Glutathione peroxidase 1 (GPX1) genetic polymorphism, erythrocyte GPX activity, and prostate cancer risk

Abstract

Glutathione peroxidase 1 (GPX1) is a ubiquitously expressed selenium-dependent enzyme that protects cells against oxidative damage by reducing hydrogen peroxide and a wide range of organic peroxides. Some epidemiological studies have correlated low GPX activity or particular GPX1 polymorphisms with enhanced risk of cancer, although these correlations have not been consistently observed in all populations. Therefore, we conducted the present study to evaluate the possible association of GPX1 Pro198Leu polymorphism and erythrocyte GPX activity with the risk of developing prostate cancer and to clarify whether erythrocyte GPX activity levels were correlated with the GPX1 Pro198Leu genotype in the Macedonian population. The GPX1 Pro198Leu genotype was determined in 82 prostate cancer cases and 123 control individuals. We found an overall protective effect of the variant Leu allele of the GPX1 polymorphism on the prostate cancer risk. Heterozygous carriers of the variant Leu allele had a significantly lower risk of prostate cancer compared with homozygous wild-type individuals (OR, 0.38; 95% CI, 0.20-0.75; P = 0.004). Erythrocyte GPX activity was analyzed in 73 cases and 91 controls. The erythrocyte GPX activity in the cancer group was lower than in the healthy controls. Additionally, we compared the erythrocyte GPX activity in the control group of 90 subjects and found no significant differences by genotype. These findings suggest that individual susceptibility of prostate cancer may be modulated by GPX1 polymorphism and that the combination of genetic factors involved in oxidative response with environmental carcinogens may play an important role in prostate carcinogenesis.

Nutritional Countermeasures Targeting Reactive Oxygen Species in Cancer: From Mechanisms to Biomarkers and Clinical Evidence

“…A significant inverse relationship between geographical availability of Se and carcinogenesis has been observed (69), and a similar inverse association has also been found between baseline plasma Se levels and the risk of advanced prostate cancer in many, but not all case-control and prospective cohort studies (Table 3) (11,152,192,204,279). The antitumorigenic effect of Se and selenoproteins for prostate cancer was then further supported in a mouse model (86) as well as in a study showing that the GPX1 polymorphism can play an important role in predisposition to prostate carcinogenesis (16). Similarly, GPX2 has been reported to inhibit carcinogenesis by exerting hydroperoxide removal and suppression of COX2 expression (26,44).…”

Effects of Selenium Status and Polymorphisms in Selenoprotein Genes on Prostate Cancer Risk in a Prospective Study of European Men

“…15), and the correlation of plasma Se concentration with erythrocyte GPx1 activity was stronger in individuals of CC subjects than in TT subjects (43). The influence of GPX1 (rs1050450) genotype on erythrocyte GPx1 activity was not confirmed in two small studies (17,44), but an experimental study with breast cancer cells transfected with either the prolinecontaining or leucine-containing allele showed a greater induction of enzyme activity by Se in cells homozygous for the common allele (CC; ref. 45).…”

“…These genes either encode for selenoproteins, which are highly expressed in the prostate (Sep15; ref. 14) and/or possess functions in Se transport (SePP) or protection from oxidative and endoplasmic reticulum stress (GPx1, GPx4, Sep15); we also focused on specific variants for which there is evidence of functional consequences and possible links to either Se status or cancer risk (10,11,(14)(15)(16)(17). Thus, our hypothesis is that selenoprotein functions within the prostate gland influence prostate cancer risk and that these functions are affected by both Se intake and genetic variation in the ability to transport Se to the prostate and Se-dependent cellular protection mechanisms.…”

Nutrigenetics and Modulation of Oxidative Stress

“…The GPX1 gene has been localized to chromosome 3p21.3 and a well-studied polymorphism at amino acid position 198 results in a proline to leucine change, which has been shown to affect GPX activity in some [34,35,36], although not all studies [37,38]. Carriers of the leucine allele have also been shown to have significantly higher levels of lipoperoxides and MDA in low-density lipoproteins [36].…”