Isoniazid metabolism and hepatotoxicity

Purpose
This study aims to assess whether NAT2 genotype affects susceptibility to moderate to severe liver injury in patients undergoing drug treatment for tuberculosis with isoniazid-containing regimens.

N-acetyltransferase 2 (NAT2) genotype as a risk factor for development of drug-induced liver injury relating to antituberculosis drug treatment in a mixed-ethnicity patient group

Tuberculosis is still a major problem in some developed and developing countries. The poor compliance to the treatment of tuberculosis patients due to the adverse events was supposed to be an important factor contributing to the high prevalence. This review aims to clarify the role and the pharmacological mechanism of the genes involved in the isoniazid-induced hepatotoxicity. We selected English articles of studies in human from PubMed up to May 2014 with the keywords pharmacogenetic, isoniazid and hepatotoxicity, N-acetyl transferase 2 (NAT2), CYP2E1 and glutathione S transferase (GST). Polymorphisms of NAT2, CYP2E1 and GST1 could increase patients' susceptibility to isoniazid-induced hepatotoxicity. The rapid acetylators of NAT2 and rapid metabolizers of CYP2E1 showed increased concentrations of hepatotoxic metabolites. However, the rapid metabolizers of GST1 could decrease the concentration of hepatotoxic metabolites. Some studies of human leukocyte antigen (HLA), Uridine 5'-dipphospho (UDP) glucuronosyltransferase (UGT), nitric oxide synthase (NOS), Broad complex, Tramtrack, Bric-a-brac (BTB) and cap'n'collar type of basic region leucine zipper factor family (CNC) homolog (BACH) and Maf basic leucine zipper protein (MAFK) polymorphisms showed their roles in isoniazid-induced hepatotoxicity by modifying the expression of antioxidant enzymes. A better insight into the role of polymorphisms of HLA, UGT, NOS, BACH and MAFK in addition to NAT2, CYP2E1 and GST1 in the hepatotoxicity of isoniazid may support physicians in monitoring patients hepatotoxicity symptoms and laboratory data and optimizing pharmacotherapy. Future studies about the role of such polymorphisms in different ethnicities are suggested.

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Pharmacogenetics of isoniazid-induced hepatotoxicity

BACKGROUND AND AIMS Isoniazid (INH) is part of the first-line-therapy for tuberculosis (TB) but can cause drug-induced liver injury (DILI). Several candidate single nucleotide polymorphisms (SNPs) have been previously identified but the clinical utility of these SNPs in the prediction of INH-DILI remains uncertain. The aim of this study was to assess the association between selected candidate SNPs and the risk of INH-DILI and to assess the clinical validity of associated variants in a Singaporean population. METHODS This was a case-control study where 24 INH-DILI cases and 79 controls were recruited from the TB control unit in a tertiary hospital. Logistic regression was used to test for the association between candidate SNPs and INH-DILI. NAT2 acetylator status was inferred from genotypes and tested for association with INH-DILI. Finally, clinical validity measures were estimated for significant variants. RESULTS Two SNPs in NAT2 (rs1041983 and rs1495741) and NAT2 slow acetylators (SA) were significantly associated with INH-DILI (OR (95% CI) = 13.86 (4.30-44.70), 0.10 (0.03-0.33) and 9.98 (3.32-33.80), respectively). Based on an INH-DILI prevalence of 10%, the sensitivity, specificity, positive and negative predictive values of NAT2 SA were 75%, 78%, 28% and 97%, respectively. The population attributable fraction (PAF) and number needed to test (NNT) for NAT2 SA were estimated to be 0.67 and 4.08, respectively. A model with clinical and NAT2 acetylator status provided significantly better prediction for INH-DILI than a clinical model alone (area under receiver operating characteristic curve = 0.863 vs. 0.766, respectively, p = 0.027). CONCLUSIONS We show the association between NAT2 SA and INH-DILI in a Singaporean population and demonstrated its clinical utility in the prediction of INH-DILI.

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Association and clinical utility of NAT2 in the prediction of isoniazid-induced liver injury in Singaporean patients.

