Methylation of the Glutathione-S-Transferase M3 Gene Promoter is Associated with Oxidative Stress in Acute-on-Chronic Hepatitis B Liver Failure

Li, Qi; Zou, Zhiqiang; Wang, Liyuan; Gao, Shuai; Fan, Yu–Chen; Long, Bo; Guo, Yan‐Mei; Xu, Ai-Ling; Han, Jie; Li, Tao; Wang, Kai

doi:10.1620/tjem.228.43

Cited by 24 publications

(33 citation statements)

References 36 publications

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“…Thus, lipid peroxidation products were introduced as potential candidates for disease progression and prognosis. Another study in which patients with acute or chronic hepatitis B whose plasma MDA levels were positively correlated with the MELD scores (r = 0.588) also supported these candidates (55). …”

Section: Resultsmentioning

confidence: 89%

Hepatitis B and its Relationship With Oxidative Stress

Alavian

Showraki

2016

Hepat Mon

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ContextDespite the great breakthroughs we have witnessed in the last 50 years in the prevention, diagnosis, and treatment of hepatitis B, we are still far from eradicating or even curing the disease. Achieving further progress in controlling this disease will not be possible without discovering the exact pathogenesis behind it. One prime suspect in the pathogenesis of various diseases is oxidative stress. This review will exclusively explore hepatitis B in the context of oxidative stress to obtain a more comprehensive clinical perspective on its pathogenesis and eventual medical therapy.Evidence AcquisitionWe systematically searched PubMed, Google Scholar, Web of Science, EMBASE, and Scopus using an extensive list of keywords in the following three categories: 1) Hepatitis B and oxidation 2) Hepatitis B and antioxidant system 3) Effects of approved anti-hepatitis B drugs on redox status. All relevant articles were obtained and reviewed carefully after the exclusion criteria were deployed.ResultsThere is great evidence indicating extensive oxidative stress occurs in hepatitis B. This oxidative stress takes place on multiple levels, including lipid peroxidation, DNA oxidation, protein oxidation, and reactive oxygen and nitrogen species production. However, there are also conflicting results with regard to antioxidant therapy and antioxidant status in hepatitis B, some of which may be explained by the concept of “compensatory gaps.” Nevertheless, further studies are indicated to reach a more thorough judgment.ConclusionsDespite the presence of vast oxidative stress in hepatitis B, antioxidant therapy is not always effective as a treatment strategy, especially considering that antioxidants can act as “double-edged swords” or antioxidants; if not used at the right time or place or in the right combination, these substances can easily become pro-oxidants. Therefore, several studies will be needed to determine suitable antioxidant therapies. We propose the “2-step Combined Antioxidant Adjuvant Therapy for hepatitis B (2CAAT Hep B)” as a new strategy for antioxidant adjuvant therapy. We also suggest developing an international platform and database for antioxidant adjuvant therapy in hepatitis B (IPAATH and IDAATH) to canalize this field of research in a standardized direction, especially when complexity is a problem.

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Section: Resultsmentioning

confidence: 89%

Hepatitis B and its Relationship With Oxidative Stress

Alavian

Showraki

2016

Hepat Mon

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“…CpG island hypermethylation of gene promoter can affect gene functions and inhibit protein expression by regulating and inactivating gene transcription [24,25]. For example, aberrant methylation of CpG island of the GSTM3 gene promoter is involved in oxidative injury upon liver failure [26]. Furthermore, CpG island methylation of the BRCA1 gene promoter is associated with breast cancer, and can therefore be used as a biological marker of breast cancer [27].…”

Section: Discussionmentioning

confidence: 99%

Correlation of CpG Island Methylation of the Cytochrome P450 2E1/2D6 Genes with Liver Injury Induced by Anti-Tuberculosis Drugs: A Nested Case-Control Study

Zhang

Zhu

et al. 2016

IJERPH

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This study investigated the role of CpG island methylation of the CYP2E1 and CYP2D6 genes in liver injury induced by anti-TB drugs from an epigenetic perspective in a Chinese cohort. A 1:1 matched nested case-control study design was applied. Pulmonary tuberculosis (TB) patients, who underwent standard anti-TB therapy and developed liver injury were defined as cases, while those who did not develop liver injury were defined as control. The two groups were matched in terms of sex, treatment regimen, and age. In 114 pairs of cases, CpG island methylation levels of the CYP2E1 and CYP2D6 genes in plasma cell-free DNA were found to be significantly correlated with the occurrence of anti-TB drug-induced liver injury (ADLI), with odds ratio (OR) values of 2.429 and 3.500, respectively (p < 0.01). Moreover, through multivariate logistic regression analysis, CpG island methylation of the CYP2E1 and CYP2D6 genes in plasma cell-free DNA were found to be significantly correlated with the occurrence of ADLI, with adjusted OR values of 4.390 (95% confidence interval (CI): 1.982–9.724) and 9.193 (95% CI: 3.624–25.888), respectively (p < 0.001). These results suggest that aberrantly elevated methylation of CpG islands of the CYP2E1 and CYP2D6 genes in plasma cell-free DNA may increase the risk of ADLI in Chinese TB patients.

