[1]路 燕,雷 宇,章礼久,等.不同性别小鼠对乙酰氨基酚急性肝损伤的敏感性差异[J].常州大学学报(自然科学版),2017,(06):83-91.[doi:10.3969/j.issn.2095-0411.2017.06.012]
　LU Yan,LEI Yu,ZHANG Lijiu,et al.Different Sensitivity of Acetaminophen-Induced Acute Liver Injury in Mice of Different Genders[J].Journal of Changzhou University(Natural Science Edition),2017,(06):83-91.[doi:10.3969/j.issn.2095-0411.2017.06.012]
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不同性别小鼠对乙酰氨基酚急性肝损伤的敏感性差异()
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常州大学学报(自然科学版)[ISSN:2095-0411/CN:32-1822/N]

卷:
期数:
2017年06期
页码:
83-91
栏目:
其他
出版日期:
2017-12-10

文章信息/Info

Title:
Different Sensitivity of Acetaminophen-Induced Acute Liver Injury in Mice of Different Genders
作者:
路 燕1; 2; 雷 宇3; 章礼久1; 徐德祥2
1.安徽医科大学第二附属医院 消化内科,安徽 合肥 230601; 2.安徽医科大学 毒理系,安徽 合肥 230032; 3.安徽医科大学第一附属医院 肿瘤内科,安徽 合肥 230022
Author(s):
LU Yan1; 2;  LEI Yu3;  ZHANG Lijiu;  XU Dexiang2
1. Department of Gastroenterology, Second Affiliated Hospital, Anhui Medical University, Hefei 230601, China; 2. Department of Toxicology, Anhui Medical University, Hefei 230032, China; 3. Department of Oncology, First Affiliated Hospital, Anhui Medic
关键词:
对乙酰氨基酚;  肝损伤;  性别
Keywords:
acetaminophen;  liver injury;  gender
分类号:
R 114
DOI:
10.3969/j.issn.2095-0411.2017.06.012
文献标志码:
A
摘要:
对乙酰氨基酚(APAP)过量使用是临床药物性肝损伤常见原因之一。然而不同性别人群对APAP急性肝损伤可能存在差异,进一步探索其机制对预防和治疗不同人群APAP急性肝损伤有一定的意义。采用幼年ICR小鼠和成年ICR小鼠(雌、雄若干只)各分成APAP给药组和对照组,APAP给药组小鼠经腹腔注射给予APAP(300mg/kg),对照组给予生理盐水。结果显示APAP处理后4h和24h成年雄性小鼠血清ALT水平均高于成年雌性小鼠; 组织病理学观察到成年雄性小鼠肝脏坏死面积明显大于成年雌性小鼠; TUNEL结果提示成年雄性小鼠肝脏TUNEL阳性细胞数明显高于成年雌性小鼠。APAP处理后4h成年雄性小鼠肝脏p-JNK水平明显高于成年雌性小鼠。免疫组化显示APAP处理后4h和24h成年雄性小鼠肝脏3-NT阳性细胞数明显多于成年雌性小鼠。APAP处理后成年雄性小鼠肝脏GSH消耗量较成年雌性小鼠大,且GSSG/GSH比值上升较成年雌性小鼠更明显。成年雄性小鼠肝脏GPX和GST活性均低于成年雌性小鼠。因此APAP急性肝损伤的性别差异只存在于成年小鼠,具体表现为成年雄性小鼠比成年雌性小鼠肝损伤更严重。
Abstract:
Acetaminophen overdose is one of the causes of common clinical drug-induced liver injury. However, it may exist difference of APAP-induced liver injury from different genders. Exploring its risk factors have profound significance for clinical treatment of APAP-induced liver injury in different populations. It used immature ICR mice and adult ICR mice(males and females). All mice were divided into two groups: APAP treatment group and control group. APAP treatment group mice were i.p. injected with APAP(300 mg/kg), while control group mice were i.p. saline. Serum ALT of adult male mice were higher than adult female mice both at 4h and 24 h after APAP injection. Liver necrotic areas of adult male mice were larger than adult female mice. TUNEL assay prompted liver TUNEL positive cells in adult male mice were significantly higher than adult female mice. 3-NT expression of liver in adult male mice were significantly higher than adult female mice both at 4h and 24 h after APAP injection. Futhermore, p-JNK level of adult male mice were significantly higher than adult female mice at 4 h after APAP induced. Depletion of GSH in adult male mice were larger than adult female mice. GSSG / GSH ratio of adult male mice were risen higher than adult female mice. GPX and GST activity of adult male mice were lower than adult female mice. Gender differences on APAP-induced acute liver injury were observed only in adult mice. Adult male mice were more susceptible to hepatotoxicity.

