Genotoxicity in mouse lymphoma cells of chemicals capable of Michael addition.
Over the past several years, we have been evaluating the mutagenicity and clastogenicity of compounds capable of Michael-type reactions. These compounds, including acrylamide, several acrylate and methacrylate esters, vinyl sulfones, and phorone, have been evaluated using TK+/- -3.7.2C mouse lymphoma cells. Mutagenic chemicals induced increases in the number of small colony tk- deficient mutants. This suggested a clastogenic mechanism which was confirmed by demonstrating increases in aberrations and micronucleus frequencies in cultured cells. Vinyl sulfone was found to be the most effective chemical mutagen with induction of genotoxic effects at concentrations as low as 0.25 microgram/ml. The other compounds also produced positive results, but at higher concentrations. Since these compounds are known to deplete glutathione, phorone, a model glutathione depleter, was examined and found to produce similar effects as the other compounds in mouse lymphoma cells. These results suggest that the direct-acting Michael-type reaction has activity relevant to producing a genotoxic effect. Since acrylamide has been found to be a potent germ cell mutagen, this mechanism may be also relevant in the induction of heritable mutagenic risk.
Dearfield
K L
KL
Health Effects Division, Office of Pesticide Programs, US Environmental Protection Agency, Washington, DC 20460.
Harrington-Brock
K
K
Doerr
C L
CL
Rabinowitz
J R
JR
Moore
M M
MM
D000179:Acrylates / Q000378:metabolism / Q000633:toxicity; D000818:Animals; D001711:Biotransformation; D002452:Cell Count; D007659:Ketones / Q000633:toxicity*; D008223:Lymphoma; D051379:Mice; D009152:Mutagenicity Tests / Q000706:statistics & numerical data; D009153:Mutagens / Q000737:chemistry / Q000633:toxicity*; D013450:Sulfones / Q000633:toxicity*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000179:Acrylates; D007659:Ketones; D009153:Mutagens; D013450:Sulfones; C060916:methyl vinyl sulfone; C009873:divinyl sulfone; C040833:ethyl acrylate; C018637:phorone; C035956:methyl acrylate