title: Uptake of the nitroimidazole drug megazol by African trypanosomes.
abstract: Megazol, CL 64,855 (2-amino-5-[1-methyl-5-nitro-2-imidazolyl]-1,3, 4-thiazole) has been shown to be extremely effective in clearing experimental infections of African trypanosomes. An unusual amino-purine transporter termed P2, implicated in the transport of both the diamidine and melaminophenyl arsenical classes of drug in Trypanosoma brucei, recognised chemical groups on compounds which are also present on megazol. Megazol interacted with this carrier protein, as judged by its ability to inhibit P2 adenosine transport and to abrogate in vitro arsenical-induced lysis in a dose-dependent manner. However, parasites resistant to melaminophenyl arsenical and diamidine drugs due to lack of the P2 transporter showed no resistance to megazol. This is because passive diffusion represented the major route of entry. Initial rates of uptake were not saturable within the limit of megazol's solubility and did not conform to thermodynamic precepts compatible with carrier-mediated uptake. Adenosine and other P2 transporter substrates, even at high concentration, had little impact on megazol uptake. Uptake was biphasic, with a very rapid equilibration across the membrane followed by a slower accumulation over time. The equilibration phase represented a simple passive diffusion, with the subsequent uptake probably being due to metabolism of the drug.
authors.affiliation: Division of Infection of Immunity, Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow, UK. m.barrett@bio.gla.ac.uk
authors.forename: M P
authors.initials: MP
authors.lastname: Barrett
authors.forename: A H
authors.initials: AH
authors.lastname: Fairlamb
authors.forename: B
authors.initials: B
authors.lastname: Rousseau
authors.forename: G
authors.initials: G
authors.lastname: Chauvière
authors.forename: J
authors.initials: J
authors.lastname: Perié
mesh_terms: D000349:Africa; D000818:Animals; D001692:Biological Transport; D004347:Drug Interactions; D004351:Drug Resistance; D009593:Nitroimidazoles / Q000378:metabolism*; D009705:Nucleosides / Q000494:pharmacology; D018048:Receptors, Purinergic P2 / Q000187:drug effects; D013696:Temperature; D013830:Thiadiazoles / Q000378:metabolism*; D013997:Time Factors; D014344:Trypanocidal Agents / Q000378:metabolism*; D014346:Trypanosoma brucei brucei / Q000378:metabolism*; D014353:Trypanosomiasis, African / Q000378:metabolism
chemical_list: D009593:Nitroimidazoles; D009705:Nucleosides; D018048:Receptors, Purinergic P2; D013830:Thiadiazoles; D014344:Trypanocidal Agents; C013378:megazol