P-glycoprotein (Mdr1a/1b) and breast cancer resistance protein (Bcrp) decrease the uptake of hydrophobic alkyl triphenylphosphonium cations by the brain.

TitleP-glycoprotein (Mdr1a/1b) and breast cancer resistance protein (Bcrp) decrease the uptake of hydrophobic alkyl triphenylphosphonium cations by the brain.
Publication TypeJournal Article
Year of Publication2013
AuthorsPorteous, CM, Menon, DK, Aigbirhio, FI, Smith, RAJ, Murphy, MP
JournalBiochim Biophys Acta
Volume1830
Issue6
Pagination3458-65
Date Published2013 Jun
ISSN0006-3002
KeywordsAnimals, ATP Binding Cassette Transporter, Subfamily B, ATP Binding Cassette Transporter, Subfamily G, Member 2, ATP-Binding Cassette Transporters, Blood-Brain Barrier, Heterocyclic Compounds, Liver, Mice, Mice, Knockout, Mitochondrial Diseases, Nerve Tissue Proteins, Organophosphorus Compounds, Organoselenium Compounds
Abstract

BACKGROUND: Mitochondrial dysfunction contributes to degenerative neurological disorders, consequently there is a need for mitochondria-targeted therapies that are effective within the brain. One approach to deliver pharmacophores is by conjugation to the lipophilic triphenylphosphonium (TPP) cation that accumulates in mitochondria driven by the membrane potential. While this approach has delivered TPP-conjugated compounds to the brain, the amounts taken up are lower than by other organs.METHODS: To discover why uptake of hydrophobic TPP compounds by the brain is relatively poor, we assessed the role of the P-glycoprotein (Mdr1a/b) and breast cancer resistance protein (Bcrp) ATP binding cassette (ABC) transporters, which drive the efflux of lipophilic compounds from the brain thereby restricting the uptake of lipophilic drugs. We used a triple transgenic mouse model lacking two isoforms of P-glycoprotein (Mdr1a/1b) and the Bcrp.RESULTS: There was a significant increase in the uptake into the brain of two hydrophobic TPP compounds, MitoQ and MitoF, in the triple transgenics following intra venous (IV) administration compared to control mice. Greater amounts of the hydrophobic TPP compounds were also retained in the liver of transgenic mice compared to controls. The uptake into the heart, white fat, muscle and kidneys was comparable between the transgenic mice and controls.CONCLUSION: Efflux of hydrophobic TPP compounds by ABC transporters contributes to their lowered uptake into the brain and liver.GENERAL SIGNIFICANCE: These findings suggest that strategies to bypass ABC transporters in the BBB will enhance delivery of mitochondria-targeted antioxidants, probes and pharmacophores to the brain.

DOI10.1016/j.bbagen.2013.02.005
Alternate JournalBiochim. Biophys. Acta
Citation Key10.1016/j.bbagen.2013.02.005
PubMed ID23454352
PubMed Central IDPMC3898886
Grant ListMC_U105663142 / / Medical Research Council / United Kingdom