title: Menadione kills trophozoites and cysts of Giardia intestinalis.
abstract: Production of reactive oxygen species by redox cycling in the presence of low levels of oxygen has been studied as a possible approach to anti-protozoal chemotherapeutic strategy. Incubation of the diplomonad flagellate Giardia intestinalis with 2-methy-1,4-naphthoquinone (menadione), under anaerobic conditions, gave UV absorption changes characteristic of reduction to menadiol; partial reversal was observed on admitting O(2). Under microaerobic conditions, similar to those on the surface of the jejunal mucosa, trophozoites consumed O(2) rapidly in the presence of menadione; reaction products included singlet O(2) (monitored by single photon counting of O(2)-dependent low-level chemiluminescence) and H(2)O(2) (measured by the formation of Complex I of microperoxidase). Trophozoites became swollen and incapable of regulatory volume control; these irreversible responses led to loss of motility, cessation of flagellar activity and cell death. Comparison of the sensitivities of trophozoites to metronidazole and menadione gave LC(50) values ( microg x ml(-1)) of 1.2 and 0.7, respectively; corresponding values for cysts (measured by in vitro excystation capacities) were >50 and 1.3. Menadione (LD(50) in mice, 0.5 g kg(-1)) is therefore a potentially more useful and general anti-giardial agent than metronidazole, as it is active against cysts as well as trophozoites.
authors.affiliation: Department of Applied Biology, University of Hull, UK.
authors.forename: Timothy
authors.initials: T
authors.lastname: Paget
authors.affiliation: School of Biotechnology and Bio-molecular Sciences, University of New South Wales, Sydney, Australia.
authors.forename: Sarah
authors.initials: S
authors.lastname: Maroulis
authors.affiliation: School of Biotechnology and Bio-molecular Sciences, University of New South Wales, Sydney, Australia.
authors.forename: Andrew
authors.initials: A
authors.lastname: Mitchell
authors.affiliation: School of Biotechnology and Bio-molecular Sciences, University of New South Wales, Sydney, Australia.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Edwards
authors.affiliation: Department of Biology, Northeastern University, Boston, MA 02115, USA.
authors.forename: Edward L
authors.initials: EL
authors.lastname: Jarroll
authors.affiliation: Microbiology Group (BIOSI 1, Main Building), Cardiff University, PO Box 915, Cardiff CF10 3TL, UK.
authors.forename: David
authors.initials: D
authors.lastname: Lloyd
mesh_terms: D000693:Anaerobiosis; D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology*; D016829:Giardia lamblia / Q000187:drug effects* / Q000254:growth & development* / Q000502:physiology; D006861:Hydrogen Peroxide / Q000378:metabolism; D008795:Metronidazole / Q000494:pharmacology; D010100:Oxygen / Q000494:pharmacology; D010101:Oxygen Consumption; D021261:Parasitic Sensitivity Tests; D017382:Reactive Oxygen Species / Q000378:metabolism; D024483:Vitamin K 3 / Q000494:pharmacology*
chemical_list: D000981:Antiprotozoal Agents; D017382:Reactive Oxygen Species; D008795:Metronidazole; D024483:Vitamin K 3; D006861:Hydrogen Peroxide; D010100:Oxygen