A, The I, Plasterk RH, Borst P. 1993. The expression of two P-
glycoprotein (pgp) genes in transgenic Caenorhabditis elegans is confined to intestinal
cells. EMBO J 12:1615-1620.
3. Ruetz S, Gros P. 1994. Phosphatidylcholine translocase: a physiological role for the mdr2
gene. Cell 77:1071-1081.