Park Sang Won, Kang Jung-Woo, Lee Sun-Mee
Department of Pharmacology, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju 52727, Republic of Korea.
School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do 16419, Republic of Korea.
Toxicol Appl Pharmacol. 2016 Feb 1;292:30-9. doi: 10.1016/j.taap.2015.12.025. Epub 2015 Dec 31.
This study was designed to investigate the role of heme oxygenase-1 (HO-1) in hepatic drug metabolizing dysfunction after ischemia/reperfusion (IR) in alcoholic fatty liver (AFL). Rats were fed a Lieber-DeCarli diet for five weeks to allow for development of AFL and were then subjected to 90min of hepatic ischemia and 5h of reperfusion. Rats were pretreated with hemin (HO-1 inducer) or ZnPP (HO-1 inhibitor) for 16h and 3h before hepatic ischemia. After hepatic IR, ethanol diet (ED)-fed rats had higher serum aminotransferase activities and more severe hepatic necrosis compared to the control diet (CD)-fed rats. These changes were attenuated by hemin and exacerbated by ZnPP. The activity and gene expression of HO-1 and its transcription factor (Nrf2) level increased significantly after 5h of reperfusion in CD-fed rats but not in ED-fed rats. After reperfusion, cytochrome P450 (CYP) 1A1, 1A2, and 2B1 activities were reduced to levels lower than those observed in sham group, whereas CYP2E1 activity increased. The decrease in CYP2B1 activity and the increase in CYP2E1 activity were augmented after hepatic IR in ED-fed animals. These changes were significantly attenuated by hemin but aggravated by ZnPP. Finally, CHOP expression and PERK phosphorylation, microsomal lipid peroxidation, and levels of proinflammatory mediators increased in ED-fed rats compared to CD-fed rats after reperfusion. These increases were attenuated by hemin. Our results suggest that AFL exacerbates hepatic drug metabolizing dysfunction during hepatic IR via endoplasmic reticulum stress and lipid peroxidation and this is associated with impaired HO-1 induction.
本研究旨在探讨血红素加氧酶-1（HO-1）在酒精性脂肪肝（AFL）缺血/再灌注（IR）后肝脏药物代谢功能障碍中的作用。大鼠喂食Lieber-DeCarli饮食5周以诱导AFL形成，随后进行90分钟肝脏缺血和5小时再灌注。在肝脏缺血前16小时和3小时，大鼠分别用血红素（HO-1诱导剂）或锌原卟啉（ZnPP，HO-1抑制剂）预处理。肝脏IR后，与喂食对照饮食（CD）的大鼠相比，喂食乙醇饮食（ED）的大鼠血清转氨酶活性更高，肝坏死更严重。这些变化被血红素减轻，被ZnPP加重。在CD喂养的大鼠再灌注5小时后，HO-1及其转录因子（Nrf2）水平的活性和基因表达显著增加，而在ED喂养的大鼠中未增加。再灌注后，细胞色素P450（CYP）1A1、1A2和2B1活性降低至低于假手术组观察到的水平，而CYP2E1活性增加。在ED喂养的动物肝脏IR后，CYP2B1活性的降低和CYP2E1活性的增加更为明显。这些变化被血红素显著减轻，但被ZnPP加重。最后，与CD喂养的大鼠相比，再灌注后ED喂养的大鼠中CHOP表达和PERK磷酸化、微粒体脂质过氧化以及促炎介质水平增加。这些增加被血红素减轻。我们的结果表明，AFL通过内质网应激和脂质过氧化加剧肝脏IR期间的肝脏药物代谢功能障碍，这与HO-1诱导受损有关。
