rs1695 — GSTP1 Ile105Val

GSTP1 Ile105Val — Your Body's Chemical Defense Shield

Glutathione S-transferase Pi 1 (GSTP1) is one of the most important Phase II detoxification enzymes¹¹ Phase II detoxification enzymes
Phase II enzymes conjugate activated toxins with water-soluble molecules (like glutathione) so they can be excreted in urine or bile. Phase I enzymes activate toxins; Phase II neutralizes them. in the human body. It catalyzes the conjugation of glutathione²² glutathione
A tripeptide (glutamate-cysteine-glycine) that is the body's master antioxidant and primary substrate for Phase II detoxification reactions to a broad range of electrophilic compounds -- carcinogens, chemotherapy drugs, products of oxidative stress, and environmental pollutants including heavy metals. GSTP1 provides the majority of GST activity in the lung and is widely expressed in the liver, kidneys, and gastrointestinal tract.

The rs1695 variant causes an isoleucine-to-valine substitution at position 105 (Ile105Val), right in the hydrophobic substrate-binding pocket (H-site)³³ hydrophobic substrate-binding pocket (H-site)
The H-site is the region of the enzyme that physically contacts the electrophilic substrate. Position 105 sits on a helix alongside Tyr109, and together they define the shape and chemistry of the binding cleft. of the enzyme. This single amino acid change reshapes the active site geometry, fundamentally altering which substrates the enzyme handles efficiently -- and which it does not.

The Mechanism

The Val105 substitution has a paradoxical effect on enzyme function that depends on the substrate. For the general-purpose model substrate CDNB⁴⁴ CDNB
1-chloro-2,4-dinitrobenzene, a standard laboratory substrate used to measure GST activity broadly, the Val105 enzyme is approximately three-fold less active⁵⁵ three-fold less active
The essential role of GSTP1 I105V polymorphism in the prediction of CDNB metabolism and toxicity: In silico and in vitro insights. Toxicol In Vitro, 2023 than the Ile105 form. However, for the diol epoxides of polycyclic aromatic hydrocarbons (PAHs)⁶⁶ diol epoxides of polycyclic aromatic hydrocarbons (PAHs)
Reactive metabolites of combustion products found in cigarette smoke, grilled meat, and vehicle exhaust; benzo[a]pyrene diol epoxide (BPDE) is the most studied, the Val105 enzyme shows seven-fold higher catalytic efficiency⁷⁷ seven-fold higher catalytic efficiency
Watson MA et al. Human glutathione S-transferase P1 polymorphisms: relationship to lung tissue enzyme activity and population frequency distribution. Carcinogenesis, 1998 compared to the Ile105 form. This substrate-dependent shift means carriers of the Val105 allele process PAH carcinogens more efficiently but have reduced capacity for many other electrophilic toxins and oxidative stress products.

The variant also affects the enzyme's thermal stability -- the Val105 protein is less stable than the Ile105 form, which may reduce the total pool of functional GSTP1 protein available for detoxification under physiological conditions.

Critically, GSTP1 also metabolizes sulforaphane⁸⁸ sulforaphane
The principal bioactive isothiocyanate from cruciferous vegetables (broccoli, kale, Brussels sprouts). Sulforaphane activates the Nrf2 pathway, which upregulates dozens of detoxification and antioxidant enzymes., the key compound from cruciferous vegetables that activates the Nrf2/ARE pathway⁹⁹ Nrf2/ARE pathway
Nuclear factor erythroid 2-related factor 2 / Antioxidant Response Element -- the master regulator of cellular antioxidant defense. When activated, Nrf2 drives expression of over 200 cytoprotective genes.. The Val105 variant has reduced specific activity toward sulforaphane, which paradoxically may allow more sulforaphane to reach its target (Nrf2) rather than being conjugated and eliminated. This creates a complex interplay between genotype and dietary intervention.

The Evidence

Cancer risk. The most robust evidence comes from a Shanghai Breast Cancer Study¹⁰¹⁰ Shanghai Breast Cancer Study
Parl FF et al. Cruciferous vegetables, the GSTP1 Ile105Val genetic polymorphism, and breast cancer risk. Am J Clin Nutr, 2008 of 3,035 cases and 3,037 controls, which found that the Val/Val genotype was associated with a 1.50-fold increased breast cancer risk (OR 1.50, 95% CI 1.12-1.99), with the effect strongest in premenopausal women (OR 2.08). A meta-analysis of 51 studies¹¹¹¹ meta-analysis of 51 studies
Wei B et al. Association between GSTP1 Ile105Val polymorphism and urinary system cancer risk. Onco Targets Ther, 2016 covering 11,762 cases and 15,150 controls found that Val allele carriers had increased prostate cancer risk (OR 1.80, 95% CI 1.19-2.73) and elevated bladder cancer risk across multiple genetic models (GG vs AA: OR 1.49, 95% CI 1.12-1.97).

