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BACKGROUND AND PURPOSE With the development of anti-TB chemotherapy, anti-TB drug-induced liver injury (ADIH) also paid close attention to. Domestic and foreign scholars in recent years is accelerating research from multiple perspectives ADIH pathogenesis, which subcellular level is undoubtedly affected by the more attention one more help from the most basic to understanding ADIH. The occurrence of liver injury is the result of drugs imbalance of toxic metabolites in the liver and its detoxification process. Well-known mitochondrial is the most important intracellular organelles, and contains abundant mitochondria in mammalian liver cells, when TB patients taking anti-TB drugs is bound to affect important physiological function of mitochondria and mitochondrial DNA (mtDNA), so we have plenty of reason to believe that the hepatocyte mitochondrial damage and ADIH has a close relationship. Copy mouse liver injury model we apply several common first-line anti-TB drugs, detailed monitoring of changes in the mouse liver mitochondria indicators from the subcellular level, through the study mitochondrial damage in mice ADIH the role, to explore ADIH pathogenesis and for our clinicians Science, reasonable use of anti-TB drugs, TB individualized treatment and reduce the occurrence of ADIH provide a theoretical basis. Methods 150 mice were randomly divided into five groups for the control group (C group), respectively rifampin group (RFP), isoniazid group (INH), pyrazinamide (PZA) group and three drugs mixed group (MIX). Control group 0.3ml / d saline, rifampicin 135mg/kg.d, isoniazid 90 mg / kg.d, the pyrazinamide 315mg/kg.d, mixed group (135 90 315) mg / kg. d, daily gavage once the medication 3 days, 7 days, 15 days later batches mice were sacrificed and the specimens were taken. All animals weighed prior to administration, of Qiemo administration fasting 12h. Dynamic observation groups: ① medication before and after the change in body weight; ② liver index differences; ③ electron microscopy of liver cell ultrastructural changes; ④ hepatocyte mitochondrial malondialdehyde (MDA) content; ⑤ hepatic mitochondrial superoxide dismutase (SOD) activity changes; dynamic changes of the the ⑥ hepatocyte mitochondrial glutathione peroxidase (GSH-PX); (vii) the mtDNA the total methylation level change; ⑧ mtDNA 8-hydroxy-deoxyguanosine (8-OH-dG) content changes. Results the mice their own weight in addition to the control group, the the PZA group and medication 3 days after the RFP group, the rest of the drug group in each time period will result in varying degrees of ease of the mouse's own weight. Liver index change medication three days later, the treated mice liver index compared with the control group slightly elevated, but not significantly; 7 days after treatment, compared with the control group, the rest of the group liver index were higher and the MIX group compared with the other four groups, a statistically significant difference; medication after 15 days and 7 days after treatment, similar to, but compared with the control group, elevated liver index trend more obvious MIX group with the rest There were significant differences in the four groups, the addition significant difference compared with the control group, RFP group. Prolonged administration time, with the RFP, the liver index gradually increased, compared with medication 3 days, 7 days after the medication and the medication after 15 days were statistically significant; PZA administration time prolonged, liver index gradually increased than 3 days after treatment, the medication after 15 days there is a statistically significant difference, and 7 days after treatment compared to 15 days after treatment, the same significant difference, but INH and MIX With the prolongation of treatment time, little change in liver index. Medication 3 days after the body weight of mice decreased the value of changes in body weight in mice, compared to the control group with INH group and the the MIX group with RFP compared are statistically different; 7 days after the body weight of mice decreased but the medication less small, there was no statistically significant difference between the groups compared; medication for 15 days after the body weight of mice reduced very significantly, the remaining four treatment group compared with the control group were statistically significant. In addition, the medication 3 days, 7 days, 15 days, weight change values ??were not statistically different between the treatment group. The content of MDA in liver mitochondria, there was no statistically significant difference between drug group. However, extension of time with the medication each drug group MDA content were increased in varying degrees, which similar to the RFP and INH medication 7 days and 15 days later than 3 days after the treatment, a statistically significant difference; MIX group after 15 days of drug and medication 3 days later than the significant difference; PZA medication 3 days, 7 days, 15 days was not statistically significant. Mitochondrial SOD activity in mouse hepatocytes, medication for 3 days, a slight decrease in the trend in the treated group compared with the control group, but no significant difference; 7 days after treatment, compared with the control group, RFP, IHN and MIX group significant difference statistically significant difference, and the PZA group compared to the RFP and MIX group; medication 15 days with medication 7 days after the similar, but compared to PZA with IHN also statistically significant. MIX medication after 15 days with the medication three days later phase With prolonging medication time drug group mice liver mitochondrial SOD activity have different levels of reduction, RFP medication 7 days and 15 days and 3 days after treatment, a statistically significant difference compared; than statistically significant; although the mouse liver mitochondrial SOD activity of INH and PZA extension of time with the medication to reduce the trend but little change. In liver mitochondrial GSH-PX vitality, medication after 3 days, compared with the control group, a statistically significant difference in the RFP group, PZA group and MIX group; similar medication after 7 days and 15 days after treatment, compared with the control group, RFP group, INH group, PZA group and MIX group are statistically different, but in the medication after 15 days, the the INH group with the RFP group compared statistically different the PZA group, also a statistically significant difference compared with RFP. No significant rule changes with the the medication time extension of each drug group mice liver mitochondrial GSH-PX activity, but the RFP, INH, PZA three drugs, medication, 7 days and 15 days with 3 days after treatment, compared to the mouse liver mitochondria GSH-PX activity there is a statistically significant difference, which medication after 15 days and 7 days after treatment, compared to the significant difference in the PZA group. In the mouse hepatocytes mtDNA methylation level of anti-TB drugs of mtDNA methylation levels substantially no obvious rule, but medication for 7 days, significant difference compared to the control group and the MIX group, PZA statistically significant difference compared with MIX groups. With the administration time prolonged drug group liver cell mtDNA methylation level there is no significant variation. Medication for 7 days in mouse hepatocytes mtDNA content of 8-OH-dG and similar medication after 15 days, compared with the control group, and the rest of the treatment group were statistically significant, but the medication for 15 days after the RFP group and INH group significant difference compared with the MIX group. With the medication time extension of RFP, PZA, MIX three drugs group mtDNA content of 8-OH-dG gradually increase, which compared with medication 3 days, 7 days and 15 days after the medication significant difference, but in the MIX group medication after 7 days and 15 days after treatment, compared to a statistically significant difference. Electron microscopy mitochondria found: drug groups have varying degrees of swelling in the liver mitochondria, matrix porosity, crest shorter, fracture, vague, incomplete film or even disappear, as well as the vacuoles or contents morphological changes in the mitochondrial. Conclusions of anti-TB drugs can cause liver mitochondria the MDA and mtDNA in 8-OH-dG elevated levels of SOD and GSH-PX activity decreased; trend of as medication time extend the damage was heavier; three types of anti-TB drugs joint medication can increase the degree of damage of mouse liver mitochondria.
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