Reactivity of catecholamines and related substances in the mouse lymphoma L5178Y cell assay for mutagens.
Using the L5178Y mouse lymphoma cell thymidine kinase locus and the Salmonella his locus assays, the mutagenic potentials of several catecholamines and related compounds were examined. No supplementary metabolic activation systems were used. In the mouse lymphoma assay, the dihydroxybenzenes catechol and hydroquinone had similar and appreciable mutagenic potentials, whereas resorcinol was less active. Derivatives of catechol, such as dopamine and epinephrine, were mutagenic, whereas the related monohydroxylated compounds tyramine and synephrine were inactive. The primary amine, arterenol, and the corresponding secondary amine, epinephrine, induced similar mutagenic responses. Carboxylation of the side chain of dopamine, giving L-dopa, reduced the maximum mutagenic response. The introduction of charged groups directly on to the aromatic ring also reduced mutagenic activity, while an intervening methylene reversed this effect. Thus, 3,4-dihydroxyhydrocinnamic acid was more active than 3,4-dihydroxybenzoic acid. The compound active at the lowest doses was 4-tert-butyl catechol. The activities of these compounds are highly dependent upon substituent groups. Experiments with superoxide dismutase gave circumstantial evidence for some of the mutagenic activity being due to superoxide anion. Active oxygen species might be responsible for some of the observed effects, but this cannot be concluded from the superoxide dismutase experiments. Mutagenic responses in Salmonella were very low but were significant for L-dopa in three strains and for epinephrine and arterenol in one strain. Limited DNA association studies of 14C-dopamine suggest interactions in L5178Y and Salmonella cells and in mouse liver. The mutagenicity of dopamine in L5178Y is reduced by high serum concentrations during the exposure period, while the apparent association with DNA is unaffected.
McGregor
D B
DB
Department of Mutagenic and Cellular Toxicology, Inveresk Research International Limited, Musselburgh, Scotland.
Riach
C G
CG
Brown
A
A
Edwards
I
I
Reynolds
D
D
West
K
K
Willington
S
S
D000818:Animals; D001555:Benzene Derivatives / Q000494:pharmacology*; D002374:Catalase / Q000378:metabolism; D002395:Catecholamines / Q000494:pharmacology*; D002396:Catechols / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism / Q000494:pharmacology*; D007940:Leukemia L5178 / Q000473:pathology*; D007942:Leukemia, Experimental / Q000473:pathology*; D009152:Mutagenicity Tests; D010636:Phenols / Q000494:pharmacology; D011506:Proteins / Q000378:metabolism; D012486:Salmonella typhimurium / Q000187:drug effects; D013329:Structure-Activity Relationship; D013482:Superoxide Dismutase / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014969:Xanthine Oxidase / Q000378:metabolism
D001555:Benzene Derivatives; D002395:Catecholamines; D002396:Catechols; D010636:Phenols; D011506:Proteins; D013481:Superoxides; D004247:DNA; D002374:Catalase; D013482:Superoxide Dismutase; D014969:Xanthine Oxidase; D004298:Dopamine