Pulmonary toxicity of acrylonitrile: covalent interaction and effect on replicative and unscheduled DNA synthesis in the lung.
Acrylonitrile (VCN)-induced lung toxicity was studied following a single oral dose (46.5 mg/kg). The mechanism of toxic injury was investigated by assessing the covalent interaction of [2,3-14C]VCN with pulmonary DNA. The effect of the same dose on replicative DNA synthesis and repair in the lungs of treated rats was also investigated. Histologic examination revealed that lungs of VCN-treated animals showed moderate to marked hyperplasia of the Clara cells lining the bronchioles. [14C]Lung tissue uptake was extremely fast, having a maximum at 0.5 h after treatment (150 DPM tissue). Radioactivity in lung tissue declined gradually as a function of time, but was still detected at 72 h after treatment (59 DPM/mg tissue). Covalent binding of [14C]VCN-derived radioactivity to pulmonary DNA was time-dependent, reaching a maximum at 12 h following treatment (61 DPM/mg DNA) and was still detected at 72 h (27 DPM/mg DNA) indicating the incomplete removal of radioactivity covalently bound to DNA. Replicative DNA synthesis in lung tissue was significantly decreased at all time points studied (59, 55 and 72% of control at 0.5, 6 and 24 h, respectively). The DNA repair in the lung was increased by 2-fold at 0.5 h and 1.6-fold at 6 h following VCN oral treatment. The histologic and biochemical results presented in this study provide evidence for the acute genetic toxicity of VCN (and/or its metabolites) in lung tissue following a single oral dose of VCN.
Ahmed
A E
AE
Department of Pathology, University of Texas Medical Branch, Galveston 77555-0605.
Abdel-Aziz
A H
AH
Abdel-Rahman
S Z
SZ
Haque
A K
AK
Nouraldeen
A M
AM
Shouman
S A
SA
D000181:Acrylonitrile / Q000493:pharmacokinetics / Q000633:toxicity*; D000818:Animals; D004247:DNA / Q000096:biosynthesis*; D004260:DNA Repair / Q000187:drug effects*; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
D004247:DNA; D000181:Acrylonitrile