Mutagenicity and effect on gap-junctional intercellular communication of 4,4'-methylenebis(2-chloroaniline) and its oxidized metabolites.
Oxidized metabolites of 4,4'-methylenebis(2-chloroaniline) (MBOCA) were tested for direct mutagenicity in a Salmonella typhimurium assay and for effects on gap-junctional communication of WB-F344 rat liver cells. The mutagenicities of the N-hydroxy, mononitroso and o-hydroxy (ring) metabolites of MBOCA were assayed without adding activating enzyme systems, using the frame-shift sensitive strain TA98 and the base pair substitution sensitive strain TA100. The mutagenicity of the hydroxylamine was demonstrated by a linear increase in the formation of mutant colonies in both strains, with a formation of two revertants/nmol by TA98 and 21 revertants/nmol by TA100. The mononitroso metabolite showed a slight positive effect on TA100, but effects were masked by its cytotoxicity towards this strain. This metabolite was neither mutagenic nor cytotoxic to TA98. The o-hydroxy and the dinitroso metabolites were negative for mutagenicity at concentrations up to 50 and 500 micrograms/plate, respectively. The effects of parent MBOCA and N-hydroxy, mononitroso and o-hydroxy metabolites on cell-cell communication were determined by a scrape loading/fluorescent dye transfer technique. Cytotoxicity was assessed by determination of colony-forming efficiency and lactate dehydrogenase release. MBOCA itself caused an inhibition of dye transfer at concentrations of 7.5, 11.3 and 15 nmol/ml, whereas measures of cytotoxicity were not seen until 15 and 30 nmol/ml for LDH release and plating efficiency, respectively. None of the oxidized metabolites were active in inhibiting dye transfer at non-cytotoxic concentrations.
Kuslikis
B I
BI
Department of Pharmacology and Toxicology, Michigan State University, East Lansing 48824.
Trosko
J E
JE
Braselton
W E
WE
D000818:Animals; D002450:Cell Communication / Q000187:drug effects*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003114:Colony-Forming Units Assay; D007365:Intercellular Junctions / Q000187:drug effects*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008099:Liver / Q000166:cytology; D008753:Methylenebis(chloroaniline) / Q000378:metabolism / Q000633:toxicity*; D009152:Mutagenicity Tests; D009154:Mutation; D010084:Oxidation-Reduction; D051381:Rats; D011919:Rats, Inbred Strains; D012475:Salmonella / Q000235:genetics
D008753:Methylenebis(chloroaniline); D007770:L-Lactate Dehydrogenase