Lecture 7

• Transport proteins


  • Membrane-bound — transport molecules across membranes
  • Influx or efflux
  • Classes — ion channels, transporters, aquaporins, pumps
• Transport protein families and superfamilies

  • ABC family — 49 genes in 7 subfamilies
  • SLC superfamily — 65 gene families, 458 human genes
• Role of transport proteins in drug disposition

  1. Absorption — Entry of drugs from gut → blood, Protective role — prevent access of some xenobiotics

  2. Distribution — Entry into target organs and to liver for metabolism

  3. Excretion — Renal + biliary excretion
• ABC transporters


  • Seven subfamilies — A-G
  • Naming = ABC-family letter-gene number
  • Function primarily as efflux transporters — export xenobiotics
• Variants of ABC transporters

  • MDR = Multidrug resistance (ABCB)
  • MRP = Multidrug resistance associated proteins (ABCC)
  • BSEP = Bile Salt Export Pump (ABCB family)
  • BCRP = Breast Cancer Resistance protein (ABCG2)
• Structure of ABC transporters

  • No of TMDs vary — 1-3
  • ATP binding sites = nucleotide binding domains
• ABCB1 (P-glycoprotein; P-gp, MRP1)

  • 28 introns, 28 exons
  • Over 50 SNPs identified
  • Common SNPs — Exon 12 (silent C1236T), Exon 21 (Ala393Ser (G2677T/A)), Exon 26 (Silent C3435T)
  • Common haplotypes — TTC, CGT, CGC
  • Proposed effects — Changes to mRNA protein expression + stability, Changes to transport activity and substrate specificity, Reduced transport capacity → reduced drug efflux
• ABCG2 (Breast Cancer Resistance Protein; BCRP)

  • First detected in breast cancer — most important function is in drug absorption and biliary excretion
  • Physiological role in uric acid excretion — normally limits drug absorption
  • Many SNPs identified
  • Variant 421C>A — High frequencies, Varies with ethnicity, Significant risk factor for gout, Results in aa change: Gln141Lys, Effects — Impaired protein folding + cellular processing, Protein expression reduced by 30-40%, Reduced transport activity — reduced efflux + increased drug absorption
• SLCO1B1 (Organic ion transporter OATP1B)

  • OATP1B1 transports anionic drugs — hydrophilic compounds → liver — reduce systemic availability
  • Many polymorphisms give rise to aa substitutions
  • Variants — Decreased transport (SLCO1B1*5 (Val174Ala)), Increased transport activity (SLCO1B1*14 (Pro155Thr), SLCO1B1*20 (Leu643Phe))
• Glucose-6-phosphate dehydrogenase (G6PDH) pharmacogenetics

  • Produces glutathione (GSH)
  • Low G6PDH + lack of NADPH ⇒ haemolytic anaemia due to low GSH in erythrocytes
  • Genetic defect, Common in African/Mediterranean origin — protective against malaria, Exposure to drug/pro-oxidant xenobiotic → haemolytic anaemia
  • Variants — A- (Asp142Asn and Val68Met), Mahidol (Gly163Ser), Mediterranean (Ser188Phe), Vanua Lava (Leu128Pro), Viangchan (Val291Met), Clinical severity varies — class I(most)-V (mild)
  • Compounds associated with drug-induced haemolysis — Nitrofurantoin, Primaquine, Sulfamethoxazole, Acetanilide, Naphthalene