Journal
CHEMICAL RESEARCH IN TOXICOLOGY
Volume 30, Issue 2, Pages 574-582Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.chemrestox.6b00301
Keywords
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Funding
- Jacobs School of Medicine and Biomedical Science funds
- USPHS [R21 ES023684]
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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 in silico. Carbaryl and carbofuran then were tested for competition with 2-[I-125]-iodomelatonin (300 pM) binding to hMT(1), or hMT(2) receptors stably expressed in CHO cells. Carbaryl and carbofuran showed higher affinity for competition with 2-[I-125]-iodomelatonin binding to the hMT2 compared to the hMT(1) melatonin receptor (33 and 3S-fold difference, respectively) as predicted by the molecular modeling. In the presence of GTP (100 mu M), which decouples the G-protein linked receptors to modulate signaling, the apparent efficacy of carbaryl and carbofuran for 2-[I-125]-iodomelatonin binding for the hMT(1) melatonin receptor was not affected but significantly decreased for the hMT(2) 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.
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