Benzene-induced genotoxicity in mice in vivo detected by the alkaline comet assay: reduction by CYP2E1 inhibition
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Benzene-induced genotoxicity in mice in vivo detected by the alkaline comet assay : reduction by CYP2E1 inhibition. / Tuo, J; Loft, S; Thomsen, M S; Poulsen, H E.
In: Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis, Vol. 368, No. 3-4, 05.07.1996, p. 213-9.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Benzene-induced genotoxicity in mice in vivo detected by the alkaline comet assay
T2 - reduction by CYP2E1 inhibition
AU - Tuo, J
AU - Loft, S
AU - Thomsen, M S
AU - Poulsen, H E
PY - 1996/7/5
Y1 - 1996/7/5
N2 - The myelotoxic and genotoxic effects of benzene have been related to oxidative DNA damage after metabolism by CYP2E1. Single cell gel electrophoresis (alkaline comet assay) detects DNA damage and may thus be a convenient method for the study of benzene genotoxicity. Benzene exposure to NMRI mice as a single oral gavage at 40, 200 or 450 mg/kg resulted in dose-related DNA damage indicated by an increased comet tail length of peripheral blood lymphocytes and bone marrow nucleated cells sampled 6 h after exposure. After a dose of 40 mg/kg, there was a 1.6-fold increase of 'tail length' in bone marrow nucleated cells in comparison with the control (p < 0.01). There was no significant increase in DNA damage in peripheral blood lymphocytes in the same animals. At 200 mg/kg, the tail length was 4.8-fold and 4.0-fold increased in the two cell types, respectively (p < 0.01). At 450 mg/kg, the tail length was further increased to 5.4-fold and 6.6-fold of the control values, respectively (p < 0.01). Pretreatment with propylene glycol (5 microliters/g b.wt., twice with a 60-min interval), a selective CYP2E1 inhibitor, reduced the increase in the tail length by about half at all doses in both cell types (p < 0.01). By comparing our data with those from genotoxicity studies on benzene using other methods, we conclude that the 'alkaline comet assay' is a sensitive method to detect DNA damage induced by benzene. We also infer that CYP2E1 contributes, at least partly, to the formation of the 'comet'-inducing metabolites in the chosen cell types.
AB - The myelotoxic and genotoxic effects of benzene have been related to oxidative DNA damage after metabolism by CYP2E1. Single cell gel electrophoresis (alkaline comet assay) detects DNA damage and may thus be a convenient method for the study of benzene genotoxicity. Benzene exposure to NMRI mice as a single oral gavage at 40, 200 or 450 mg/kg resulted in dose-related DNA damage indicated by an increased comet tail length of peripheral blood lymphocytes and bone marrow nucleated cells sampled 6 h after exposure. After a dose of 40 mg/kg, there was a 1.6-fold increase of 'tail length' in bone marrow nucleated cells in comparison with the control (p < 0.01). There was no significant increase in DNA damage in peripheral blood lymphocytes in the same animals. At 200 mg/kg, the tail length was 4.8-fold and 4.0-fold increased in the two cell types, respectively (p < 0.01). At 450 mg/kg, the tail length was further increased to 5.4-fold and 6.6-fold of the control values, respectively (p < 0.01). Pretreatment with propylene glycol (5 microliters/g b.wt., twice with a 60-min interval), a selective CYP2E1 inhibitor, reduced the increase in the tail length by about half at all doses in both cell types (p < 0.01). By comparing our data with those from genotoxicity studies on benzene using other methods, we conclude that the 'alkaline comet assay' is a sensitive method to detect DNA damage induced by benzene. We also infer that CYP2E1 contributes, at least partly, to the formation of the 'comet'-inducing metabolites in the chosen cell types.
KW - Animals
KW - Benzene
KW - Cytochrome P-450 CYP2E1
KW - Cytochrome P-450 Enzyme Inhibitors
KW - Cytochrome P-450 Enzyme System
KW - DNA
KW - DNA Damage
KW - Male
KW - Mice
KW - Oxidoreductases, N-Demethylating
KW - Propylene Glycol
KW - Propylene Glycols
M3 - Journal article
C2 - 8692227
VL - 368
SP - 213
EP - 219
JO - Mutation Research Letters
JF - Mutation Research Letters
SN - 0027-5107
IS - 3-4
ER -
ID: 156510197