title: Effects on Mycobacterium avium replication in normal human macrophages by deferiprone (L1) and other iron chelators. Possible implications on toxicity.
abstract: Mycobacterium avium growth in cultured human macrophages is influenced by serum lipids, transferrin and iron levels. Iron-saturated transferrin enhances M. avium growth, whereas apotransferrin inhibits mycobacterial replication. The ability of iron chelators to mimic the effects of transferrin on intracellular and extracellular M. avium growth was examined. Smooth, transparent, AIDS patient derived M. avium 7497 scrovar 4 was used to infect 7-day cultured human macrophages. Growth was measured by determining the colony-forming units (CFU) after infected macrophages were lysed 0 to 7 days after infection. The new iron chelating drug deferiprone (1,2-dimethyl-3-hydroxypyrid-4-one or L1, CAS 30652-11-0), 1-ethyl-2-methyl-3-hydroxypyrid-4-one (L1NEt), 1-propyl-2-methyl-3-hydroxypyrid-4-one (L1NPr), 1-allyl-2-methyl-3-hyproxypyrid-4-one (L1NAll), and 3,4-dihydroxycinnamic acid enhanced intracellular and extracellular mycobacterial replication at concentrations of 0.1-2.5 micrograms/ml. 2-Pyridinecarboxaldehyde-2-quinolylhydrazone (PCQH) inhibited intracellular replication from 0.1-1.0 microgram/ml. Most, but not all of the PCQH-induced intracellular inhibition could be eliminated using iron at concentrations greater than 1.0 microgram/ml. Iron also suppressed the effects of PCQH on extracellular M. avium replication. These results indicate that iron chelators may have variable effects at different concentrations and can significantly alter both intracellular and extracellular M. avium replication. It is suggested that at low concentrations deferiprone and other aketohydroxypyridine chelators could enhance the growth of M. avium but at high concentrations may function as adjunct therapy with other antimicrobials against infections with M. avium. These findings are important for therapeutic considerations and dose protocol design in relation to the new iron chelating drug deferiprone, which is currently used in thalassaemia and other iron loaded patients, some of whom are suffering from AIDS.
authors.affiliation: Department of Basic Sciences and Oral Research School of University of Colorado Health Sciences Center, Denver, Colorado, USA.
authors.forename: George S
authors.initials: GS
authors.lastname: Douvas
authors.forename: Mary H
authors.initials: MH
authors.lastname: May
authors.forename: Annita
authors.initials: A
authors.lastname: Kolnagou
authors.forename: George J
authors.initials: GJ
authors.lastname: Kontoghiorghes
mesh_terms: D002478:Cells, Cultured; D015169:Colony Count, Microbial; D003470:Culture Media; D000077543:Deferiprone; D006801:Humans; D066298:In Vitro Techniques; D007502:Iron Chelating Agents / Q000494:pharmacology* / Q000633:toxicity; D050356:Lipid Metabolism; D008264:Macrophages / Q000187:drug effects / Q000382:microbiology*; D009162:Mycobacterium avium / Q000187:drug effects / Q000254:growth & development*; D010084:Oxidation-Reduction; D011728:Pyridones / Q000494:pharmacology* / Q000633:toxicity
chemical_list: D003470:Culture Media; D007502:Iron Chelating Agents; D011728:Pyridones; D000077543:Deferiprone