Abstract
BackgroundAnti-tuberculosis (anti-TB) drug-induced liver injury (ADLI) is one of the most common adverse effects associated with TB treatment. Cytochrome P450 (CYP) 1A1 and glutathione S-transferase (GST) P1 are important phase I/II metabolizing enzymes involved in drug metabolism and detoxification. Genetic polymorphism and CpG island methylation have been reported as factors influencing the expression of CYP1A1 and GSTP1.ObjectiveThis study aimed to determine the potential relationships of CYP1A1 and GSTP1 polymorphisms and CpG island methylation with ADLI risk.DesignThis was a population-based one-to-one matched case–control study.SettingThe subjects were patients with TB receiving treatment in China from December 2010 to June 2013.PatientsIn total, 127 patients with TB and ADLI (case group) and 127 patients with TB but without liver injury (control group) were included in this study. Subjects were matched in terms of sex, age, and therapeutic regimen.MethodsThe general condition of each patient was assessed using questionnaires. The CYP1A1 MspI and GSTP1 Ile105Val polymorphisms as well as methylation status were detected by polymerase chain reaction (PCR)–restriction fragment length polymorphism and the methylation-specific PCR method.ResultsWe found no significant difference in GSTP1 and CYP1A1 genotypes between the two groups, probably because the sample size was not large enough; however, patients with ADLI had significantly higher GSTP1 and CYP1A1 promoter methylation rates than control subjects [odds ratio (OR) = 2.467 and 2.000, respectively]. After adjusting for drinking, which significantly differed between the groups as per univariate analysis, we found that hypermethylation of GSTP1 and CYP1A1 promoters was associated with ADLI (OR = 2.645 and 2.090, respectively).ConclusionHypermethylation of CpG islands of GSTP1 and CYP1A1 promoters may thus play important roles in the development of ADLI and provide evidence of being used as novel markers for ADLI risk prediction.
Highlights
Tuberculosis (TB) is one of the major global health problems, with approximately 8.6 million individuals affected by the disease and 1.3 million deaths worldwide in 2012 alone [1]
We found no significant difference in GSTP1 and CYP1A1 genotypes between the two groups, probably because the sample size was not large enough; patients with Anti-TB drug-induced liver injury (ADLI) had significantly higher GSTP1 and CYP1A1 promoter methylation rates than control subjects [odds ratio (OR) = 2.467 and 2.000, respectively]
After adjusting for drinking, which significantly differed between the groups as per univariate analysis, we found that hypermethylation of GSTP1 and CYP1A1 promoters was associated with ADLI (OR = 2.645 and 2.090, respectively)
Summary
Tuberculosis (TB) is one of the major global health problems, with approximately 8.6 million individuals affected by the disease and 1.3 million deaths worldwide in 2012 alone [1]. Anti-TB drug-induced liver injury (ADLI) is one of the most significant and serious adverse effects of TB treatment. The incidence of ADLI varies from 5.0% to 33.0% in different populations [2, 3] Such an adverse effect of the TB treatment significantly hampers global TB epidemic control. Anti-TB drugs are metabolized mainly by drug-metabolizing enzymes (DME) such as phase I enzymes [e.g., cytochrome P450 (CYP)], which help bioactivate toxic substances, and phase II enzymes [e.g., glutathione S-transferase (GST)], which can reduce the toxicity of electrophilic compounds formed by phase I enzymes [4]. Anti-tuberculosis (anti-TB) drug-induced liver injury (ADLI) is one of the most common adverse effects associated with TB treatment. Cytochrome P450 (CYP) 1A1 and glutathione S-transferase (GST) P1 are important phase I/II metabolizing enzymes involved in drug metabolism and detoxification. Genetic polymorphism and CpG island methylation have been reported as factors influencing the expression of CYP1A1 and GSTP1
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