RESUMO
P300 and HDAC1 can be involved in the development of various liver diseases by regulating gene transcription. Endoplasmic reticulum stress (ERS) is one of the main pathways of apoptosis and is activated during inflammatory responses, but the roles of P300 and HDAC1 in ERS in antituberculosis drug-induced liver injury (ADLI) are not clear. This study confirms that isoniazid can change the states of P300 and HDAC1 in HL-7702 hepatocyte metabolism and induce ERS, causing hepatocyte injury and apoptosis. When combined with C646, however, P300 can be reduced. HL-7702 cells were flattened, and the cytoplasm became crinkled. To a certain extent, ERS was relieved, but hepatocytes suffered worse damage, and the rate of cell apoptosis markedly increased. When MS-275 was applied, HDAC1 level was increased, cell fusion appeared, and fluorescence intensity of endoplasmic reticulum was weakened. In addition, ERS was aggravated, but liver injury was relieved, and the apoptosis rate significantly decreased. Therefore, alteration of P300 and HDAC1 status and ERS are involved in ADLI, and changes in P300 and HDAC1 can regulate ERS and then affect cell damage.
RESUMO
This study explores the mechanism of histone acetylation under the effect of oxidative stress in rat liver injury induced by isoniazid (INH). Fifty-six adult SD rats were selected and divided randomly into INH groups (48) and control (8). Rats in INH groups were intragastrically injected with 55 mg kg-1 day-1 for 3, 7, 10, 14, 21, and 28 days, and control rats were given an equal volume of distilled water. Pathological changes in liver tissues were observed by HE staining. Western blot analysis was conducted to measure the expression levels of H3k14ac and H4k8ac. The activities of HAT, HDAC and IL-1ß, and TNF-α were detected by ELISA in liver tissues. Real-time RT-PCR analysis was performed to determine the protein expression levels of HAT, HDAC, and IL-1ß and the mRNA expression of TNF-α. The levels of superoxide dismutase (SOD) and malondialdehyde (MDA) were assayed by biochemical methods in liver tissues. At different time points, the SOD activity decreased, whereas the MDA content significantly increased after 14 days (FSOD = 11.15, FMDA = 7.42, P < 0.01). During this period, the expression of histone acetylated H3K14 and H4K8 acetylation decreased compared with the control group (FH3K14 = 4.18, FH4K8 = 3.87, P < 0.05); by contrast, HDAC1 and HDAC2 showed a high expression level compared with those in the control group (FHDAC1 = 29.13, FHDAC2 = 58.34, P < 0.01). Moreover, the expression of CBP/P300 was lower than that in the control group (FCBP/P300 = 12.18, P = 0.001), and the protein contents of IL-1ß and TNF-α in rat liver tissues were up-regulated (FIL-1ß = 44.88, FTNF-α = 41.56, P < 0.01). These results suggest that histone acetylation is involved in INH-induced rat liver injury. Furthermore, the hypoacetylation of histones H3K14 and H4K8 is negatively correlated with oxidative stress-mediated rat liver injury.