Effects of N-acetyltransferase 2 (NAT2), CYP2E1 and Glutathione-S-transferase (GST) genotypes on the serum concentrations of isoniazid and metabolites in tuberculosis patients

Abstract

-For the purpose of a side-effect monitoring of isoniazid (INH), we investigated the relationship between the genotypes of drug-metabolizing enzymes involved in INH metabolism and the serum concentrations of INH and its metabolites in 129 tuberculosis patients hospitalizing in the National Hospital Organization Chiba-East Hospital. Genotype distributions of N-acetyltransferase 2 (NAT2), CYP2E1*5B, CYP2E1*6, Glutathione-S-transferase (GST) M1 and GST T1 were similar to those already reported in Japanese populations. Acetylating pathway of INH to acetyl isoniazid (AcINH) tended to shift to the hydrolytic pathway generating hydrazine (Hz) with the increase of mutant alleles in NAT2 gene.tration of rifampicin (RFP) than in which RFP was not detected. The effect of CYP2E1 gene polymorphisms on the serum concentration of Hz was rarely observed, while that of GST gene polymorphism was observed in intermediate acetylators of NAT2. Hz tended to accumulate in patients with GST M1 null genotype. Therefore, it is conceivable that the risk factors of Hz accumulation are as follows: NAT2 slow acetylator phenotype, high concentration of serum RFP, and GST M1 null genotype. In these cases, we think it's necessary to pay attention to the development of hepatic disorder caused by Hz.

Effect of gene–gene and gene–environment interactions associated with antituberculosis drug-induced hepatotoxicity

“…PZA increases the hepatotoxicity of INH [34], and nontoxic concentrations of INH and hydrazine increase in-vitro PZA hepatotoxicity [35]. Several surveys reported that genetic alterations in the enzymes involved in the metabolic pathways of INH were associated with hepatotoxicity [36][37][38][39]. We investigated the pharmacogenetics of INH, and our results support this hypothesis.…”

“…The median age of the total study population was 29 (23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36) years and 128 (46.9%) patients were women. The median BMI was 20.8 (18.7-22.4) kg/m 2 and 5.7% were severely underweight.…”

“…Fukino et al [36] reported that the Hz concentration was higher in GSTM1-null than wild-type patients. No individual or combined association between GSTT1 null and GSTM1 null with hepatotoxicity was found in our population (Table 3).…”

Pharmacogenetics and Metabolism: Past, Present and Future

“…As shown in Figure 5, is theoretically possible that GST isoforms, which are genetically determined to a great extent, may also influence INH metabolism. In this way, a study found that well known GSTM1 null genotype influenced the serum concentration of Hz in the NAT2 slow acetylators independently of their CYP2E1 phenotype (Fukino et al 2008). Thus, more efforts are necessary to uncover the important question: interactions between NAT2 and CYP2E1 phenotypes, in addition to the GSTs, may have potential risks for isoniazid-induced hepatotoxicity?…”

Acetylator Status on Tuberculosis Patients Receiving Isoniazid-Contained Antituberculosis Regiment

“…Several studies had been studied about the relationship between acetylator status and risk of hepatotoxic; all of which showed a significant correlation. 3,5,6,9,10,11,12 Otherwise, the proportions of slow acetylator were varies in several studies. Thus indicated the different risk for hepatotoxic effect in different population.…”