Protection by disulfiram and diethyldithiocarbamate against hypoxia-induced lethality in mice.
The effects of disulfiram (DS) and its major metabolite, diethyldithiocarbamate (DEDC), on the survival time under normobaric and hypobaric hypoxia were examined in mice. At an ambient temperature of 24 degrees C, DS at 0.5-3.0 mmol/kg (i.p.) caused a marked dose-dependent prolongation of the survival time in mice subjected to both types of hypoxia. DEDC also prolonged the survival time, but the effect was less at its higher doses with decreased brain superoxide dismutase. The maximum effects of DS and DEDC were found at 3 hr and 1 hr after injection, respectively. Of the metabolites of DEDC, the copper complex with DEDC caused a significant effect, whereas neither diethylamine nor carbon disulfide did. Furthermore, DS, DEDC and copper complex caused marked hypothermia, and the time course changes of hypothermia by DS and DEDC closely paralleled those of the degree of anti-hypoxic effects, respectively. At an ambient temperature of 36 degrees C, in which the body temperature was maintained near the normal level, both DS and DEDC still exhibited a weak anti-hypoxic effect. These results suggest that DEDC itself, formed as a metabolite of DS, and partly the copper complex produced the anti-hypoxic effect, which could not be explained by concomitant hypothermia alone.
Masukawa
T
T
Department of Clinical Biochemistry, Faculty of Pharmaceutical Sciences, Setsunan University, Osaka, Japan.
Nakanishi
K
K
D000704:Analysis of Variance; D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D001921:Brain / Q000201:enzymology; D003300:Copper; D004221:Disulfiram / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D004050:Ditiocarb / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D000860:Hypoxia / Q000188:drug therapy* / Q000401:mortality; D007274:Injections, Intraperitoneal; D051379:Mice; D009942:Organometallic Compounds / Q000494:pharmacology; D013482:Superoxide Dismutase / Q000378:metabolism; D015996:Survival Rate; D013696:Temperature
D009942:Organometallic Compounds; C067982:bis(N,N-diethyldithiocarbamate)Cu (II) complex; D003300:Copper; D004050:Ditiocarb; D013482:Superoxide Dismutase; D004221:Disulfiram