ABSTRACT
<p><b>BACKGROUND</b>Chronic intermittent hypoxia (CIH) has been associated with abnormalities in the liver, which is the most important organ for drug metabolism. This study aimed to investigate the effect of CIH on theophylline metabolism in mouse liver.</p><p><b>METHODS</b>Eight C57BL/6J mice were exposed to CIH for 12 weeks. Eight C57BL/6J mice were exposed to room air as a control group. Serum levels of alanine aminotransferase and aspartate aminotransferase were measured. Liver histology was observed by light and electron microscopy. Total hepatic cytochrome P450 concentration was measured. Hepatocytes were isolated and incubated with 15 mg/ml theophylline for four hours. After incubation, the theophylline concentration in the supernatant was measured and the theophylline metabolism rate was calculated.</p><p><b>RESULTS</b>CIH did not affect the serum transaminase levels. Livers from mice exposed to CIH showed hepatocellular edema, and liver cells had fuzzy rough endoplasmic reticulum under the electron microscope. The theophylline metabolism rate was significantly inhibited by CIH compared with controls; (16.60 ± 2.43)% vs. (21.58 ± 4.52)% (P = 0.02). The total liver cytochrome P450 concentration in the CIH group was significantly lower than in the control group; (0.83 ± 0.08) vs. (1.13 ± 0.21) mol/mg microsomal protein (P = 0.004).</p><p><b>CONCLUSION</b>CIH decreases theophylline metabolism by mouse hepatocytes, which may correlate with the downregulation of cytochrome P450 expression by CIH.</p>
Subject(s)
Animals , Male , Mice , Chronic Disease , Cytochrome P-450 Enzyme System , Physiology , Hepatocytes , Metabolism , Hypoxia , Metabolism , Liver , Metabolism , Mice, Inbred C57BL , Theophylline , MetabolismABSTRACT
<p><b>BACKGROUND</b>Chronic intermittent hypoxia is the most important pathophysiologic feature of sleep apnea syndrome. The present study aimed to determine whether chronic intermittent hypoxia, which is associated with sleep apnea syndrome, can cause or increase damage to liver cell ultrastructure induced by isoniazid and rifampicin in mice.</p><p><b>METHODS</b>Based on a 2 × 2 full factorial design consisting of two factors of chronic intermittent hypoxia and isoniazid plus rifampicin, 32 male C57B6J mice were randomized into the control group, the chronic intermittent hypoxia group, the isoniazid plus rifampicin group, and the chronic intermittent hypoxia + isoniazid plus rifampicin group. Twelve weeks after treatment, we examined the ultrastructure of liver cells and quantitatively analyzed mitochondrial morphology in C57B6J mice.</p><p><b>RESULTS</b>Chronic intermittent hypoxia did not significantly affect the ultrastructure of liver cells. The main effect of chronic intermittent hypoxia did not lead to an increase of mean profile area or mean perimeter of mitochondria, and a decrease of numerical density on area of mitochondria (all P > 0.05). Isoniazid plus rifampicin significantly affected liver cell ultrastructure. The main effect of isoniazid plus rifampicin resulted in an increase of mean profile area and mean perimeter of mitochondria, and a decrease of numerical density on area of mitochondria (all P < 0.05). Moreover, there was a positive interaction among the chronic intermittent hypoxia and the isoniazid plus rifampicin groups for mean profile area, mean perimeter, and numerical density on area of mitochondria (all P < 0.05).</p><p><b>CONCLUSION</b>Chronic intermittent hypoxia and isoniazid plus rifampicin treatment lead to synergistic liver cell ultrastructural injury.</p>