Carbamate Insecticides Target Human Melatonin Receptors

Carbaryl (1-naphthyl methylcarbamate) and carbofuran (2,3-dihydro-2,2-dimethyl-7-benzofuranyl methylcarbamate) are among the most toxic insecticides, implicated in a variety of diseases including diabetes and cancer among others. Using an integrated pharmacoinformatics based screening approach, we have identified these insecticides to be structural mimics of the neurohormone melatonin and were able to bind to the putative melatonin binding sites in MT₁ and MT₂ melatonin receptors <i>in silico</i>. Carbaryl and carbofuran then were tested for competition with 2-[¹²⁵I]-iodomelatonin (300 pM) binding to hMT₁ or hMT₂ receptors stably expressed in CHO cells. Carbaryl and carbofuran showed higher affinity for competition with 2-[¹²⁵I]-iodomelatonin binding to the hMT₂ compared to the hMT₁ melatonin receptor (33 and 35-fold difference, respectively) as predicted by the molecular modeling. In the presence of GTP (100 μM), which decouples the G-protein linked receptors to modulate signaling, the apparent efficacy of carbaryl and carbofuran for 2-[¹²⁵I]-iodomelatonin binding for the hMT₁ melatonin receptor was not affected but significantly decreased for the hMT₂ melatonin receptor compatible with receptor antagonist/inverse agonist and agonist efficacy, respectively. Altogether, our data points to a potentially new mechanism through which carbamate insecticides carbaryl and carbofuran could impact human health by altering the homeostatic balance of key regulatory processes by directly binding to melatonin receptors