Mutagenicity of acrylonitrile and its metabolite 2-cyanoethylene oxide in human lymphoblasts in vitro.
The mutagenicity of the rat carcinogen acrylonitrile (ACN) and its metabolite 2-cyanoethylene oxide (CNEtO) was assessed in vitro in human lymphoblasts using the heterozygous thymidine kinase (tk) locus as a genetic marker. ACN was tested in both the presence and absence of an Aroclor-induced rat-liver homogenate S9. In the absence of S9, ACN was not mutagenic over the concentration range tested (0.4-1.5 mM X 2 h). In the presence of S9, the mutagenic response of ACN was enhanced, resulting in a significant response at a concentration of 1.4 mM X 2 h. CNEtO, the proposed ultimate mutagenic metabolite of ACN, induced a significant mutagenic response without activation at 100 microM and 150 microM X 2 h. Two phenotypic classes of spontaneous and CNEtO-induced tk-/- mutants were observed; one class of mutants (tkn) had a normal growth rate relative to wild-type while the second class (tks) grew at a slower rate. The molecular nature of these two phenotypic classes was investigated by Southern blot analysis. CNEtO-induced tkn mutant clones (11/12) and 7/9 tkn spontaneous mutants had no detectable alterations in their tk restriction fragment pattern. In contrast, 25/26 tks mutants analyzed (spontaneous and CNEtO-induced) had lost a 14.8-kb polymorphic fragment of the +tk allele.
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Department of Cellular and Molecular Toxicology, Chemical Industry Institute of Toxicology, Research Triangle Park, NC 27709.
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D000181:Acrylonitrile / Q000494:pharmacology*; D000818:Animals; D001711:Biotransformation; D002478:Cells, Cultured; D005027:Ethylene Oxide / Q000031:analogs & derivatives* / Q000494:pharmacology; D005819:Genetic Markers; D006801:Humans; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D009152:Mutagenicity Tests; D009153:Mutagens / Q000494:pharmacology; D009570:Nitriles / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013937:Thymidine Kinase / Q000235:genetics
D005819:Genetic Markers; D009153:Mutagens; D009570:Nitriles; C033154:2-cyanoethylene oxide; D013937:Thymidine Kinase; D005027:Ethylene Oxide; D000181:Acrylonitrile