Potential Disruption of Systemic Hormone Transport by Tobacco Alkaloids Using Computational Approaches

Area of Science:

• Endocrinology
• Toxicology
• Molecular Biology

Background:

• Tobacco/nicotine is a major public health threat due to its toxicity and addictive nature.
• Nicotine disrupts endocrine homeostasis, affecting gonadal, adrenal, and thyroid hormones.
• Understanding nicotine's interaction with hormone transport is crucial for public health.

Purpose of the Study:

• To characterize the structural binding interactions of nicotine and its metabolites (cotinine, trans-3'-hydroxycotinine, 5'-hydroxycotinine) with key hormone carrier proteins.
• To identify specific amino acid residues involved in these interactions.
• To elucidate the potential impact on hormone transport and homeostasis.

Main Methods:

• Computational analysis of binding interactions between nicotine/metabolites and carrier proteins (SHBG, CBG, TBG).
• Identification of key amino acid residues through analysis of nonbonded contacts and hydrogen bonds.
• Assessment of the impact on accessible surface area (ASA) upon ligand binding.

Main Results:

• Nicotine and its metabolites form nonbonded contacts and hydrogen bonds with SHBG, CBG, and TBG.
• Specific residues like Phe-67 and Met-139 (SHBG), Trp-371 and Asn-264 (CBG), and Ser-23, Leu-269, Lys-270, Asn-273, Arg-381 (TBG) are critical for binding.
• Interacting residues often overlap with those for native hormone ligands, suggesting competitive binding.

Conclusions:

• Nicotine and its metabolites compete with native ligands for binding to SHBG, CBG, and TBG.
• This competition may lead to the disbalance of testosterone, estradiol, cortisol, progesterone, thyroxine, and triiodothyronine transport and homeostasis.
• The findings highlight a potential mechanism for nicotine's adverse endocrine effects.