TY - JOUR
T1 - Pretreatment with valproic acid, a histone deacetylase inhibitor, enhances the sensitivity of the peripheral blood micronucleus assay in rodents
AU - Ahmad, T.
AU - Shekh, K.
AU - Khan, S.
AU - Vikram, A.
AU - Yadav, L.
AU - Parekh, C. V.
AU - Jena, G. B.
N1 - Funding Information:
This work was funded by The National Institute of Pharmaceutical Education and Research (NIPER) , S.A.S. Nagar, Mohali, Punjab 160062, India. The authors are grateful to Aurobindo Pharma Ltd. (Andhra Pradesh, India) for providing the generous gift sample of zidovudine. The authors would also like to thank the anonymous reviewers as well as the editor for their critical comments and suggestions to improve the interpretation of our findings and clarity in presentation. We also thank Ms. Priyanka P. Trivedi for the language correction of the manuscript.
PY - 2013/2/18
Y1 - 2013/2/18
N2 - Micronucleus (MN) assay is widely used for the determination of the genotoxic potential of new chemical entities. Improvement in the sensitivity of MN assay will be advantageous for the successful detection of marginally active genotoxins. In the past, several improvements have been made in the automated scoring of micronuclei, while very few attempts have been taken to improve the sensitivity of manual micronuclei detection. The present study aims to validate the effect of valproic acid (VPA) pretreatment on the sensitivity of peripheral blood micronucleus (PBMN) assay using cyclophosphamide (CP, 50. mg/kg), methotrexate (MTX, 20. mg/kg) and zidovudine (AZT, 400. mg/kg) in rodents. However, to find out the optimum VPA pretreatment time as well as to detect the effect of species and age difference, separate experiments were conducted on young Swiss albino mice (24-28 days) and Sprague-Dawley rats (21-24 days), in which significant increase in MN induction was observed with 3-day VPA pretreatment in both the species. Based on these results, studies on adult mice were conducted with 3-day VPA pretreatment along with CP or MTX or AZT. The results of the present study clearly demonstrate that the 3-day VPA pretreatment significantly enhances the sensitivity of PBMN assay in peripheral blood (PB) in adult mice. After validation with other standard genotoxins as well as other HDAC (histone deacetylase) inhibitors, this model may be useful for the detection of marginally active DNA damaging agents.
AB - Micronucleus (MN) assay is widely used for the determination of the genotoxic potential of new chemical entities. Improvement in the sensitivity of MN assay will be advantageous for the successful detection of marginally active genotoxins. In the past, several improvements have been made in the automated scoring of micronuclei, while very few attempts have been taken to improve the sensitivity of manual micronuclei detection. The present study aims to validate the effect of valproic acid (VPA) pretreatment on the sensitivity of peripheral blood micronucleus (PBMN) assay using cyclophosphamide (CP, 50. mg/kg), methotrexate (MTX, 20. mg/kg) and zidovudine (AZT, 400. mg/kg) in rodents. However, to find out the optimum VPA pretreatment time as well as to detect the effect of species and age difference, separate experiments were conducted on young Swiss albino mice (24-28 days) and Sprague-Dawley rats (21-24 days), in which significant increase in MN induction was observed with 3-day VPA pretreatment in both the species. Based on these results, studies on adult mice were conducted with 3-day VPA pretreatment along with CP or MTX or AZT. The results of the present study clearly demonstrate that the 3-day VPA pretreatment significantly enhances the sensitivity of PBMN assay in peripheral blood (PB) in adult mice. After validation with other standard genotoxins as well as other HDAC (histone deacetylase) inhibitors, this model may be useful for the detection of marginally active DNA damaging agents.
KW - Cyclophosphamide
KW - Methotrexate
KW - Micronuclei
KW - Valproic acid
KW - Zidovudine
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U2 - 10.1016/j.mrgentox.2012.10.009
DO - 10.1016/j.mrgentox.2012.10.009
M3 - Article
C2 - 23142536
AN - SCOPUS:84873472536
SN - 1383-5718
VL - 751
SP - 19
EP - 26
JO - Mutation Research - Genetic Toxicology and Environmental Mutagenesis
JF - Mutation Research - Genetic Toxicology and Environmental Mutagenesis
IS - 1
ER -