Induction of micronuclei in mouse bone-marrow erythrocytes in association with hypothermia after administration of the sigma receptor ligand E-5842.

Abstract

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.

• Authors: Antonio Guzmán, Concepción García, Ana-Paz Marín, Maria Teresa Ruiz, Araceli Tortajada, Antonio R Fernández de Henestrosa
• Journal: Mutation research (Mutat Res) Vol. 565 Issue 1 Pg. 11-22 (Dec 31 2004) ISSN: 0027-5107 [Print] Netherlands
• PMID: 15576235 (Publication Type: Journal Article)

Chemical References

• E 5842
• Mutagens
• Pyridines
• Triazoles
• Cyclophosphamide
• Colchicine

Topics

• Animals
• Body Temperature (drug effects)
• Bone Marrow Cells (drug effects, physiology)
• Colchicine (pharmacology)
• Cyclophosphamide (pharmacology)
• Erythrocytes (drug effects, physiology)
• Hypothermia (chemically induced)
• Male
• Mice
• Micronuclei, Chromosome-Defective (chemically induced)
• Micronucleus Tests
• Molecular Structure
• Mutagens (pharmacology)
• Pyridines (chemistry, pharmacology)
• Triazoles (chemistry, pharmacology)