2016-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/645812Hepatitis due to anti-tuberculosis (TB) drugs is the most important adverse eventof anti-TB chemotherapy. In 2007 to 2008 we conducted a prospective study toinvestigate risk factors of hepatitis during anti-TB treatment. We found that anti-TBdrugs-induced hepatitis occurred in 16.5% of TB patients. Risk factors included: 1)women; 2) N-acetyl transferase 2 (NAT2) slow acetylator; 3) High HBV viral load,and 4) end-stage renal disease.To explore why women have higher risk of anti-TB drugs-induced liver injury thanmen (24 vs. 12%), we conducted a study to investigate the influence of singlenucleotide polymorphisms (SNPs) in the regulatory region of pregnane X receptor(PXR) gene. We found that females with genotype AA at rs2461823 of PXR were 6times more risky of developing anti-TB drugs-induced liver injury than those havingother genotypes. No such association was found in males.To investigate whether final steps in anti-TB drugs-induced liver injury arerelated to mitochondrial ATP production failure, we studied mitochondrial complex I(NADH dehydrogenase) gene variants in patients with liver injury due to anti-TBdrugs and those without. We found that mitochondrial complex I subunit ND4L SNPsoccurred only in patients with anti-TB drugs-induced liver injury; yet complex Isubunit ND5 SNPs occurred only in female patients with anti-TB drugs-induced liverinjury. Thus final steps in anti-TB drugs-induced liver injury might be related to theATP shortage from mitochondrial complex I dysfunction, and gender can influencethe mechanism. (The study is still going on.)Recently keratin gene K8/K18 variants have been associated with liver cirrhosisand drug-induced liver injury, especially fatal episodes (including anti-TB drugINH-induced), and keratins have been reported to modulate the shape and functionof mitochondria. Moreover, rats with low mitochondrial ND6 mRNA expression inblood were found to be susceptible to CCl4-induced liver injury. Therefore wehypothesized that K8/K18 SNP genotype/haplotype (through affecting mitochondriafunction), and blood mitochondrial ND6 mRNA expression may be associated withanti-TB drugs-induced liver injury. The distribution of K8/K18 SNP genotypesand haplotypes, and the percentage of low ND6 mRNA expression may be differentbetween females and males, and the differences may contribute to the higher risk ofanti-TB drugs-induced liver injury in females.We plan to enroll 300 TB patients in 2 years. We’ll sample peripheral blood,sequence K8/K18 SNPs and analyze mitochondria ND6 mRNA expression. Wewill compare K8/K18 SNP genotype/haplotype distribution and ND6 mRNAexpression between TB patients with drug-induced liver injury and those without,and analyze if K8/K18 SNPs and low ND6 mRNA expression contribute to the higherrisk of anti-TB drugs-induced liver injury in females than males.