POLYMORPHISMS OF NAT2, CYP2E1 AND GST ENZYME GENES AND PRESENCE OF ADVERSE REACTION TO ANTITUBERCULOSIS DRUGS IN PERUVIAN POPULATION

In Peru, 24,581 people were diagnosed with tuberculosis (TB) in 2020. Although TB treatments are effective, 3.4–
13% are associated with drug-induced liver injury (DILI). Among the first-line antituberculosis drugs, isoniazid
is the main drug responsible for DILI appearance. In liver, INH is metabolized by N-acetyltransferase-2 (NAT2),
cytochrome P4502E1 (CYP2E1), and glutathione S-transferase (GST) with two isoforms, GSTT1 and GSTM1. Based
on previous studies, we hypothesized that the presence of slow CYP2E1 genotype, NAT2 slow acetylators, GSTT1 and
GSTM1 null genotypes induce DILI in TB patients. In this cross-sectional study of 377 participants who completed
their anti-TB treatment, we genotyped SNPs: rs1041983, rs1801280, rs1799929, rs1799930, rs1208, and rs1799931
for NAT2 and rs3813867 and rs2031920 for CYP2E1, and also the presence or absence of 215- and 480-bp bands of
GSTM1 and GSTT1, respectively. We found that rapid, intermediate, and slow NAT2 acetylator were 15%, 38%, and
47%, respectively; null GSTM1 and GSTT1 genotype were 47.21% and 30.24%, respectively. Neither genotype was
prevalent in the patients who developed DILI (n=16). However, we found that the combination of intermediate
NAT2 acetylators and CYP2E1 c1/c1 genotype protected (OR=0.16; p=0.049) against the development of DILI, and
the combination of GSTM1 present genotype, GSTT1 null genotype, fast NAT2 acetylators, and CYP2E1 c1/c1 genotype
had a risk for the development of DILI (OR=11; p=0.017). We propose that the presence of polymorphisms in the
genes studied could help in therapeutic drug monitoring minimizing its risk for side effects or toxicity