ABSTRACT
The neurotoxicity of ziram is largely unknown. In this study, we investigated the direct inhibitions of ziram on rat neurosteroid synthetic and metabolizing enzymes, 5α-reductase 1 (SRD5A1), 3α-hydroxysteroid dehydrogenase (AKR1C14), and retinol dehydrogenase 2 (RDH2). Rat SRD5A1, AKR1C14, and RDH2 were cloned and transiently expressed in COS1 cells, and the effects of ziram on these enzymes were measured. Ziram inhibited rat SRD5A1 and AKR1C14 with IC50 values of 1.556 ± 0.078 and 1.017 ± 0.072 µM, respectively, when 1000 nM steroid substrates were used. Ziram weakly inhibited RDH2 at 100 µM, when androstanediol (1000 nM) was used. Ziram competitively inhibited SRD5A1 and non-competitively inhibited AKR1C14 when steroid substrates were used. Docking study showed that ziram bound to NADPH-binding pocket of AKR1C14. In conclusion, our results demonstrated that ziram inhibited SRD5A1 and AKR1C14 activities, thus possibly interfering with neurosteroid production in rats.
Subject(s)
Aldehyde Reductase/antagonists & inhibitors , Fungicides, Industrial/toxicity , Membrane Proteins/antagonists & inhibitors , Neurotransmitter Agents/biosynthesis , Ziram/toxicity , 3-Oxo-5-alpha-Steroid 4-Dehydrogenase/chemistry , 3-Oxo-5-alpha-Steroid 4-Dehydrogenase/genetics , 3-Oxo-5-alpha-Steroid 4-Dehydrogenase/metabolism , Alcohol Oxidoreductases/antagonists & inhibitors , Alcohol Oxidoreductases/chemistry , Alcohol Oxidoreductases/genetics , Alcohol Oxidoreductases/metabolism , Aldehyde Reductase/chemistry , Aldehyde Reductase/genetics , Aldehyde Reductase/metabolism , Animals , Binding Sites , Binding, Competitive , COS Cells , Chlorocebus aethiops , Fungicides, Industrial/chemistry , Fungicides, Industrial/metabolism , Membrane Proteins/chemistry , Membrane Proteins/genetics , Membrane Proteins/metabolism , Molecular Docking Simulation , Protein Binding , Protein Conformation , Risk Assessment , Structure-Activity Relationship , Transfection , Ziram/chemistry , Ziram/metabolismABSTRACT
In short-term static bioaccumulation experiments with 14C-labelled zinc ethylenebisdithiocarbamate (zineb) and zinc dimethyldithiocarbamate (ziram) both compounds were rapidly disseminated through the tissues. Whole-body accumulation was low, with bioconcentration factors less than 100. Whole-body elimination was rapid with 45% and 25% of the initial radioactivity from ziram and zineb, respectively, being retained by the end of the 16-day depuration period. Pigmented tissues appeared to be major distribution sites as well. This may be related to the affinity of the compounds and/or their degradation products to melanin or to complexation with phenoloxidase, a copper-containing enzyme involved in melanin synthesis. Autoradiography also revealed a high labelling of thyroid follicles. The results show that dithiocarbamates are selectively localized in various tissues, reported to be the target organs for their toxic action. The observed differences in toxicokinetics between zineb and ziram may, in part, explain the differences in toxicity to fish between ethylenebisdithiocarbamates and dialkyldithiocarbamates.
Subject(s)
Salmonidae/metabolism , Thiocarbamates/metabolism , Trout/metabolism , Zineb/metabolism , Ziram/metabolism , Animals , Mathematics , Time Factors , Tissue DistributionABSTRACT
The cytogenetic activity of some substances formed in agricultural plants during metabolism of pesticides of four classes of chemical compounds was studied in the culture of human peripheric blood lymphocytes. Metabolites were shown either to have mutagenic properties similar to those of the initial compounds (ziramtetramethylthiourea, both being mutagens; captan-phthalimide, both possessing no cytogenetic activity) or to be considerably transformed in comparison with them as a result of deactivation (benomile-MBC) or activation (betanal-MHPC) processes. The latter variant if being determined for the genetic hazard of the pesticide necessitates to take into account data on the mutagenic character of those metabolites which really might enter the human organism.