Pharmacogenetic Study of Drug-Metabolising Enzyme Polymorphisms on the Risk of Anti-Tuberculosis Drug-Induced Liver Injury: A Meta-Analysis

Abstract

BackgroundThree first-line antituberculosis drugs, isoniazid, rifampicin and pyrazinamide, may induce liver injury, especially isoniazid. This antituberculosis drug-induced liver injury (ATLI) ranges from a mild to severe form, and the associated mortality cases are not rare. In the past decade, many investigations have focused the association between drug-metabolising enzyme (DME) gene polymorphisms and risk for ATLI; however, these studies have yielded contradictory results.MethodsPubMed, EMBASE, ISI web of science and the Chinese National Knowledge Infrastructure databases were systematically searched to identify relevant studies. A meta-analysis was performed to examine the association between polymorphisms from 4 DME genes (NAT2, CYP2E1, GSTM1 and GSTT1) and susceptibility to ATLI. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. Heterogeneity among articles and their publication bias were also tested.Results38 studies involving 2,225 patients and 4,906 controls were included. Overall, significantly increased ATLI risk was associated with slow NAT2 genotype and GSTM1 null genotype when all studies were pooled into the meta-analysis. Significantly increased risk was also found for CYP2E1*1A in East Asians when stratified by ethnicity. However, no significant results were observed for GSTT1.ConclusionsOur results demonstrated that slow NAT2 genotype, CYP2E1*1A and GSTM1 null have a modest effect on genetic susceptibility to ATLI.

Polymorphisms in CYP2E1, GSTM1 and GSTT1 and anti-tuberculosis drug-induced hepatotoxicity

“…Polymorphisms in CYP2E1 are present at higher frequencies in Asians than any other populations (Garte et al 2001), with a frequency of about 20-30% of the *5B allele (Khan et al 2009). According to the meta-analysis study by Cai (Cai et al 2012) the NAT2 slow genotypes, CYP2E1*1A and GSTM1 null have a modest effect on the genetic susceptibility to hepatotoxicity. Another study reported that the administration of the flavonoid quercetin could neutralize the hepatotoxicity mediator CYP2E1 (Tang et al, 2013).…”

“…Anti-tuberculosis drug-induced hepatitis (ATDinduced hepatitis) is an important clinical problem, being the most severe adverse effect during tuberculosis (TB) treatment (Tostmann et al 2008, Walker et al 2009, Cai et al 2012. Currently, the 6-month therapy consists in the combination of the drugs isoniazid (INH), rifampicin (RMP), pyrazinamide (PZA) and ethambutol (EMB) (Stine et al 2013).…”

Acetylator Status on Tuberculosis Patients Receiving Isoniazid-Contained Antituberculosis Regiment

“…NAT2 enzyme is responsible for acetylation step of isoniazid metabolism. 3,4,5,6,7,8,9 The activity of NAT2 (acetylator status) was strongly related to genetic variation on NAT2 gene. People with slow acetylator characteristic would have higher risk of hepatotoxic effect after tuberculosis treatment.…”

“…Several studies had been studied about the relationship between acetylator status and risk of hepatotoxic; all of which showed a significant correlation. 3,5,6,9,10,11,12 Otherwise, the proportions of slow acetylator were varies in several studies. Thus indicated the different risk for hepatotoxic effect in different population.…”

“…Slow acetylator was considered to be a significant risk factor related to hepatotoxic effect of antituberculosis. 3,5,6,9,10,11,12 The acetylator status of tuberculosis patients based on subject characteristics were shown on Table 2. Isoniazid was considered to be antituberculosis that most responsible for the incidence of hepatotoxic effect after tuberculosis treatment.…”