Background Isoniazid [isonicotinic acid (INA) hydrazide, INH; PubChem ID 3767] [1] is a first-line antimycobacterial agent used to treat active or latent tuberculosis (TB) infections generated by Mycobacterium tuberculosis [2–4]. INH has been in clinical use for over 60 years [1] and standard regimens for active TB infections include 2 months of treatment with INH, rifampicin, pyrazinamide, and ethambutol or streptomycin, followed by an additional 4 months of INH and rifampicin treatment [2,4,5]. Management of latent TB infections typically involves administration of INH alone (for 6 or 9 months) or in combination with rifapentine (for 3 months) to individuals at high risk of developing active TB [6,7]. Although effective, current therapeutic regimens are very lengthy and difficult to implement [8], and TB remains a major global health problem, with more than 9 million new cases and 1.5 million deaths reported in 2013 [9].

PharmGKB summary: isoniazid pathway, pharmacokinetics.

BACKGROUND AND OBJECTIVE Of three first-line anti-tuberculosis (anti-TB) drugs, isoniazid is most commonly associated with hepatotoxicity. Differences in INH-induced toxicity have been attributed to genetic variability at several loci, NAT2, CYP2E1, GSTM1and GSTT1, that code for drug-metabolizing enzymes. This study evaluated whether the polymorphisms in these enzymes were associated with an increased risk of anti-TB drug-induced hepatitis in patients and could potentially be used to identify patients at risk of liver injury. 

METHODS AND DESIGN In a cross-sectional study, 2244 tuberculosis patients were assessed two months after the start of treatment. Anti-TB drug-induced liver injury (ATLI) was defined as an ALT, AST or bilirubin value more than twice the upper limit of normal. NAT2, CYP2E1, GSTM1 and GSTT1 genotypes were determined using the PCR/ligase detection reaction assays. 

RESULTS 2244 patients were evaluated, there were 89 cases of ATLI, a prevalence of 4% 9 patients (0.4%) had ALT levels more than 5 times the upper limit of normal. The prevalence of ATLI was greater among men than women, and there was a weak association with NAT2*5 genotypes, with ATLI more common among patients with the NAT2*5*CT genotype. The sensitivity of the CT genotype for identifying patients with ATLI was 42% and the positive predictive value 5.9%. CT ATLI was more common among slow acetylators (prevalence ratio 2.0 (95% CI 0.95,4.20) )compared to rapid acetylators. There was no evidence that ATLI was associated with CYP2E1 RsaIc1/c1genotype, CYP2E1 RsaIc1/c2 or c2/c2 genotypes, or GSTM1/GSTT1 null genotypes. 

CONCLUSIONS In Xinjiang Uyghur TB patients, liver injury was associated with the genetic variant NAT2*5, however the genetic markers studied are unlikely to be useful for screening patients due to the low sensitivity and low positive predictive values for identifying persons at risk of liver injury.

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The incidence of liver injury in Uyghur patients treated for TB in Xinjiang Uyghur autonomous region, China, and its association with hepatic enzyme polymorphisms nat2, cyp2e1, gstm1 and gstt1.

The invention discloses a special tool for replacing a split conductor spacer rod, consisting of an insulator rod and a telescopic rod, wherein the insulation rod is connected with the telescopic rod into a whole, an insulation hanger is arranged on the upper end of the telescopic device, an insulation drag hook is arranged at the lower end of the telescopic device, the hanger and the drag hook are same in direction, when the telescopic device is in the stretched state, the distance between the hanger and the hook is larger than the interval between split conductors, and when the telescopic device is in the retracting state, the distance between the hanger and the hook is equal to the intervals of the split conductors. Due to the development success of the special tool for replacing the split conductor spacer rod disclosed by the invention, various problems of complicated operation, long work time, high labor intensity and the like caused by the conventional work method can be solved, not only is the operation safety of a maintainer reinforced, and the electrified overhaul operation level is further close to the standard operation. Meanwhile, the power cut for overhaul can be avoided, the loss of power consumption can be reduced, and the reliability of a power supply circuit and the system stability can be improved.

