Does the GSTP1 rs1695 AG genotype alter glutathione-conjugation activity?

GSTP1 rs1695 is a common coding variant with a well-established biochemical consequence: the AG genotype encodes the Ile105/Val105 heterozygous state. Its relevance is enzymatic rather than a uniform prediction of detoxification capacity or clinical outcome.

Molecular and functional evidence

• rs1695 is c.313A>G: the A allele encodes Ile105 and the G allele Val105. Thus, AG carriers are expected to express both Ile105- and Val105-containing GSTP1 subunits.
• Purified recombinant allozymes show altered glutathione-conjugation kinetics, including substrate affinity, turnover, and catalytic efficiency. In human lung cytosol, CDNB-conjugating activity in Ile/Val individuals was intermediate (62.1 ± 4.2 nmol·mg⁻¹·min⁻¹) between reported Ile/Ile and Val/Val activity.

Substrate-specific mechanism

• Ile105Val remodels the enzyme’s hydrophobic substrate-binding H-site, altering pocket geometry, hydrophobicity, and steric accommodation. The glutathione-binding G-site is not the principal affected region.
• With CDNB, Val105-containing enzyme had a higher Km than Ile105 (1.15 vs 0.33 mM in Ala114-background proteins), consistent with lower apparent substrate affinity and reduced catalytic efficiency.
• This is not a universal loss of function: Val105 can show greater activity toward ethacrynic acid and substantially greater efficiency toward some polycyclic-aromatic-hydrocarbon diol epoxides.

Additional biochemical consideration

• Val105-containing GSTP1 is reported to be approximately two- to threefold less thermally stable than the Ile105 form, which could further influence enzyme performance under particular experimental or cellular conditions.

Bottom line

• The claim is supported: rs1695 AG produces the GSTP1 Ile105/Val105 variant state, and the substitution can alter glutathione conjugation. Its effect is substrate-dependent—potentially lower for some electrophiles and higher for others—so AG should not be interpreted as globally reduced or increased GSTP1 function.