Effects of Ischemia/Reperfusion on Hepatic Secretion and Microsomal Drug- Metabolism in rat

ABSTRACT

Ischemia causes tissue necrosis in a wide variety of pathologic conditions. Permanent deprivation of blood flow is lethal to any tissue and the prudent therapy for ischemia unquestionably is reperfusion. While reperfusion is necessary to reverse the progression towards ischemic death, reperfusion is also thought to be accompanied by its own component of injury. Oxygen free radicals, formed during ischemia/reperfusion, have been proposed as one of the main causes of reperfusion injury. Free radical attacks on biological membrane, such as mitochondria and endoplasmic reticulum, and can lead to the oxidative destruction of the polyunsaturated fatty acids of the membranes through lipid peroxidation. However, direct association between microsomal lipid peroxidation in vivo after ischemia/reperfusion and changes in secretory function and drug metabolism on the liver have not been established. Therefore, present study was performed to evaluate the hepatic secretory function and the hepatic microsomal drug metabolizing enzyme activity after ischemia/reperfusion preparation in rat liver. Further, the effect of oxygen free radical scavengers was investigated. The animals were divided into sham operation group and ischemia/reperfusion group. The ischemia/reperfusion group was subdivided into non-treated control and treated (with superoxide dismutase, allopurinol, alpha-tocopherol, deferoxamine) groups. Hepatic ischemia was produced by clamping the left branches of portal vein and hepatic artery, resulting in complete ischemia to the median and left lobes while the right lobes remained per Fused to prevent intestinal congestion. Reperfusion was permitted by declamping after 1 hour. After 1 or 5 hours of reperfusion, bile was collected, blood was obtained from abdominal aorta, and liver microsomes were isolated. The results are as follows. Serum aminotransferase was increased 15~20 times by ischemia/reperfusion. However, this increase was attenuated by free radical scavengers, especially 5 hours of reperfusion. The wet weight-to-dry weight ratio of the liver was significantly increased by ischemia/reperfusion. alpha-tocopherol pretreatment minimized the increase of ratio. Malondialdehyde level in the liver microsomal fraction was significantly increased after ischemia/reperfusion, but this increase was attenuated by scavenger pretreatment, especially alpha-tocopherol. Bile flow and cholate output but not the bilirubin output, were decreased after ischemia/reperfusion. The free radical scavenger pretreahnent restored the secretion significantly. Cytochrome P-450 content was significantly decreased after ischemia/reperfusion and ameliorated by free radical scavenger pretreatment. NADPH cytochrome P-450 reductase activity and aminopyrine N-demethylase activity were also decreased and improved by free radical scavengers pretreatment. These results indicate that ischemia/reperfusion deteriorates the hepatic secretory function as well as hepatic microsomal drug metabolizing enzyme activity, and the oxygen free radical scavengers attenuate the functional changes of the liver induced by ischemia/reperfusion.