In vitro and in vivo evaluation of the antihypertensive drug atenolol in cultured human lymphocytes: effects of long-term therapy.
The genotoxicity of atenolol, a beta-blocker antihypertensive drug, both in vitro and in vivo, was cytogenetically tested for its ability to induce sister chromatid exchange (SCE) and micronuclei (MN) in cultured peripheral lymphocytes. Also, fluorescence in situ hybridization (FISH) with a centromeric probe was performed to determine the origin of the induced MN. The in vivo study was carried out, on the one hand, on four patients under antihypertensive treatment with atenolol and, on the other hand, on four matched control individuals taking an oral dose of atenolol. The in vitro study was performed on the control individuals by adding the drug to the culture medium at a final concentration similar to the levels found in plasma. When a comparison was made, the frequency of SCE did not show significant differences in any case. A statistically significant increase in the frequency of MN was detected in patients but not in control individuals either in vitro or in vivo. FISH analysis revealed statistically significant differences between patients and control individuals without the drug with respect to the frequency of centromeric signals in MN. Taking all these observations together, our data suggest that chronic exposure to atenolol resulted mainly in the induction of chromosome loss, so an aneugenic activity could be predicted. Different sensitivity to the compound was observed among control individuals. Nevertheless, all of them responded to the presence of atenolol in the same way in both assays. Interindividual variability was also reported. The intervariability seen in patients suggested an adaptive response to the chemical after long-term therapy.
Télez
M
M
Departamento Biología Animal y Genética, Facultad de Ciencias, Universidad del País Vasco, Bilbao, Spain. ggbtesem@lg.ehu.es
Martínez
B
B
Criado
B
B
Lostao
C M
CM
Penagarikano
O
O
Ortega
B
B
Flores
P
P
Ortiz-Lastra
E
E
Alonso
R M
RM
Jiménez
R M
RM
Arrieta
I
I
D000959:Antihypertensive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001262:Atenolol / Q000494:pharmacology* / Q000627:therapeutic use; D002478:Cells, Cultured; D002503:Centromere / Q000187:drug effects / Q000235:genetics; D006801:Humans; D006973:Hypertension / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D017404:In Situ Hybridization, Fluorescence; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects*; D015162:Micronucleus Tests; D009153:Mutagens; D012016:Reference Values; D012854:Sister Chromatid Exchange / Q000187:drug effects*
D000959:Antihypertensive Agents; D009153:Mutagens; D001262:Atenolol