Does GSTP1 rs1695 GG alter glutathione S-transferase activity and low selenium weaken thyroid antioxidant defenses?

Maintaining cellular redox homeostasis depends on both genetic architecture and essential micronutrient cofactors. Disruptions in these pathways can compromise metabolic detoxification and organ-specific antioxidant defenses.

Genetic variation and altered GSTP1 activity

The GSTP1 rs1695 single nucleotide polymorphism (c.313A>G) causes an isoleucine-to-valine substitution at codon 105 (Ile105Val) in the enzyme's hydrophobic H-site. The homozygous GG (Val/Val) genotype alters active site geometry and reduces thermal stability. This genetic variant shifts the enzyme's substrate-dependent catalytic efficiency: it exhibits significantly lower conjugation activity and a higher Km (lower affinity) for standard model electrophiles like 1-chloro-2,4-dinitrobenzene (CDNB), but displays up to a three-fold increase in catalytic efficiency for bulky hydrophobic substrates, such as polycyclic aromatic hydrocarbon (PAH) diol-epoxides.

Selenium deficiency and thyroid antioxidant defenses

The thyroid gland requires high concentrations of selenium to synthesize essential selenoproteins, including glutathione peroxidases (GPx1, GPx3, and GPx4), which neutralize the hydrogen peroxide (H₂O₂) generated during thyroid hormone synthesis. Under low selenium status, GPx enzymes are among the first to lose activity due to their position in the cellular selenoprotein hierarchy. This rapid drop in GPx expression and enzymatic activity impairs H₂O₂ detoxification, leading to an accumulation of reactive oxygen species (ROS), subsequent thyrocyte injury, and a heightened risk of autoimmune thyroid dysfunction.

Bottom line

• The GSTP1 rs1695 GG genotype alters glutathione S-transferase activity, reducing clearance of small electrophiles while increasing efficiency for bulky carcinogens, while low selenium status independently weakens thyroid antioxidant defenses by downregulating glutathione peroxidase activity, exposing thyrocytes to elevated oxidative stress and potential autoimmune damage.