| Summary: | 碩士 === 國立陽明大學 === 藥理學研究所 === 97 === There is two thirds of the global population living under the threat of tuberculosis (TB), and about nine percent of the patients receiving TB drugs may develop adverse drug reactions (ADRs). Gene, gender, age and past medication history are risk factors for TB drugs-induced adverse reactions, but there is no confident evidence showing which factor is the most crucial. Isoniazid (INH) is one of the first-line antituberculosis medication in prevention and treatment. Cytochrome P450 2E1 (CYP2E1), Glutathione S-transferase Mu 1 (GSTM1), and N-acetyltransferase 2 (NAT2) are thought to be involved in its metabolism. Previous studies suggested that the genetic polymorphisms of these three drug-metabolizing enzymes are associated with TB drug–induced hepatitis. The first aim of this study is to clarify whether that polymorphisms of the genes that encode these enzymes associates with the TB drugs-induced adverse reactions. Furthermore, since tuberculosis patients are always administrated with multiple TB drugs, it is hard to distinguish which TB drug caused these adverse reactions. The second aim of this study is to establish an in vitro T cell culture system to find out which TB drug causes the adverse drug reactions. In this study, DNA sequencing method was used to prove the relationship between genetic polymorphisms of TB drug-metabolizing enzymes and the adverse drug reactions. Three SNPs (RS1208、RS1799930、RS1799931) causing residue changes were found in higher frequencies in the TB drug-hypersensitive patients (n=17). In addition, there are two significant SNPs associated with TB drugs–induced ADRs in the promoter region of GSTM1 gene (n=8). Nevertheless, the sample size for the genetic association study is not sufficient, therefore there is no conclusive result of the relationship between the genetic polymorphisms of TB drugs-metabolizing enzymes and the incidence of TB drug adverse reactions. In addition, cytokine releasing assay was used to exam the activation of TB-drug specific T cells upon the stimulation of TB drugs. Certain TB drugs were able to stimulate the T cells of hypersensitive patients to proliferate and secrete more TNF-alpha. These results suggest that using an in vitro T cell culture system to identify the culprit drug of anti-TB-agents induced hypersensitivity is feasible. The underlying mechanism of anti-TB-agents induced hypersensitivity mechanism is unclear and awaits the further in-depth study.
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