Macromolecular binding of the thyroid carcinogen 3-amino-1,2,4-triazole (amitrole) catalyzed by prostaglandin H synthase, lactoperoxidase and thyroid peroxidase.
3-Amino-1,2,4-triazole, a thyroid carcinogen and goitrogen, is negative in a wide variety of short-term mutagenicity assays. However, amitrole induces gene mutations and morphological transformation in Syrian hamster embryo fibroblasts, cells known to carry out the prostaglandin H synthase (PHS)-mediated peroxidative metabolism of other carcinogens. Therefore, we have investigated the peroxidase-mediated binding of [14C]amitrole to macromolecules in vitro. We report here the PHS- and lactoperoxidase-catalyzed binding of [14C]amitrole to protein and tRNA, as well as protein binding by rat and hog thyroid peroxidase. PHS was an order of magnitude more active than lactoperoxidase and two orders of magnitude more active than thyroid peroxidase. The low levels of binding observed with thyroid peroxidase could be explained by the rapid and potent inhibition of this enzyme by amitrole. Although the thyroid peroxidase-mediated binding of amitrole was quite low, it was not inhibitable by compounds that would be expected to be competing substrates in vivo (i.e. I-, monoiodotyrosine, diiodotyrosine). Neither catalase nor horseradish peroxidase catalyzed binding of [14C]amitrole. It was also observed that an interaction between amitrole and protein and/or nucleic acid resulted in the slow generation of hydrogen peroxide, which then served as a substrate to drive peroxidase-mediated binding of [14C]amitrole. These data suggest that PHS may be responsible for conversion of amitrole to a mutagenic intermediate in Syrian hamster embryo cells. Furthermore, the generation of reactive metabolites of amitrole by thyroid peroxidase and/or PHS may contribute to the complete carcinogenicity of this compound by adding a mutagenic response to its potent hormonal effects.
D000640:Amitrole / Q000378:metabolism*; D000818:Animals; D002374:Catalase / Q000494:pharmacology; D006735:Horseradish Peroxidase / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000378:metabolism; D007453:Iodide Peroxidase / Q000494:pharmacology*; D007784:Lactoperoxidase / Q000494:pharmacology*; D010544:Peroxidases / Q000494:pharmacology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000494:pharmacology*; D011485:Protein Binding; D012343:RNA, Transfer / Q000378:metabolism; D051381:Rats; D013552:Swine; D014230:Triazoles / Q000378:metabolism*
D014230:Triazoles; D012343:RNA, Transfer; D006861:Hydrogen Peroxide; D006735:Horseradish Peroxidase; D007784:Lactoperoxidase; D010544:Peroxidases; D002374:Catalase; D007453:Iodide Peroxidase; D011451:Prostaglandin-Endoperoxide Synthases; D000640:Amitrole