The role of Trypanosoma brucei MRPA in melarsoprol susceptibility

• Published in: Molecular and biochemical parasitology Vol. 146; no. 1; pp. 38 - 44
• Main Authors: Alibu, Vincent P., Richter, Christina, Voncken, Frank, Marti, Gabriela, Shahi, Sanjay, Renggli, Christina Kunz, Seebeck, Thomas, Brun, Reto, Clayton, Christine
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.03.2006
• Subjects: ABC transporter; Animals; Arsenicals - pharmacology; Blotting, Western - methods; Cell Line; Electrophoresis, Polyacrylamide Gel; Female; Gene Expression; Humans; Melarsoprol - chemistry; Melarsoprol - pharmacology; Melarsoprol - therapeutic use; Melarsprol resistance; Membrane Transport Proteins - analysis; Membrane Transport Proteins - biosynthesis; Membrane Transport Proteins - physiology; Mice; Multidrug Resistance-Associated Proteins - analysis; Multidrug Resistance-Associated Proteins - biosynthesis; Multidrug Resistance-Associated Proteins - physiology; Parasitic Sensitivity Tests - methods; Protozoan Proteins - analysis; Protozoan Proteins - biosynthesis; Protozoan Proteins - physiology; Reverse Transcriptase Polymerase Chain Reaction; Treatment Failure; Trypanocidal Agents - chemistry; Trypanocidal Agents - pharmacology; Trypanocidal Agents - therapeutic use; Trypanosoma brucei; Trypanosoma brucei brucei - drug effects; Trypanosoma brucei brucei - genetics; Trypanosoma brucei brucei - metabolism; Trypanosomiasis, African - drug therapy; Trypanosomiasis, African - parasitology; Trypanosoma brucei; Melarsprol resistance; ABC transporter
• ISSN: 0166-6851; 1872-9428
• DOI: 10.1016/j.molbiopara.2005.10.016

We previously showed that over-expression of Trypanosoma brucei MRPA, a member of the multidrug resistance protein family in T. brucei, reproducibly resulted in resistance to the anti-trypanosomal drug melarsoprol in vitro. MRPA is predicted to mediate efflux of melarsoprol as a conjugate with trypanothione, a glutathione–spermidine conjugate which is the major small thiol in trypanosomes. Here, we show that depletion of MRPA by RNA interference resulted in moderate hypersensitivity to both melarsoprol and melarsen oxide. Over-expression of MRPA alone is not sufficient to cause melarsoprol resistance in vivo, although it is sufficient in vitro. This discrepancy is not an effect of drug metabolism since over-expression of MRPA alone conferred resistance to melarsoprol and its principle metabolite, melarsen oxide, in vitro. Over-expression of MRPA was not detected in four melarsoprol-resistant trypanosome isolates from sleeping sickness patients.