Hepatic changes in adenine nucleotide levels and adenosine 3'-monophosphate forming enzyme in streptozotocin-induced diabetic mice

抄録

To elucidate the pathophysiological significance of adenosine 3'-monophosphate (3'-AMP) forming enzyme in mice, the effect of streptozotocin (STZ) on the enzyme activities and adenine nucleotide levels in the ICR mice (4-week-old) liver was examined. After 2 weeks, treatment with a single dosage of STZ (100, 150 or 200 mg/kg i.p.) induced a dose-dependent hyperglycemia and hypoinsulinemia but had no effect on serum alanine aminotransferase activity, indicating that STZ generated type 1 diabetes without hepatitis. In the diabetic liver, the activities of superoxide dismutase (SOD), catalase and ATP levels decreased, and the microsomal CYP2E1 activity increased. Changes of these biological activities might disrupt the cellular homeostatic balance of reactive oxygen species (ROS) production. The activities of 3'-AMP forming enzyme, one of the ribonucleases, in hepatic homogenates were not altered. However, in the STZ 200 mg/kg group, the cytosolic forming enzyme activities were enhanced, and inversely, the mitochondrial activity was reduced significantly, indicating that the decrease in the mitochondrial activity may be accelerated by development of diabetes due to the decrease in the antioxidant defense system and/or increase in ROS production. With the decrease in the 3'-AMP forming enzyme activity, the levels of 3'-AMP, a P-site inhibitor of adenylate cyclase, in mitochondrial were significantly reduced. These results obtained suggested that change in the mitochondrial 3'-AMP forming enzyme activity might reflect the pathophysiological change of mitochondrial function with the development of diabetes. Our results also suggested that change in cytosolic enzyme activity might serve as a new biomarker of oxidative stress because significant negative correlation between the activities of cytosolic 3'-AMP forming enzyme and SOD was found in the early stage of diabetes.