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OBJECTIVE：To prelimi narily investigate the possible mechanism of orazamide to prevent anti-tuberculosis drug-induced liver injury （ATB-DILI）. METHODS ：A total of 60 Kunming mice were randomly divided into blank group ，model group，positive control group [diammonium glycyrrhizinate 60 mg/（kg·d）]，orazamide low-dose ，medium-dose and high-dose groups [ 80，160，320 mg/（kg·d）]，with 10 mice in each group. Except for blank group ，other groups were given isoniazid [ 75 mg/（kg·d）]+rifampicin [ 75 mg/（kg·d）] for 14 days intragastrically to induce ATB-DILI model. At the same time ，administration groups were given relevant medicine intragastrically ，blank group and model group were given normal saline intragastrically. The administration volume was 20 mL/（kg·d），once a day ，for consecutive 14 days. The general conditions of the mice were observed and recorded every day ，such as growth and development ，mental and diet state. After last medication ，liver index was calculated ， and HE staining was adopted to observe pathological changes of liver tissue of mice. The positive expression of high mobility group protein B 1 （HMGB1） and NF-κ B in liver tissue were detected by streptavidin biotin-peroxidase complex （SABC） immuno- histochemistry. The serum levels of liver function indexes in serum ，the protein expression of advanced glycation end product receptor（RAGE）and TNF-α in liver tissue were detected by ELISA. RESULTS：Compared with blank group ，the growth and development of mice in the model group were slow ，and their appetite and spirit were poor. The liver index ，serum levels of TBIL ， DBIL，ALT，AST，ALP，TBA and γ-GT were increased significantly （P＜0.05）. Structural disorder of liver lobules ，degeneration and necrosis of liver cells and inflammatory cell infiltration were observed. The expression of HMGB 1，NF-κB，RAGE and TNF-α in liver tissue were elevated significantly （P＜0.05）. Compared with model group ，the general condition of mice were all improved to different extents in orazamide low-dose ，medium-dose and high-dose groups ，positive control group ，while liver index and above serum indexes were all decreased significantly （P＜0.05）. The pathological changes of liver tissue were all improved to different extents ，while the protein expression of HMGB 1，NF-κB，RAGE and TNF-α were all decreased significantly（P＜0.05）. The improvement of above indexes in orazamide high-dose group were all significantly better than orazamide low-dose and medium-dose groups （P＜0.05）；the levels of ALP and TBA in orazamide high-dose group were significantly lower than positive control group （P＜0.05）. CONCLUSIONS ：Orazamide can prevent ATB-DILI induced by isoniazid combined with rifampicin in mice，the mechanism of which may be associated with down-regulating the protein expression of HMGB 1 and RAGE in liver tissue and inhibiting the secretion of inflammatory factors.
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Objective No study has been reported on the association between the abnormal methylation of drug metabolic enzymes and anti-tuberculosis drug-induced liver injury (ATLI). This article aimed to investigate the relationship of ATLI with the methylation of the CpG islands in the promoter regions of cytochrome P450 2E1 (CYP2E1) and glutathione s-transferase M1 (GSTM1) in Chinese Mongolian patients with tuberculosis (TB). Methods This retrospective study included 93 cases of TB diagnosed and treated in the TB prevention and treatment institutions of Tongliao, Inner Mongolia, between September 2016 and December 2017, which were divided into an ATLI (n = 31) and a non-ATLI group (n = 62), the former with and the latter without ATLI within 6 months after anti-TB medication. We compared the methylation levels of the CYP2E1 and GSTM1 genes between the two groups of patients and analyzed the risk factors of ATLI. Results In comparison with the non-ATLI controls, the patients of the ATLI group showed significantly lower methylation levels in the promoter regions of CYP2E1 (0.759 ± 0.066 vs 0.694 ± 0.091, P < 0.05) and GSTM1 (0.207 ± 0.093 vs 0.187 ± 0.092, P < 0.05). Multivariate logistic regression analysis revealed that the main risk factors of ATLI included alcohol consumption (OR = 5.329, 95% CI: 1.442-19.697, P < 0.05) and methylation in the CYP2E1 promoter region (OR = 0.312, 95% CI: 0.165-0.591, P < 0.05) in the TB patients. Conclusion ATLI is associated with the methylation level in the promoter region of the CYP2E1 gene in Chinese Mongolian patients with tuberculosis, indicating that the methylation of CYP2E1 could be used as a biomarker in the prevention and control of ATLI.
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Objective To explore the expression levels of serum nitric oxide(NO)and nitric oxide synthase(NOS) between Han and Uyghur nationality patients with anti-tuberculosis drug-induced liver injury(ATDLI). Methods Patients with confirmed ATDLI in Chest Hospital of Xinjiang Uyghur Autonomous Region and First Affiliated Hos-pital of the Medical College of Shihezi University between January 2015 and May 2016 were chosen and divided into Han group and Uyghur group.By detecting the expression levels of NO and NOS in serum of ATDLI patients,ex-pression levels of serum NO and NOS in ATDLI patients of different gender,body mass index(BMI),and liver function injury were compared.Results 100 ATDLI patients in Han group and 135 in Uyghur group were recruited in study. Expression levels of NO and TNOS in Han group were(134.24±27.60)μmol/L and(33.01 ±4.23)U/mL respectively,in Uyghur groups were(97.10±17.41)μmol/L and(27.41 ±3.95)U/mL respectively,serum levels of NO,TNOS,iNOS,and eNOS in Han patients were all higher than Uyghur patients,difference was statistically significant(P<0.01). In Han ATDLI group,serum levels of NO and TNOS in male patients were both higher than female patients(P<0.05);in Uyghur ATDLI group,serum levels of NO,TNOS,and iNOS in male patients were all higher than female patients(P<0.01). The expression levels of serum NO,TNOS,and iNOS of Han group were all higher than the same gender in Uyghur group(P<0.001),difference in levels of NO and TNOS among different body mass index(BMI)groups in Han and Uyghur patients were both statistically significant(P<0.01). In both group,levels of NO and TNOS in obese patients were both higher than lean patients and normal weight patients(P<0.05). The correlation analysis showed that NO levels of Han and Uyghur groups were both positively correlated with BMI(r=0.444,0.677,respectively,P<0.01). There were significant differences in serum NO and NOS levels between Han and Uyghur patients with different degrees of liver injury(P<0.05);NO and NOS levels in both groups with mild liver injury were both lower than those with moderate and severe injury (P<0.001).Conclusion Serum NO and NOS levels between ATDLI Han group and Uyghur group are different,serum NO level is related to BMI,and it can increase with the degree of liver injury.