Acylcarnitine profiles in acetaminophen toxicity in the mouse: comparison to toxicity, metabolism and hepatocyte regeneration.
Acylcarnitine profiles in acetaminophen toxicity in the mouse: comparison to toxicity, metabolism and hepatocyte regeneration.
复制标题
DOI：
10.3390/metabo3030606
复制
发表时间：
2013-08-02
期刊：
影响因子：
4.1
通讯作者：
James L
中科院分区：
文献类型：
--
作者：
Bhattacharyya S;Pence L;Beger R;Chaudhuri S;McCullough S;Yan K;Simpson P;Hennings L;Hinson J;James L
高剂量对乙酰氨基酚（APAP）导致肝毒性，涉及母体化合物的代谢活化、反应性中间体N-乙酰基-对苯醌亚胺（NAPQI）与肝蛋白的共价结合以及肝谷胱甘肽的消耗。脂肪酸β-氧化受损与APAP诱导肝毒性的既往研究有关。为了更好地理解APAP毒性中毒性与肝脏中脂肪酸β-氧化之间的关系，在小鼠的时程研究中，检查了长链酰基肉毒碱的代谢组学测定与肝毒性、氧化代谢和肝再生的既定标志物的关系。雄性B6 C3 F1小鼠用APAP（200 mg/kg IP）或盐水处理，并在APAP后1、2、4、8、24或48 h处死。在1小时，肝谷胱甘肽耗尽和APAP蛋白加合物显着增加。丙氨酸氨基转移酶（ALT）水平在4和8 h升高，而增殖细胞核抗原（PCNA）表达，指示肝细胞再生，在24 h和48 h明显。棕榈酰、油酰和肉豆蔻酰肉毒碱的升高在2-4 h时明显，同时在肝切片中开始油红O染色。到8小时，酰基肉毒碱水平低于基线水平，并在24和48小时保持较低水平。偏最小二乘（PLS）模型表明，小鼠血清中酰基肉毒碱的积累与APAP蛋白加合物和肝脏谷胱甘肽水平直接相关。总体而言，在小鼠中的APAP毒性的血清酰基肉毒碱的动力学遵循双相模式，涉及早期升高后的代谢阶段的毒性和后期耗尽的酰基肉毒碱。
High doses of acetaminophen (APAP) result in hepatotoxicity that involves metabolic activation of the parent compound, covalent binding of the reactive intermediate N-acetyl-p-benzoquinone imine (NAPQI) to liver proteins, and depletion of hepatic glutathione. Impaired fatty acid β-oxidation has been implicated in previous studies of APAP-induced hepatotoxicity. To better understand relationships between toxicity and fatty acid β-oxidation in the liver in APAP toxicity, metabolomic assays for long chain acylcarnitines were examined in relationship to established markers of liver toxicity, oxidative metabolism, and liver regeneration in a time course study in mice. Male B6C3F1 mice were treated with APAP (200 mg/kg IP) or saline and sacrificed at 1, 2, 4, 8, 24 or 48 h after APAP. At 1 h, hepatic glutathione was depleted and APAP protein adducts were markedly increased. Alanine aminotransferase (ALT) levels were elevated at 4 and 8 h, while proliferating cell nuclear antigen (PCNA) expression, indicative of hepatocyte regeneration, was apparent at 24 h and 48 h. Elevations of palmitoyl, oleoyl and myristoyl carnitine were apparent by 2–4 h, concurrent with the onset of Oil Red O staining in liver sections. By 8 h, acylcarnitine levels were below baseline levels and remained low at 24 and 48 h. A partial least squares (PLS) model suggested a direct association of acylcarnitine accumulation in serum to APAP protein adduct and hepatic glutathione levels in mice. Overall, the kinetics of serum acylcarnitines in APAP toxicity in mice followed a biphasic pattern involving early elevation after the metabolism phases of toxicity and later depletion of acylcarnitines.