Induction of micronuclei in mouse bone-marrow erythrocytes in association with hypothermia after administration of the sigma receptor ligand E-5842.
Oral administration of E-5842, a new sigma1 receptor ligand being developed as an antipsychotic drug, to male mice at single doses of 50, 100, 200 and 400 mg/kg produced marked and sustained decreases in rectal temperature. Both the intensity and the duration of the hypothermic effect increased with dose. Maximum decreases from the mean pre-administration temperature (36.2 degrees C) ranged from 7.5 to 12.9 degrees C for animals receiving 50 and 400 mg/kg doses, respectively. Examination of bone-marrow smears obtained 24, 48 and 72 h after administration revealed a slight but statistically significant (p < 0.05) increase in the frequency of micronucleated polychromatic erythrocytes (MNPCE) at the 48 h sampling for animals receiving the 200 mg/kg dose. These animals showed decreases from pre-administration temperature of approximately 12 degrees C, with recovery being observed 24 h after administration. When the hypothermic effect of E-5842 administration was avoided by housing treated animals under conditions of increased environmental temperature (30 degrees C) for 24 h, MNPCE frequency reverted to vehicle control values. Further, in E-5842-treated animals with an increased MNPCE frequency there was a shift in the distribution of the relative areas of micronuclei in MNPCE towards higher values. In addition, there was a statistically significant increase (p < 0.001) in the number of relatively large micronuclei (micronucleus diameter > or = 1/4 cytoplasm diameter) similar to that produced by administration of the mitotic spindle inhibitor colchicine (1 mg/kg), suggesting disturbance of mitotic apparatus as the possible underlying mechanism. The results suggest that the slight increase in MNPCE frequency observed 48 h after administration of a 200 mg/kg dose of E-5842 is due to a hypothermic effect and not to a direct effect of E-5842 on DNA.
Guzmán
Antonio
A
Department of Toxicology, ESTEVE, Mare de Déu de Montserrat 221, 08041 Barcelona, Spain. aguzman@esteve.es
García
Concepción
C
Marín
Ana-Paz
AP
Ruiz
Maria Teresa
MT
Tortajada
Araceli
A
Fernández de Henestrosa
Antonio R
AR
D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D001854:Bone Marrow Cells / Q000187:drug effects / Q000502:physiology; D003078:Colchicine / Q000494:pharmacology; D003520:Cyclophosphamide / Q000494:pharmacology; D004912:Erythrocytes / Q000187:drug effects / Q000502:physiology; D007035:Hypothermia / Q000139:chemically induced*; D008297:Male; D051379:Mice; D048629:Micronuclei, Chromosome-Defective / Q000139:chemically induced*; D015162:Micronucleus Tests; D015394:Molecular Structure; D009153:Mutagens / Q000494:pharmacology; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology*
C117757:E 5842; D009153:Mutagens; D011725:Pyridines; D014230:Triazoles; D003520:Cyclophosphamide; D003078:Colchicine