参考文献/References:

[1] DAVERN T J. Drug-induced liver disease[J]. Clin Liver Dis, 2012, 16(2): 231-245.
[2]LEE K K, IMAIZUMI N, CHAMBERLAND S R, et al. Targeting mitochondria with methylene blue protects mice against acetaminophen-induced liver injury[J]. Hepatology, 2015, 61(1): 326-336.
[3]LANCASTER E M, HIATT J R, ZARRINPAR A. Acetaminophen hepatotoxicity: an updated review[J]. Arch Toxicol, 2015, 89(2): 193-199.
[4]SCHILLING A, COREY R, LEONARD M, et al. Acetaminophen: old drug, new warnings[J]. Cleve Clin J Med, 2010, 77(1): 19-27.
[5]BLIEDEN M, PARAMORE L C, SHAH D,et al. A perspective on the epidemiology of acetaminophen exposure and toxicity in the United States[J]. Expert Rev Clin Pharmacol, 2014, 7(3): 341-348.
[6]ANDERSON M E. Determination of glutathione and glutathione disulfide in biological samples[J]. Methods Enzymol, 1985,113:548-555.
[7]KJARTANSDOTTIR I, BERGMANN O M, ARNADOTTIR R S, et al. Paracetamol intoxications: a retrospective population-based study in Iceland[J]. Scand J Gastroenterol, 2012, 47(11): 1344-1352.
[8]MCGILL M R, SHARPE M R, WILLIAMS C D, et al. The mechanism underlying acetaminophen-induced hepatotoxicity in humans and mice involves mitochondrial damage and nuclear DNA fragmentation[J]. J Clin Invest, 2012, 122(4): 1574-1583.
[9]ROHRER P R, RUDRAIAH S, GOEDKEN M J, et al. Is nuclear factor erythroid 2-related factor 2 responsible for sex differences in susceptibility to acetaminophen-induced hepatotoxicity in mice? [J]. Drug Metab Dispos, 2014, 42(10): 1663-1674.
[10]SHENG Y, LIANG Q, DENG Z, et al. Acetaminophen induced gender-dependent liver injury and the involvement of GCL and GPX[J]. Drug Discov Ther, 2013, 7(2): 78-83.
[11]MASUBUCHI Y, NAKAYAMA J, WATANABE Y. Sex difference in susceptibility to acetaminophen hepatotoxicity is reversed by buthionine sulfoximine[J]. Toxicology, 2011, 287(1/2/3): 54-60.
[12]TARLOFF J B, KHAIRALLAH E A, COHEN S D, et al. Sex-and age-dependent acetaminophen hepato- and nephrotoxicity in Sprague-Dawley rats: role of tissue accumulation, nonprotein sulfhydryl depletion, and covalent binding[J]. Fundam Appl Toxicol, 1996, 30(1): 13-22.
[13]WAGNER E F, NEBREDA A R. Signal integration by JNK and p38 MAPK pathways in cancer development[J]. Nat Rev Cancer, 2009, 9(8): 537-549.
[14]DAVIS R J. Signal transduction by the JNK group of MAP kinases[J]. Cell, 2000, 103(2): 239-252.
[15]SEKI E, BRENNER D A, Karin M. A liver full of JNK: signaling in regulation of cell function and disease pathogenesis, and clinical approaches[J]. Gastroenterology, 2012, 143(2): 307-320.
[16]SAITO C, LEMASTERS J J, JAESCHKE H. C-Jun N-terminal kinase modulates oxidant stress and peroxynitrite formation independent of inducible nitric oxide synthase in acetaminophen hepatotoxicity[J]. Toxicol Appl Pharmacol, 2010, 246(1/2): 8-17.
[17]ZHANG Y F, HE W, XU D X, et al. Role of receptor interacting protein(RIP)1 on apoptosis-inducing factor-mediated necroptosis during acetaminophen-evoked acute liver failure in mice[J]. Toxicol Lett, 2014, 225(3): 445-453.
[18]SAITO C, ZWINGMANN C, JAESCHKE H. Novel mechanisms of protection against acetaminophen hepatotoxicity in mice by glutathione and N-acetylcysteine[J]. Hepatology, 2010, 51(1): 246-254.
[19]DAI G, HE L, CHOU N, et al. Acetaminophen metabolism does not contribute to gender difference in its hepatotoxicity in mouse[J]. Toxicol Sci, 2006, 92(1):33-41.
[20]DU K, WILLIAMS C D, MCGILL M R, et al. Lower susceptibility of female mice to acetaminophen hepatotoxicity: role of mitochondrial glutathione, oxidant stress and C-jun N-terminal kinase[J]. Toxicol Appl Pharmacol, 2014, 281(1): 58-66.

备注/Memo

备注/Memo:
收稿日期:2017-08-09。
作者简介:路燕(1986—),女,江苏常州人,博士,中级,主要从事药物性肝损伤研究。通讯联系人:徐德祥(1962—),E-mail:xudex@126.com
更新日期/Last Update: 1900-01-01