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. 2020 Jul 28:2020:9414196.
doi: 10.1155/2020/9414196. eCollection 2020.

A Systematic Review of the Various Effect of Arsenic on Glutathione Synthesis In Vitro and In Vivo

Shanshan Ran  1 , Jiaqing Liu  1 , Shugang Li  2
Affiliations

A Systematic Review of the Various Effect of Arsenic on Glutathione Synthesis In Vitro and In Vivo

Shanshan Ran et al. Biomed Res Int. .

Abstract

Background: Arsenic is a toxic metalloid widely present in nature, and arsenic poisoning in drinking water is a serious global public problem. Glutathione is an important reducing agent that inhibits arsenic-induced oxidative stress and participates in arsenic methylation metabolism. Therefore, glutathione plays an important role in regulating arsenic toxicity. In recent years, a large number of studies have shown that arsenic can regulate glutathione synthesis in many ways, but there are many contradictions in the research results. At present, the mechanism of the effect of arsenic on glutathione synthesis has not been elucidated.

Objective: We will conduct a meta-analysis to illustrate the effects of arsenic on GSH synthesis precursors Glu, Cys, Gly, and rate-limiting enzyme γ-GCS in mammalian models, as well as the regulation of p38/Nrf2 of γ-GCS subunit GCLC, and further explore the molecular mechanism of arsenic affecting glutathione synthesis.

