study of the effect of estrogen hormonal modulation on liver ischemic reperfusion in rats

ABSTRACT

Ischemia/reperfusion [I/R] injury of the liver impaired hepatic regeneration and predisposed to liver failure. The prime factors contributing to injury are decreased nitric oxide [NO] level which favor vasoconstriction, increased production of reactive oxygen species [ROS], increased level of adhesion molecules and leukostasis, which further impair the hepatic microcirculation in the early reperfusion phase. Heat shock protein 70 [HSP70] was shown to be induced by stress. Of the present work was to study the effect of estrogen hormonal modulation on hepatic injury during I/R model in male rats and to investigate the possible involvement of HSP 70 in the gender dimorphic response of the liver to this injury. Forty adult male albino rats were used in this work. They were divided into 5 groups [each of eight rats]; eight rats were taken as normal sham operated group.The remaining rats were subjected to total hepatic I/R. Each group received a specific treatment given intraperitoneally [ip] including 17-beta estradiol [E[2]], raloxifene [Ral.] and genistein [Gen.] one hour before surgical procedure. The sham operated rats were injected with the veichle dimethyl sulfoxide solution. The I/R group was pretreated with the vehicle. Several parameters including serum transaminases, HSP 70, ROS, Myeloperoxidase activity[MPO] and nitrite content were measured using standard assay procedures. I/R produced a significant increase in serum transaminases, MPO and ROS in liver tissue. HSP 70 was induced to a significantly higher level in I/R versus sham operated group but nitrite was significantly reduced in I/R versus sham operated rats. E[2+] I/R group had significantly lower transaminases, MPO and ROS versus I/R untreated group. A significantly higher nitrite level and HSP 70 was detected in liver tissue of E[2+] I/R versus I/R group. Ral.+I/R group showed significant lower serum transaminases, MPO and ROS in liver tissue versus I/R. Also Ral+ I/R showed significant higher nitrite and HSP70 versus I/R group. Gen.+I/R group showed decreased serum transaminases, lower MPO and ROS versus I/R. Nitrite level was significantly higher in Gen.+I/R versus I/R .Compared to E[2+] I/R or Ral.+I/R, geinstein pretreatment showed significantely lower HSP70. 17-beta estradiol pretreatment produced significant protection during hepatic I/R injury through multiple pathways. The protection was related to HSP70 induction, greater NO release, inhibition of ROS and MPO activity in liver tissue. Both the synthetic estrogen receptor modulator [SERM] raloxifene and the phytoestrogen genistein exerted significant estrogen agonist protective effects on the liver I/R injury. The mechanism of raloxifene protection was similar to estradiol, although protection due to genistein pretreatment did not involve HSP70 induction. Protection by genistein could be attributed to enhanced NO release and inhibition of ROS