The Effect Of Chronic Intermittent Hypoxia On Liver Construction And Function In Mice

Objective:To explore the effect of chronic intermittent hypoxia (CIH) on hepatic histological feature and hepatic function, including theophylline metabolism, in mice.Methods:32 male C57BL6J mice were divided into four groups, which were air control group, CIH group, anti-tuberculosis group, and CIH plus anti-tuberculosis group. Total 12 weeks CIH experiment was performed. 2 weeks before sacrifice, mice of anti-tuberculosis group and CIH plus anti-tuberculosis group were treated with rifampicin (25mg/kg/d) and isoniazid (10mg/kg/d) intragastrically, and saline as for control. Serum alanine aminotransferase and aspartate aminotransferase level were detected. Hepatic histological features were observed and hepa-tocyte ultra-structure was observed through electron microscope. Total cytochrome p-450 (CYP450) concentrations of hepatic microsomes were measured. Hepatocytes were isolated and incubated with 15mg/ml theophylline. After hepatocytes were incubated with theophylline for 4 hours, the theophylline concentration in supernatant of hepatocytes were measured.Results:There was no difference among serum aspartate aminotrans-ferase levels of air control group (19.0±9.4IU/L), CIH group (19.1±17.9IU/L), anti-tuberculosis group (9.6±2.1IU/L) and CIH plus anti-tuberculosis group (13.3±4.7IU/L) (P>0.05). There was no difference among serum alanine aminotransferase levels of air control group (65.4±27.0IU/L), CIH group (58.0±24.3IU/L), anti-tubercu-losis group (41.1±17,7IU/L) and CIH plus anti-tuberculosis group (47.8±11.6IU/L) (P>0.05). Mice exposed to CIH caused vacuolar degeneration in liver. Mice exposed to CIH showed cellular edema, fuzzy rough endoplasmic reticulum in hepatocytes, and a little collagen fiber hyperplasia in hepatic disse space. CIH plus anti-tuberculosis could intensify the ultra-structure lesion, which showed fuzzy cellular structures, cellular edema, hepatocytes necrosis, mitochondrial lesion, intensified collagen fiber hyperplasia in hepatic disse space, and abolition of part of cholangioles. Total cytochrome CYP450 concentration of hepatic microsomes of CIH group (0.83±0.08nmol/mgprotein) was lower than that of air control group (1.13±0.21nmol/mgprotein) (P=0.001). Total CYP450 concentration of hepatic microsomes of CIH plus anti-tuberculosis group (0.83±0.08nmol/mgprotein) was lower that of air control group (P=0.001) and that of anti-tuberculosis group (1.19±0.20nmol/mgprotein) (P=0.000). There was no difference between total CYP450 concentra-tion of CIH group and that of CIH plus anti-tuberculosis group(P>0.05). There was no difference between total CYP450 concentration of CIH plus anti-tuberculosis group and that of air control group (P>0.05). CIH could reduce theophylline metabolism by mouse hepatocytes (F=71.6, P=0.000). Anti-tuberculosis could enhance theophylline metabolism by hepatocytes (F=17.7, P=0.000). There was interaction between CIH and anti-tuberculosis on theophylline metabolism (F=689.4, P=0.000).Conclusion:CIH could cause histological feature lesion in mouse liver. CIH could intensify liver ultra-structure lesion caused by anti-tuberculosis drugs. CIH could affect theophylline metabolism through affect CYP450 expression in mouse liver. There was interactive effect between CIH and anti-tuberculosis drugs on theophylline metabolism.