MECHANISM AND IMMUNOGENETICS OF ANT

MECHANISM AND IMMUNOGENETICS OF ANTITUBERCULOSIS DRUG-INDUCED HEPATOTOXICITY
The biochemical mechanism and pathogenesis of drug-induced hepatotoxicity are still not entirely clear for most offending agents. These uncertainties also apply to the hepatotoxicity induced by antituberculosis agents. While a dose-related toxicity may exist, a direct correlation between serum drug levels and hepatotoxicity has not been well reported.14 Thus, the clinical relevance of therapeutic monitoring of serum rifampicin and isoniazid concentrations in managing antituberculosis drug-associated toxicity is still being explored.15 Hypersensitivity to antituberculosis drugs may be a possibility in some cases of drug-induced hepatitis,16 especially when patients present with concomitant skin rash, fever, arthralgia and eosinophilia. An altered profile of antioxidants with increased lipid peroxidation may suggest that isoniazid- and rifampicin-induced hepatotoxicity are mediated through oxidative damage.17
The interactive hepatotoxicity of isoniazid and rifampicin, as previously alluded, may be due to additive or synergistic effects. One possible mechanism is the enhancement of liver toxicity caused by monoacetyl hydrazine, hydrazine and related compounds resulting from hepatic metabolism through enzyme induction.18 This involves the hydrolase system (so-called direct pathway) (Fig. 1). The pathway is operationally more important in individuals with the slow acetylator phenotype. After some years of investigation, genotyping has revealed that the slow acetylator phenotype comprises a combination of mutant alleles of the N-acetyl transferase 2 (NAT2), as compared with the rapid acetylator phenotype (homozygous NAT2*4) and intermediate acetylator phenotype (heterozygous NAT2*4 and mutant alleles).19 Recently, other genetic polymorphisms have also been found to be associated with antituberculosis drug-induced hepatitis. These include genes of the cytochrome P450 2E120 and glutathione S-transferase M1,21 as well as certain Major Histocompatibility Complex Class II-associated HLA-DQ alleles.

Results (Indonesian) 2:

MEKANISME DAN IMMUNOGENETICS OF antituberkulosis OBAT-TERINDUKSI hepatotoksisitas
Mekanisme biokimia dan patogenesis hepatotoksisitas imbas obat masih belum sepenuhnya jelas bagi kebanyakan agen menyinggung. Ketidakpastian ini juga berlaku untuk hepatotoksisitas yang diinduksi oleh agen antituberkulosis. Sementara toksisitas terkait dosis mungkin ada, korelasi langsung antara tingkat obat serum dan hepatotoksisitas belum juga reported.14 demikian, relevansi klinis pemantauan terapi rifampisin serum dan konsentrasi isoniazid dalam mengelola antituberkulosis toksisitas obat-terkait masih dieksplorasi 0,15 Hipersensitivitas terhadap obat antituberkulosis mungkin kemungkinan dalam beberapa kasus hepatitis imbas obat, 16 terutama ketika pasien datang dengan bersamaan ruam kulit, demam, arthralgia dan eosinofilia. Profil diubah antioksidan dengan peningkatan peroksidasi lipid dapat menunjukkan bahwa isoniazid- dan rifampisin-induced hepatotoksisitas yang dimediasi melalui oksidatif damage.17
The hepatotoksisitas interaktif dari isoniazid dan rifampisin, seperti disinggung sebelumnya, mungkin karena aditif atau efek sinergis. Salah satu mekanisme yang mungkin adalah peningkatan toksisitas hati yang disebabkan oleh hidrazin monoacetyl, hidrazin dan senyawa terkait yang dihasilkan dari metabolisme hati melalui enzim induction.18 ini melibatkan sistem hidrolase (disebut jalur langsung) (Gambar. 1). Jalur secara operasional lebih penting pada individu dengan fenotipe asetilator lambat. Setelah beberapa tahun penyelidikan, genotip telah mengungkapkan bahwa asetilator fenotipe lambat terdiri dari kombinasi alel mutan dari N-asetil transferase 2 (NAT2), dibandingkan dengan fenotipe asetilator cepat (NAT2 homozigot * 4) dan menengah asetilator fenotip (heterozigot NAT2 * 4 dan alel mutan) 0,19 Baru-baru ini, polimorfisme genetik lainnya juga telah ditemukan terkait dengan antituberkulosis obat-induced hepatitis. Ini termasuk gen sitokrom P450 2E120 dan glutathione S-transferase M1,21 serta tertentu Major Histocompatibility Complex Kelas II terkait HLA-DQ alel.