Chemotherapy toxicity. GSTP1 directly metabolizes platinum-based chemotherapy drugs. A meta-analysis by Lv et al.¹²¹² meta-analysis by Lv et al.
Lv F et al. Relationship between GSTP1 rs1695 gene polymorphism and myelosuppression induced by platinum-based drugs. J Int Med Res, 2018 found that G allele carriers had 1.7-fold higher hematological adverse events and 2.6-fold higher neutropenia risk during platinum chemotherapy compared to the AA genotype. The variant also predicts cyclophosphamide-induced toxicity¹³¹³ cyclophosphamide-induced toxicity
Mokhtar GM et al. Evaluating the role of GSTP1 genetic polymorphism (rs1695, 313A>G) as a predictor in cyclophosphamide-induced toxicities. Genes Environ, 2021 including myelosuppression and gastrointestinal side effects.

Heavy metal detoxification. GSTP1 plays a direct role in conjugating heavy metals with glutathione for elimination. A study by Santos et al.¹⁴¹⁴ study by Santos et al.
Santos A et al. The GSTP1 rs1695 polymorphism is associated with mercury levels and neurodevelopmental delay in indigenous Munduruku children. Toxics, 2024 found that the rs1695 polymorphism was associated with mercury levels and neurodevelopmental outcomes, while in vitro studies show that heavy metals can directly inhibit GST variants differently¹⁵¹⁵ heavy metals can directly inhibit GST variants differently
Paiva L et al. Variants of glutathione S-transferase pi 1 exhibit differential enzymatic activity and inhibition by heavy metals. Toxicol In Vitro, 2012, with the Val105 form showing altered sensitivity to mercury and cadmium inhibition.

Oxidative stress and airway inflammation. The Val105 variant modulates allergen-provoked airway inflammation in asthmatics. A controlled allergen challenge study¹⁶¹⁶ controlled allergen challenge study
Fryer AA et al. Glutathione S-transferase P1 Ile105Val polymorphism modulates allergen-induced airway inflammation in human atopic asthmatics in vivo. Clin Exp Allergy, 2013 found that Val105/Val105 asthmatics had greater generation of acute-phase cytokines and inflammatory mediators after allergen challenge compared to other genotypes, indicating reduced capacity to buffer oxidative stress in the airways.

Practical Implications

The most actionable finding for everyday health is the interaction between GSTP1 genotype and cruciferous vegetable intake. The Shanghai study showed that women with Val/Val genotype and low cruciferous vegetable intake had 1.74-fold increased breast cancer risk, but high cruciferous intake substantially ameliorated this risk. Since the Val105 enzyme is less efficient at conjugating sulforaphane, more of this beneficial compound may actually reach its Nrf2 target -- but only if you eat enough cruciferous vegetables to begin with.

For individuals carrying one or two G alleles, supporting the body's glutathione system becomes particularly important. This means ensuring adequate intake of glutathione precursors (N-acetylcysteine, glycine, glutamine), selenium (a cofactor for glutathione peroxidase), and antioxidant-rich foods. Minimizing unnecessary exposures to environmental toxins -- especially tobacco smoke, which contains PAHs -- is also relevant, though the Val105 form is actually more efficient at clearing PAH metabolites specifically.

For anyone undergoing platinum-based chemotherapy or cyclophosphamide treatment, this variant should be discussed with the oncology team, as it may affect drug metabolism and toxicity risk.

Interactions

The most direct interaction is with rs1138272 (GSTP1 Ala114Val), another variant in the same enzyme. Together, these two SNPs define the GSTP1 haplotypes: GSTP1*A (Ile105/Ala114, wild-type), GSTP1*B (Val105/Ala114), and GSTP1*C (Val105/Val114). The GSTP1*C haplotype, carrying both variant alleles, has been associated with a 5.46-fold increased prostate cancer risk compared to GSTP1*A. The two variants are separated by approximately 1 kb with moderate linkage disequilibrium (D' approximately 0.48), so they segregate partially independently.

GSTP1 also interacts with the other major glutathione S-transferase genes -- GSTM1 and GSTT1 -- which can be completely deleted (null genotypes). The combination of GSTM1 null, GSTT1 null, and GSTP1 Val105 creates a severely compromised glutathione conjugation capacity. Studies have found up to 6-8-fold increased risk for bladder cancer and other malignancies when all three GST pathways are impaired simultaneously.