Department of Molecular Oncogenetics, Institute of Molecular Biology and Genetics of National Academy of Sciences of Ukraine, Kyiv, Ukraine.
Department of General and Molecular Pathophysiology, Bogomoletz Institute of Physiology of National Academy of Sciences of Ukraine, Kyiv, Ukraine.
Pharmacol Rep. 2017 Dec;69(6):1386-1392. doi: 10.1016/j.pharep.2017.05.020. Epub 2017 Jun 24.
Increased CYP2E1 protein and activity levels can be the main cause of stress-mediated liver damage in diabetes. In this work we investigated the quercetin properties to prevent diabetic oxidative liver injury through inhibition of CYP2E1.
Animals were randomly divided into three groups (n=5 for each group): non-diabetic control, STZ-diabetic rats and STZ-diabetic rats administered with quercetin (50mg/kg bw, per day, during 30days). Markers of oxidative stress and liver injury, hepatocyte ultrastructure and levels of CYP2E1 protein and activity were examined using biochemical, electron microscopy and molecular biological methods.
It was shown that symptoms of diabetes (hyperglycemia, bodyweight loss, damaged hepatocyte ultrastructure), signs of oxidative stress in liver (2-fold intensification of peroxide process and 2-fold depletion of antioxidants) and serum markers of liver damage (3.5-, 1.5- and 5-fold increase in levels of ALT, AST and GGT, respectively) were present in STZ-diabetic rats. We found 3- and 2.5-fold increase in levels of protein and activity of CYP2E1 in the liver of STZ-diabetic rats. We demonstrated that the administration of quercetin leads to significant decrease in CYP2E1 activity (5- and 2-times compared to STZ-diabetic and control group, respectively). That was accompanied by normalization of pro-oxidant-antioxidant balance, improving the ultrastructure of hepatocytes and rates of serum markers of liver injury.
CYP2E1 can play a crucial role in stress-induced pathological processes in the liver in diabetes, and the inhibition of the enzyme by quercetin during the development of diabetes mainly prevents the oxidative damage in liver.
CYP2E1 蛋白和活性水平的增加可能是糖尿病中介导应激导致肝损伤的主要原因。在这项工作中，我们研究了槲皮素通过抑制 CYP2E1 来预防糖尿病氧化肝损伤的特性。
动物随机分为三组（每组 5 只）：非糖尿病对照组、链脲佐菌素糖尿病大鼠组和链脲佐菌素糖尿病大鼠给予槲皮素（50mg/kg bw，每天，30 天）组。使用生化、电子显微镜和分子生物学方法检测氧化应激和肝损伤标志物、肝细胞超微结构以及 CYP2E1 蛋白和活性水平。
结果表明，糖尿病症状（高血糖、体重减轻、肝细胞超微结构受损）、肝脏氧化应激迹象（过氧化物过程增强 2 倍，抗氧化剂减少 2 倍）和血清肝损伤标志物（ALT、AST 和 GGT 水平分别增加 3.5 倍、1.5 倍和 5 倍）均存在于链脲佐菌素糖尿病大鼠中。我们发现链脲佐菌素糖尿病大鼠肝脏中 CYP2E1 蛋白和活性增加了 3 倍和 2.5 倍。我们证明槲皮素的给药导致 CYP2E1 活性显著降低（与链脲佐菌素糖尿病组和对照组相比分别降低 5 倍和 2 倍）。这伴随着促氧化剂-抗氧化剂平衡的正常化，改善了肝细胞的超微结构和血清肝损伤标志物的速率。
CYP2E1 在糖尿病中介导应激的肝脏病理过程中可能发挥关键作用，而在糖尿病发展过程中，酶的抑制主要可预防肝脏的氧化损伤。