Results: This meta-analysis included 30 studies in vivo and 58 studies in vitro, among which in vivo studies showed that arsenic exposure could reduce the contents of GSH (SMD = -2.86, 95% CI (-4.45, -1.27)), Glu (SMD = -1.11, 95% CI (-2.20,-0.02)), and Cys (SMD = -1.48, 95% CI (-2.63, -0.33)), with no statistically significant difference in p38/Nrf2, GCLC, and GCLM. In vitro studies showed that arsenic exposure increased intracellular GSH content (SMD = 1.87, 95% CI (0.18, 3.56)) and promoted the expression of p-p38 (SMD = 4.19, 95% CI (2.34, 6.05)), Nrf2 (SMD = 4.60, 95% CI (2.34, 6.86)), and GCLC (SMD = 1.32, 95% CI (0.23, 2.41)); the p38 inhibitor inhibited the expression of Nrf2 (SMD = -1.27, 95% CI (-2.46, -0.09)) and GCLC (SMD = -5.37, 95% CI (-5.37, -2.20)); siNrf2 inhibited the expression of GCLC, and BSO inhibited the synthesis of GSH. There is a dose-dependent relationship between the effects of exposure on GSH in vitro. Conclusions. These indicate the difference between in vivo and in vitro studies of the effect of arsenic on glutathione synthesis. In vivo studies have shown that arsenic exposure can reduce glutamate and cysteine levels and inhibit glutathione synthesis, while in vitro studies have shown that chronic low-dose arsenic exposure can activate the p38/Nrf2 pathway, upregulate GCLC expression, and promote glutathione synthesis.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Search process and results.
Figure 2
Figure 2
In vivo experiment quality evaluation results. This study included 36 articles with a low risk rate of more than 75 percent.
Figure 3
Figure 3
In vitro experiment quality evaluation results. This study included 52 articles with a low risk rate of more than 75 percent.
Figure 4
Figure 4
Meta-analysis of the effects of arsenic exposure on GSH in vivo. The forest plot shows the effect of arsenic treatment on GSH in the experiment and control group. SMD: standardized mean difference; IV: independent variable; 95% CI: 95% confidence interval; SD: standard deviation. The P value of the overall test effect is 0.00001; when P < 0.05, the difference was considered statistically significant.
Figure 5
Figure 5
Meta-analysis of the effects of arsenic exposure on GSH in vitro. The forest plot shows the effect of arsenic treatment on GSH in experiment and control group. SMD: standardized mean difference; IV: independent variable; 95% CI: 95% confidence interval; SD: standard deviation. The P value of the overall test effect is 0.02; when P < 0.05, the difference was considered statistically significant.
Figure 6
Figure 6
Meta-analysis of the effects of arsenic on Glu, Cys, and Gly in vivo. SMD; standardized mean difference. The P value of the Glu's overall effect test is 0.04. The P value of the Cys's overall effect test is 0.01. The P value of the Gly's overall effect test is 0.36. When P < 0.05, the difference was considered statistically significant.
Figure 7
Figure 7
Meta-analysis of the effects of arsenic on Glu, Cys, and Gly in vitro. SMD: standardized mean difference. The P value of the Glu's overall effect test is 0.96. The P value of the Cys's overall effect test is 0.19. When P < 0.05, the difference was considered statistically significant.
Figure 8
Figure 8
Meta-analysis of the effects of arsenic on p38, p-p38, and Nrf2 in vivo. SMD: standardized mean difference. Both ends of the segment represent the upper and lower limits of 95% CI, and the length of the segment represents the 95% CI range. When the 95% CI range contains 0, the difference is not statistically significant.
Figure 9
Figure 9
Meta-analysis of the effects of arsenic on p38, p-p38, and Nrf2 in vitro. SMD: standardized mean difference. Both ends of the segment represent the upper and lower limits of 95% CI, and the length of the segment represents the 95% CI range. When the 95% CI range contains 0, the difference is not statistically significant.
Figure 10
Figure 10
Meta-analysis of the effect of p38 inhibitor on Nrf2 in vitro. SMD: standardized mean difference. The P value of the overall effect test is 0.04. When P < 0.05, the difference was considered statistically significant.
Figure 11
Figure 11
Meta-analysis of the effects of siNrf2 and p38 inhibitor on GCLC in vitro. SMD: standardized mean difference. Compared with control, the P value of the siNrf2 group's overall effect test is 0.02, and the P value of the p38 inhibitor group's overall effect test is 0.00001. When P < 0.05, the difference was considered statistically significant.
Figure 12
Figure 12
Meta-analysis of the effect of arsenic on the GCLC of r-GCS subunits in vitro. The forest plot shows the effect of arsenic treatment on GSH in the experiment and control group. SMD: standardized mean difference; IV: independent variable; 95% CI: 95% confidence interval; SD: standard deviation. The P value of the overall test effect is 0.02; when P < 0.05, the difference was considered statistically significant.
Figure 13
Figure 13
Meta-analysis of the effect of arsenic on the GCLM of r-GCS subunits in vitro. The forest plot shows the effect of arsenic treatment on GSH in the experiment and control group. SMD: standardized mean difference; IV: independent variable; 95% CI: 95% confidence interval; SD: standard deviation. The P value of the overall test effect is 0.14; when P < 0.05, the difference was considered statistically significant.
Figure 14
Figure 14
Effect of in vitro arsenic combined with r-GCS inhibitor on GSH. SMD: standardized mean difference. Compared with control, the P value of the arsenic group's overall effect test was <0.001, and the P value of the arsenic+BSO group's overall effect test was <0.001. When P < 0.05, the difference was considered statistically significant.
Figure 15
Figure 15
Meta-analysis of the effect of arsenic on the GCLC of r-GCS subunits in vivo. The forest plot shows the effect of arsenic treatment on GSH in the experiment and control group. SMD: standardized mean difference; IV: independent variable; 95% CI: 95% confidence interval; SD: standard deviation. The P value of the overall test effect is 0.66; when P < 0.05, the difference was considered statistically significant.
Figure 16
Figure 16
Meta-analysis of the effect of arsenic on the GCLM of r-GCS subunits in vivo. The forest plot shows the effect of arsenic treatment on GSH in the experiment and control group. SMD: standardized mean difference; IV: independent variable; 95% CI: 95% confidence interval; SD: standard deviation. The P value of the overall test effect is 0.20; when P <0.05, the difference was considered statistically significant.
Figure 17
Figure 17
Dose-response relationship of arsenic exposure dose to GSH in vitro.
Figure 18
Figure 18
Subgroup analysis of arsenic exposure doses in vivo. SMD: standardized mean difference. Both ends of the line segment represent the upper and lower limits of 95% CI, and the length of the line segment represents the 95% CI range. When the 95% CI range contains 0, the difference is not statistically significant compared with the control group.
Figure 19
Figure 19
Subgroup analysis of arsenic exposure doses in vitro. SMD: standardized mean difference. Both ends of the line segment represent the upper and lower limits of 95% CI, and the length of the line segment represents the 95% CI range. When the 95% CI range contains 0, the difference is not statistically significant compared with the control group.
Figure 20
Figure 20
Subgroup analysis of arsenic exposure time in vivo. SMD: standardized mean difference. Both ends of the line segment represent the upper and lower limits of 95% CI, and the length of the line segment represents the 95% CI range. When the 95% CI range contains 0, the difference is not statistically significant compared with the control group.
Figure 21
Figure 21
Subgroup analysis of arsenic exposure time in vitro. SMD: standardized mean difference. Both ends of the line segment represent the upper and lower limits of 95% CI, and the length of the line segment represents the 95% CI range. When the 95% CI range contains 0, the difference is not statistically significant compared with the control group.
Figure 22
Figure 22
Subgroup analysis of arsenic exposure species in vivo. SMD: standardized mean difference. Both ends of the line segment represent the upper and lower limits of 95% CI, and the length of the line segment represents the 95% CI range. When the 95% CI range contains 0, the difference is not statistically significant compared with control group.
Figure 23
Figure 23
Subgroup analysis of arsenic exposure species in vitro. SMD: standardized mean difference. Both ends of the line segment represent the upper and lower limits of 95% CI, and the length of the line segment represents the 95% CI range. When the 95% CI range contains 0, the difference is not statistically significant compared with the control group.
Figure 24
Figure 24
In vivo experiment published biased funnel chart. SMD: standardized mean difference. SE: standard error.
Figure 25
Figure 25
In vitro experiment published biased funnel chart. SMD: standardized mean difference. SE: standard error.
Figure 26
Figure 26
Sensitivity analysis of the effect of arsenic on GSH in vivo.
Figure 27
Figure 27
Sensitivity analysis of the effect of arsenic on GSH in vitro.
Figure 28
Figure 28
The mechanism of arsenic influence on GSH synthesis.
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