CYP2E1,GSTM1andGSTT1genetic polymorphisms and susceptibility to antituberculosis drug-induced hepatotoxicity: a nested case-control study

Abstract

This is the first study of the involvement of CYP2E1, GSTM1 and GSTT1 genetic polymorphisms in ATDH using a nested case-control population-based prospective cohort design. We could not confirm positive associations of genetic polymorphisms of CYP2E1 RsaI, CYP2E1 DraI, GSTM1 null and GSTT1 null with ATDH reported by various groups, in our Chinese TB population.

PharmGKB summary

“…Polymorphisms of the CYP2E1 gene have been examined in association with risk of INH-mediated ATT-DILI, mainly by investigators in South [40, 76–78, 84] and East [26, 35, 67, 68, 71, 74, 75, 91–93] Asia and South America [62, 63, 65, 66]. Although some studies have reported higher risk of ATT-DILI in INH-treated patients who bear high-activity alleles of CYP2E1 , particularly * 1A and * 6 [76, 84, 85, 91, 92], other studies have found no association [35, 62, 63, 65–68, 71, 74, 75, 77, 78, 86, 93, 94] and, therefore, a direct role for CYP2E1 in INH-induced hepatotoxicity remains widely controversial (Table 1). Evidence suggests that CYP2E1 polymorphisms may be associated with increased severity of INH related ATT-DILI, rather than enhanced susceptibility to it [71].…”

“…Indeed, several published studies have reported an association between GSTM1 homozygous null genotype and increased risk of ATT-DILI [26, 37, 102, 103], although the majority of studies report no association found [35, 63, 65, 74, 92, 93, 104–106] (Table 1). A similar pattern is seen for the GSTT1 homozygous null genotype, with one study from Spain describing an association with increased risk of ATT-DILI [106], but the majority of studies (in Asia or Brazil) reporting no association [35, 37, 63, 65, 74, 93, 102–105] (Table 1). Studies have also shown an additive effect of combined GSTM1 and GSTT1 null genotypes on risk of INH hepatotoxicity [40, 103], as well as of combined NAT2 , CYP2E1 , GSTM1 and/or GSTT1 polymorphic genotypes [63].…”

Association of polymorphisms in drug transporter genes (SLCO1B1 and SLC10A1) and anti-tuberculosis drug-induced hepatotoxicity in a Chinese cohort

“…Therefore previous investigators had a major research on genes encoding the phase I and II metabolism enzymes. However, lack of association were found between genetic polymorphisms of NAT2 [11], CYP2E1 [12,13], GSTM1 [13] and GSTT1 [13] and ATDH in our previous studies. Nevertheless, the present study has showed that hepatic transport, which is known as the phase III metabolism, also play an important role in the elimination of ATDs.…”

Idiosyncratic Drug-Induced Liver Injury (IDILI): Potential Mechanisms and Predictive Assays

“…There are over one hundred different variants of CYP2D6, and all of the clinically relevant variations show decreased or lack of metabolism by CYP2D6 [33, 34]. Finally, CYP2E1 metabolizes a variety of different drugs, including antitubercular compounds, alcohol, and anesthetics [35, 36]. However, there are mutant genotypes of CYP2E1 that have reduced metabolism of antitubercular drugs [22, 35, 37].…”