Polymorphism of the N -acetyltransferase 2 gene as a susceptibility risk factor for antituberculosis drug-induced hepatitis

Abstract

Antituberculosis drug-induced hepatitis is one of the most prevalent drug-induced liver injuries. Isoniazid is the major drug incriminated in this hepatotoxicity. Isoniazid is mainly metabolized to hepatotoxic intermediates by N-acetyltransferase (NAT). However, the association of polymorphic NAT acetylator status and antituberculosis drug-induced hepatitis is debatable. To determine whether acetylator status is a risk factor for antituberculosis druginduced hepatitis, we genotyped NAT2 in 224 incident tuberculosis patients who received antituberculosis treatment. Antituberculosis drug-induced hepatitis was diagnosed based on a positive isoniazid rechallenge test and exclusion of viral hepatitis. Acetylator status was determined by genotyping NAT2 in patients using a polymerase chain reaction with restriction fragment length polymorphism. Univariate analysis and logistic regression analysis were used to evaluate the risk factors of isoniazid-induced hepatitis. Thirty-three patients (14.7%) were diagnosed with antituberculosis drug-induced hepatitis. Slow acetylators had a higher risk of hepatotoxicity than rapid acetylators (26.4% vs. 11.1%, P ‫؍‬ .013). Among patients with hepatotoxicity, slow acetylators had significantly higher serum aminotransferase levels than rapid acetylators. Logistic regression showed that slow-acetylator status (odds ratio [OR], 3.66; 95% CI, 1.58-8.49; P ‫؍‬ .003) and age (OR, 1.09; 95% CI, 1.04-1.14; P < .001) were the only 2 independent risk factors for antituberculosis drug-induced hepatitis. In conclusion, slow-acetylator status of NAT2 is a significant susceptibility risk factor for antituberculosis drug-induced hepatitis. Additionally, slow acetylators are prone to develop more severe hepatotoxicity than rapid acetylators. Regular monitoring of serum aminotransferase levels is mandatory in patients receiving antituberculosis treatment, especially in slow acetylators. (HEPATOLOGY 2002;35:883-889.)

An Update on Drug-induced Liver Injury

“…Individuals with slow acetylator status have increased incidence and severity of INH-induced hepatitis. 79 A recent study from New-Delhi, India showed slow acetylator status in 71% of their patients with TB DILI compared to 45% without DILI. 80 Similarly, some 81,82 but not others 83 have found an association of CYP 2E1 genetic polymorphism and GST M1 "null" mutation and GST T1 "NULL" mutation with hepatotoxicity to antituberculous drug.…”

Pharmacogenomics: Challenges and Opportunities

“…Because these reactions often occur in an apparently unpredictable fashion, they have been termed "idiosyncratic," and a genetic predisposition is often invoked. Accrual of patient sets in which to test this idea will require multi-center collaborations (46), and the initial focus of genetic analysis has been on a small number of genes chosen because they may be associated with disease susceptibility (41,42,(47)(48)(49)(50).…”

Genetic variation in carboxylesterase genes and susceptibility to isoniazid-induced hepatotoxicity

“…[10][11][12][13][14] N-acetyltransferase 2 (NAT2) is directly involved in INH metabolism, and genetic variation in the NAT2 gene has been reported to be a risk factor for INHinduced hepatotoxicity. There is wide variability in reported associations of NAT2 variants with INH-induced hepatotoxicity in different populations; [15][16][17][18] however, controversy remains regarding the importance of NAT2 variation for this ADR in different ethnic groups. Factors that may contribute to heterogeneity of NAT2/hepatotoxicity associations include genetic differences between populations 17 and contributions of variation in other genes to this ADR.…”

“…It is likely that NAT2 variation accounts for only a portion of INH-induced hepatotoxicity. [15][16][17][18] An amidase enzyme(s) catalyzes two steps in the metabolism of INH. 19,20 There is strong evidence from an animal model that amidase activity levels influence hepatotoxicity; rabbits treated with an amidase inhibitor, bis-p-nitrophenyl phosphate, at the same time they are dosed with INH fail to develop the severe hepatotoxicity developed by animals treated with INH alone.…”