The Clinical Characteristic Of Antituberculosis Drug-induced Liver Injury And Its Relationship With Gene Polymorphism Of Drug Metabolizing Enzymes

Objective1. To study the clinical characteristics and predisposing factor of antituberculosis drug-induced liver injury (ATDILI).2. To study the relationship between the gene polymorphism of drug metabolizing emzymes (DME),including NAT2, CYP2E1, GSTM1, GSTT1, MnSOD, and NQO1,and ATDILI,and to illuminate the molecular mechanism of ATDILI.Methods1. The clinical characteristics and correlative factors of 2457 cases with tuberculosis (TB) who had been inpatiented for initial treatment between 2005 and 2009 were retrospectively analyzed.2. The genes of NAT2, CYP2E1, MnSOD, NQO1 from 101 TB cases with ATDILI and 107 TB cases without ATDILI were amplified and sequenced. Their genotypes were determined and the genotype frequencies were compared between cases and controls using SPSS12.0 software. The relationship between gene polymorphisms and ATDILI was analyzed.3. The genes of GSTM1, GSTT1 were multiplely amplified, the relation between GSTM1, GSTT1 null genotype and ATDILI was analyzed.4. The effect of NAT2 genotype combined with CYP2E1, GSTM1,MnSOD or NQO1 genotypes on ATDILI was analyzed.Result1. Of the 2457 TB patients who received initial treatment, 267 (10.9%) patients had ATDILI; 13.6% (148/1085) female patients had ATDILI, which was significantly higher than the male patients (8.7%, 119/1372, P<0.05). Of the TB patients who accepted the liver protectant, the incidence of ATDILI was 10.0% (187/1876), which was significantly lower than in the control (13.8%, 80/581, P<0.05). The incidence of ATDILI in TB patients treated with HRZ regime (13.2%, 139/1050) was significantly higher than that in TB patients treated with HR regime (9.1%, 128/1407, P<0.05).2. Slow acetylator genotype (0R:4.74, P=0.000) had a significantly higher risk of ATDILI than rapid or media acetylator genotypes (0R:0.21, P=0.000). Of them, the genotype NAT2*6A/7B and NAT2*6A/6A had higher risk (OR: 8.40, 4.67, P<0.001). The 47CC of MnSOD gene (OR:5.77, P<0.05) had significantly higher risk of ATDILI than 47TT(OR:0.68, P>0.05) and 47TC(OR:1.03, P>0.05). The C1/C1 genotype of CYP2E1 (OR:1.67, P>0.05) had higher risk of ATDILI than the genotypes of C1/C2 (OR:0.64, P>0.05), C2/C2 (OR:0.35, P>0.05). The 609TT (OR:1.52, P>0.05) of NQO1 gene had higher risk of ATDILI than 609CC (OR:0.73, P>0.05) and 609CT (OR:0.99, P>0.05). The GSTM1 null genotype (OR: 1.64, P>0.05) had higher risk of ATDILI than GSTM1 non-null genotype (OR: 0.611, P>0.05).3. The patients with slow acetylator genotype of NAT2 combined with CYP2E1 C1/C1 genotype (OR:7.27, P=0.000)had higher risk of ATDILI than the patients only with slow acetylator genotype of NAT2 (OR:4.74, P=0.000) or with CYP2E1 C1/C1 (OR:1.67, P=0.009).4. The patients with slow acetylator genotype of NAT2 combined with GSTM1 null genotype(OR:10.21, P=0.000) had higher risk of ATDILI than the patients only with slow acetylator genotype (OR:4.74, P=0.000) or with GSTM1 null genotype (OR:1.64, P> 0.05).5. The risk of ATDILI of the patients with slow acetylator genotype of NAT2 combined with the 47CC of MnSOD gene was higher than that of the patients only with NAT2 slow acetylator genotype or with the 47CC of MnSOD gene (OR:1.64, P<0.05).6. After adjustment for age, sex and other genotype,the slow acetylator genotype of NAT2 and the 47CC of MnSOD remained an independent risk fator for ATDILI. OR were 4.929 (P=0.000), 5.77 (P<0.05), respectively。Conclusion1. The female patients with TB may be easy to develop to ATDILI. The rational use of liver protectant may reduce the incidence of ATDILI. The incidence of ATDILI in the patients treated with HRZ regime was higher than that in the patients treated with HR regime.2. The slow acetylators of NAT2, especially, the genotype NAT2*6A/7B, NAT2*6A/6A and the 47CC of MnSOD were significantly associated with a higher risk of developing ATDILI. The gene polymorphism of GSTT1 had no effect on ATDILI.3. Althought the gene polymorphism of CYP2E1, GSTM1 had no direct effect on ATDILI, the combination of NAT2 with CYP2E1 C1/C1, GSTM1 null genotype significantly increased the risk of ATDILI.