Special tool for replacing split conductor spacer rod

The invention discloses a self-turning type wire walking foreign body clearing fire attacking device which comprises a self-turning type falling pulley, a major rope, a minor rope, and a shot line. The self-turning type wire walking foreign body clearing fire attacking device further comprises a right-angle triangular support. The vertical edge of the right-angle triangular support is fixed on the major rope, and the vertical edge of the right-angle triangular support is provided with an upward extending section. When the self-turning type wire walking foreign body clearing fire attacking device is used, the upper section of the extending section exactly abuts against the lower end face of the self-turning type falling pulley. The upper right-angle edge of the right-angle triangular support is provided with another extending section extending towards the direction of the bevel edge of the right-angle triangular support, an end portion of the another extending section is provided with an L-shaped bend, and the upper end portion of the bend is provided with a U-shaped fence tank. A U-shaped alcohol lamp is arranged in the U-shaped fence tank, and the distance between the upper end of the alcohol lamp and a wire is 10 centimeters. The distance between the alcohol lamp and the major rope is 40 centimeters. A rope ring is arranged on the upper right-angle edge of the right-angle triangular support, and the minor rope is tied to the rope ring. The alcohol lamp is a jar-shaped alcohol lamp. The diameter and the height of an alcohol jar are both 8 centimeters. The height of flame formed when alcohol burns is 4 centimeters. The whole foreign body clearing link needs to be accomplished only by two persons, so that the self-turning wire walking foreign body clearing fire attacking device and the using method of the self-turning wire walking foreign body clearing fire attacking device are simple, rapid and practical.

Self-turning type wire walking foreign body clearing fire attacking deviceand using method thereof

The utility model discloses a special tool for changing a split conductor spacer. The special tool comprises an insulating bar and a telescoping device, and the insulating bar and the telescoping device are connected as an integrated one. An upper end of the telescoping device is provided with an insulating hook. A lower end of the telescoping device is provided with an insulating drag hook. The hook and the drag hook have the same direction. A distance between the hook and the drag hook is larger than a space between the split conductors when the telescoping device is stretched. When the telescoping device is retracted, a distance between the hook and the drag hook is equal to the space between the split conductors. Development success of the special tool for changing the split conductor spacer solves a plurality of problems of cumbersome working, long working time, high labour intensity, etc. brought about by the prior art. The special tool not only improves working safety of maintainers, but also makes live maintenance operation level of the maintainers stride forward standardized operation. The special tool prevents power cut for maintenance, reduces loss of power sale quantity, and improves reliability of power supply circuit and stability of a system.

Special tool for changing split conductor spacer

The utility model discloses a tool special for the hot-line cleaning of an anti-pollution porcelain insulator The tool consists of a handle and a cleaning brush The cleaning brush consists of a fixed brush and a movable brush Brush bodies of the fixed brush and the movable brush are cambered plates The fixed brush and the movable brush are double-sided brushes The fixed brush is connected with the handle through a connecting plate The movable brush is hinged with the connecting plate through a shaft The fixed brush and the movable brush enclose a circular ring with a V-shaped nick which is formed in the front end part of the cleaning brush An extension spring is arranged between the fixed brush and the movable brush, is arranged on the cambered plate on the side, where the V-shaped nick is not formed, of the circular ring which is enclosed by the fixed brush and the movable brush and provided with the V-shaped nick, and is at a certain distance away from the shaft The tool can be used for the hot-line cleaning of dust from the anti-pollution porcelain insulator, and power is not required to be cut off for a user in a cleaning process, so that the uninterruptible power utilization requirements of the user are met

Yang Lei

Papers

The incidence of liver injury in Uyghur patients treated for TB in Xinjiang Uyghur autonomous region, China, and its association with hepatic enzyme polymorphisms nat2, cyp2e1, gstm1 and gstt1.

Special tool for replacing split conductor spacer rod

Self-turning type wire walking foreign body clearing fire attacking deviceand using method thereof

Special tool for changing split conductor spacer

Tool special for hot-line cleaning of anti-pollution porcelain insulator