title: Dioxathiadiaza-heteropentalenes mediate superoxide and hydrogen peroxide production in Escherichia coli.
abstract: The dioxathiadiaza-heteropentalenes, HEP-I (4,4-dimethyl-1,7-dioxa-2,6-diaza- 7 alpha lambda 4-thia-3H,5H-benzo[cd]pentalene), HEP-II (1,7-dioxa-2, 6-diaza-4, 7 alpha lambda 4-dithia-3H, 5H-benzo[cd]pentalene), HEP-III (1,7-dioxa-2,6-diaza-4, 7 alpha lambda 4-dithia-3H, 5H-benzo[cd]pentalene-4-oxide), and HEP-IV (1,7-dioxa-2,6-diaza-4,7 alpha lambda 4-dithia-3H, 5H-benzo[cd]pentalene-4,4-dioxide), inhibited growth of Escherichia coli in a simple glucose-salt medium, with their toxicities following the order of HEP-IV greater than HEP-III greater than HEP-II greater than HEP-I. These toxicities could be suppressed by yeast extract added to the glucose-salt medium. Yeast extract also facilitated maximal induction of superoxide dismutase (SOD) and catalase. The redox potentials of HEP-I-HEP-IV and the rates of oxygen uptake dependent on heteropentalenes in cyanide-resistant respiration of E. coli were correlated with the induction of SOD and catalase. Thus, the higher the redox potential of the compounds, the more potent they were for induction of enzyme production. Under anaerobic conditions, HEP-IV did not inhibit E. coli growth. These results indicate that HEP-I-HEP-IV can be reduced within the cell of E. coli and then reoxidized by molecular oxygen, generating O2- and H2O2. The toxicities of the heteropentalenes depend largely upon superoxide and/or hydrogen peroxide toxicity, and SOD and catalase provide a defense against the potential cytotoxicity of these species.
authors.affiliation: Faculty of Pharmaceutical Sciences, University of Tokyo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Takahashi
authors.forename: T
authors.initials: T
authors.lastname: Nagano
authors.forename: M
authors.initials: M
authors.lastname: Hirobe
mesh_terms: D000332:Aerobiosis; D000693:Anaerobiosis; D001386:Azides / Q000494:pharmacology*; D003517:Cyclopentanes / Q000494:pharmacology*; D004790:Enzyme Induction; D004926:Escherichia coli / Q000187:drug effects / Q000254:growth & development* / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism*; D007700:Kinetics; D013329:Structure-Activity Relationship; D013482:Superoxide Dismutase / Q000096:biosynthesis; D013481:Superoxides / Q000378:metabolism*
chemical_list: D001386:Azides; D003517:Cyclopentanes; D013481:Superoxides; C058188:4,4-dimethyl-1,7-dioxa-2,6-diaza-7a-thia-3H,5H-benzo(cd)pentalene; C058189:1,7-dioxa-2,6-diaza-4,7a-dithia-3H,5H-benzo(cd)pentalene; C058190:1,7-(dioxa)-2,6-diaza-4,7a-dithia-3H,5H-benzo(cd)pentalene-4-oxide; C058191:1,7-dioxa-2,6-diaza-4,4-dioxide-4,7a-dithia-3H,5H-benzo(cd)pentalene; D006861:Hydrogen Peroxide; D013482:Superoxide Dismutase