tetracycline and bicyclol

Endoplasmic reticulum (ER) stress is known to be involved in the development of several metabolic disorders, including non-alcoholic fatty liver disease (NAFLD). Tetracycline can cause hepatic steatosis, and ER stress may be involved in tetracycline-induced fatty liver. Our previous study showed that bicyclol has been proven to protect against tetracycline-induced fatty liver in mice, and ER stress may also be involved in bicyclol's hepatoprotective effect. Therefore, this study was performed to investigate the underlying mechanisms associated with ER stress and apoptosis, by which bicyclol attenuated tetracycline-induced fatty liver in mice. Bicyclol (300 mg/kg) was given to mice by gavage 3 times. Tetracycline (200 mg/kg, intraperitoneally) was injected at 1 h after the last dose of bicyclol. At 6 h and 24 h after single dose of tetracycline injection, serum ALT, AST, TG, CHO and hepatic histopathological examinations were performed to evaluate liver injuries. Hepatic steatosis was assessed by the accumulation of hepatic TG and CHO. Moreover, hepatic apoptosis and ER stress related markers were determined by TUNEL, real-time PCR, and western blot. As a result, bicyclol significantly protected against tetracycline-induced fatty liver as evidenced by the decrease of elevated serum transaminases and hepatic triglyceride, and the attenuation of histopathological changes in mice. In addition, bicyclol remarkably alleviated hepatic apoptosis and the gene expression of caspase-3, and increased the gene expression of XIAP. The gene expressions of ER stress-related markers, including CHOP, GRP78, IRE-1α, and ATF6, which were downregulated by bicyclol pretreatment in tetracycline-injected mice. These results suggested that bicyclol protected tetracycline-induced fatty liver partly due to its ability of anti-apoptosis associated with ER stress.

Topics: Alanine Transaminase; Animals; Apoptosis; Aspartate Aminotransferases; Biphenyl Compounds; Cholesterol; Disease Models, Animal; Endoplasmic Reticulum Chaperone BiP; Endoplasmic Reticulum Stress; Gene Expression; Heat-Shock Proteins; Liver; Male; Mice; Mice, Inbred ICR; Non-alcoholic Fatty Liver Disease; Tetracycline; Transcription Factor CHOP; Triglycerides

Peroxisome proliferators-activated receptor alpha (PPARalpha) and oxidative stress are two important pathological factors in non-alcoholic fatty liver disease (NAFLD). Tetracycline-induced fatty liver was partly due to the disturbance of mitochondrial fatty acids beta-oxidation regulated by PPARalpha. Bicyclol was found to protect against high fat diet-induced fatty liver through modulating PPARalpha and clearing reactive oxygen species (ROS). The present study was performed to further investigate the effect of bicyclol on tetracycline-induced fatty liver and related mechanism in mice. Bicyclol (75, 150, 300 mg/kg) was given orally three times in two consecutive days. Tetracycline (200 mg/kg) was injected intraperitoneally 1h after the last administration of bicyclol. Oxidative stress, mitochondrial function, PPARalpha and its target genes were evaluated by biochemical and RT-PCR analysis. The activity of CYP4A was assessed by liquid chromatography/mass spectrometry (LC/MS) method. Bicyclol significantly protected against tetracycline-induced fatty liver by reducing the accumulation of hepatic lipids and elevation of serum aminotransferase. In addition, bicyclol remarkably alleviated the over-production of thiobarbituric acid-reactive substance. The reduced activity of mitochondrial respiratory chain (MRC) complexes I and IV and mitochondrial permeability transition (MPT) were also improved by bicyclol. Furthermore, bicyclol inhibited the decrease of PPARalpha expression and its target genes, including long-chain acyl CoA dehydrogenase (LCAD), acetyl CoA oxidase (AOX) and CYP4A at mRNA and enzyme activity level. Bicyclol protected against tetracycline-induced fatty liver mainly through modulating the disturbance of PPARalpha pathway and ameliorating mitochondrial function.

Topics: Acyl-CoA Dehydrogenase, Long-Chain; Acyl-CoA Oxidase; Administration, Oral; Alanine Transaminase; Animals; Aspartate Aminotransferases; Biphenyl Compounds; Cytochrome P-450 CYP2E1; Cytochrome P-450 CYP4A; Disease Models, Animal; Electron Transport Complex I; Electron Transport Complex IV; Fatty Acids; Fatty Liver; Lipid Peroxidation; Liver; Male; Mice; Mice, Inbred ICR; Mitochondria, Liver; Mitochondrial Membrane Transport Proteins; Mitochondrial Permeability Transition Pore; Oxidative Stress; PPAR alpha; Protective Agents; Tetracycline; Time Factors

To study the effect of bicyclol on lipid disorder and liver damage induced by tetracycline in mice, mice were given (ig) bicyclol (75, 150, and 300 mg x kg(-1)) three times before or after administration of tetracycline (180 mg x kg(-1)). The contents of hepatic lipids, MDA and GSH, serum lipids and ALT/AST levels were measured 24 hours after the injection (ip) of tetracycline. The beta-oxidation rate of hepatic mitochondrial fatty acid and hepatic secretion of VLDL were also observed. Bicyclol (150 and 300 mg x kg(-1)) provided significant protection against fatty liver by inhibiting the elevation of hepatic TG and CHO, adjusting abnormal serum lipids, inhibiting the elevation of serum ALT, AST, and ameliorating the severity of pathological changes. Furthermore, bicyclol significantly accelerated the VLDL (TG) secretion and reversed the impairment of mitochondrial oxidation, resulting in the lipid homeostasis. The increase of MDA formation and depletion of GSH that reflect lipid peroxidation induced by tetracycline were also inhibited by bicyclol administration. The results indicated that the hepatoprotection of bicyclol was mostly due to the improvement on lipid oxidation and transportation as well as the inhibition of lipid peroxidation in tetracycline-intoxicated mice.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Biphenyl Compounds; Cholesterol; Cholesterol, VLDL; Fatty Acids; Fatty Liver; Glutathione; Lipid Peroxidation; Liver; Male; Malondialdehyde; Mice; Mice, Inbred ICR; Mitochondria, Liver; Protective Agents; Random Allocation; Tetracycline; Triglycerides