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“…The modified DNA was amplified by MSP using primers specific for methylated and unmethylated GSTP1 and GSTM3. The primers sequences were the same with those in previous studies (Esteller et al 1998;Kollermann et al 2006;Li et al 2011a;Qi et al 2012). The MSP-amplified region of GSTP1 is from +78 to +168 within a CpG island in the 5′ region of GSTP1 gene.…”

Section: Sodium Bisulfite Modification and Methylation-specific Polymmentioning

confidence: 99%

“…Tumor necrosis factor-alpha (TNF-α) and malondialdehyde (MDA), markers for oxidative stress, are elevated in patients with HBV infection (Lara-Pezzi et al 1998a, b;Acar et al 2009;Tsai et al 2009). Our previous studies demonstrated that oxidative stress was associated with severity of HBV infection (Li et al 2011a;Qi et al 2012). Moreover, we found that glutathione-S-transferase P1 (GSTP1) and glutathione-S-transferase M3 (GSTM3) promoters were hypermethylated in acute-on-chronic hepatitis B liver failure, and the degree of methylation was associated with oxidative stress (Li et al 2011a;Qi et al 2012).…”

Section: Introductionmentioning

confidence: 98%

“…Our previous studies demonstrated that oxidative stress was associated with severity of HBV infection (Li et al 2011a;Qi et al 2012). Moreover, we found that glutathione-S-transferase P1 (GSTP1) and glutathione-S-transferase M3 (GSTM3) promoters were hypermethylated in acute-on-chronic hepatitis B liver failure, and the degree of methylation was associated with oxidative stress (Li et al 2011a;Qi et al 2012). DNA methylation is catalyzed by methyltransferases (DNMTs), which can be divided into "de novo" DNMTs (DNMT3a and DNMT3b) and maintenance DNMT (DNMT1) (Bird and Wolffe 1999;Denis et al 2011).…”

Section: Introductionmentioning

confidence: 99%

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Methylation of the Glutathione-S-Transferase P1 Gene Promoter Is Associated with Oxidative Stress in Patients with Chronic Hepatitis B

Fan

et al. 2016

Tohoku J. Exp. Med.

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Glutathione-S-transferase P1 (GSTP1) and glutathione-S-transferase M3 (GSTM3) catalyze the glutathione-related clearance of xenobiotics. The methylation of these gene promoters was associated with oxidative stress that induced liver damage. This study aims to explore the relationship among GSTP1 and GSTM3 methylation, DNA methyltransferases (DNMTs) expression, and oxidative stress in patients with chronic hepatitis B (CHB). We retrospectively enrolled 153 patients with CHB and 40 healthy controls (HCs). The GSTP1 and GSTM3 methylation status, DNMTs mRNA levels in peripheral mononuclear cells (PBMCs) and TNF-α and malondialdehyde (MDA) levels in plasma were detected. GSTP1 methylation was significantly higher in patients with CHB than HCs (P = 0.047). Patients with HBeAg-positive CHB showed significantly higher GSTP1 methylation than those with HBeAg-negative CHB (P = 0.017) and HCs (P = 0.007). No significant difference was observed between GSTP1 methylation in HBeAg-negative CHB and HCs (P = 0.191). DNMT1 and DNMT3a mRNA levels were significantly higher in participants with GSTP1 methylation than those without. In patients with CHB, the degree of GSTP1 promoter methylation was significantly correlated with DNMT1 mRNA, DNMT3a mRNA, TNF-α, MDA, HBeAg, ALT, AST and TBIL. In contrast, no significant difference was found between GSTM3 methylation in patients with CHB and HCs (P = 0.079). Meanwhile, no significant difference could be observed between GSTM3 promoter methylation in patients with HBeAg-positive CHB and HBeAg-negative CHB (P = 0.146). Therefore, this study demonstrated that GSTP1 hypermethylation was associated with DNMT1, DNMT3a overexpression and oxidative stress in patients with HBeAg-positive CHB.

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Methylation of the Glutathione-S-Transferase M3 Gene Promoter is Associated with Oxidative Stress in Acute-on-Chronic Hepatitis B Liver Failure

Cited by 24 publications

References 36 publications

Hepatitis B and its Relationship With Oxidative Stress

Hepatitis B and its Relationship With Oxidative Stress

Correlation of CpG Island Methylation of the Cytochrome P450 2E1/2D6 Genes with Liver Injury Induced by Anti-Tuberculosis Drugs: A Nested Case-Control Study

Methylation of the Glutathione-S-Transferase P1 Gene Promoter Is Associated with Oxidative Stress in Patients with Chronic Hepatitis B

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