Cyanamide-mediated Inhibition of N-acetyltransferase 1.

摘要: Abstract Cyanamide has been used for decades medical intentions in the treatment of alcoholism and agricultural purposes as a plant growth regulator bud-breaking agent. Its therapeutic effect is mediated by reversible inhibition aldehyde dehydrogenase it was reported to be metabolized vivo mainly via coenzyme A dependent N -acetylation -acetyltransferases. Although described substrate -acetyltransferases (NATs), cyanamide different molecular structure arylamines hydrazines, preferred substrates Therefore, more detailed investigation its interrelations with performed. We analyzed impact on NAT1 activities human monocytes (monocytic THP-1 cells) using classical p -aminobenzoic acid. found that 24 h physiologically relevant concentrations decreased activity significantly. Based this observation we performed additional experiments recombinant NAT2 achieve further insights. In detail significant dose- time-dependent observed 100 1000 μM NAT1*4. However, did not inhibit NAT2*4. Experiments testing provide evidence vitro or NAT2, liver cytosol. Therefore can conclude enzyme (around 50% 25% after 0.5 0.25 mM CA, respectively) based substrate-dependent down-regulation NAT1. Further mechanistic kinetic studies indicated reacts active site cysteine residue NAT1, leading rapid (significant 30 min 2 h 1000 100 μM respectively). Addition reduction agent dithiothreitol (DTT) modify effect, indicating oxidative processes reversed 5 mM DTT are likely involved inhibition. Taken together our results show able most interaction residue. Thereby might modulate detoxification activation arylamines.