PDF(1037 KB)
INFLUENCE OF HIGH-DOSE ATORVASTATIN ON BILE ACID METABOLISM IN MICE WITH LIVER INJURY AND RELATED MECHANISM
XIA Feifei, SONG Bingxue, SONG Yuqing, TIAN Jiawei, YAN Hui, HUANG Yuxiao, XIN Hui, LIANG Hui
PDF(1037 KB)
INFLUENCE OF HIGH-DOSE ATORVASTATIN ON BILE ACID METABOLISM IN MICE WITH LIVER INJURY AND RELATED MECHANISM
Objective To investigate the influence of high-dose atorvastatin on bile acid metabolism in mice with liver injury and its mechanism. Methods A total of 40 specific pathogen-free male C57BL/6 mice were randomly divided into normal saline group (group A) and low-, middle-, and high-dose atorvastatin groups (groups B, C, and D, respectively), with 10 mice in each group. After 30 days of intragastric administration of normal saline and atorvastatin at a dose of 10, 20, and 30 mg/kg, respectively, orbital blood was collected from the mice in each group, and these groups were compared in terms of the serum levels of total bile acid (TBA), endotoxin (ET), aspartate aminotransferase (AST), and alanine aminotransferase (ALT); after liver tissue samples were collected, HE staining was performed to observe the pathological changes of liver tissue, and PCR was used to measure the mRNA expression levels of the bile acid metabolism-related genes farnesoid X receptor (FXR) and multidrug resis-tance-associated protein 2 (MRP2) in liver tissue. Results The mice in group D had slight swelling, sporadic inflammatory cell infiltration, and feather-like degeneration in liver tissue. Compared with the other groups, group D had significant increases in the serum levels of TBA, ET, AST, and ALT (P<0.05). Compared with group A, groups C and D had significant reductions in the relative mRNA expression levels of FXR and MRP2 in liver tissue (P<0.05), and compared with group B, group D had significant reductions in the relative mRNA expression levels of FXR and MRP2 in liver tissue (P<0.05). Conclusion Atorvastatin can induce the increase in serum TBA level in mice and lead to changes in the expression of the downstream FXR and MRP2 genes associated with bile acid metabolism in liver tissue, and abnormal bile acid metabolism in liver tissue caused by high-dose administration may be one of the main causes of atorvastatin hepatotoxicity.
Atorvastatin ; Chemical and drug induced liver injury ; Bile acid ; Metabolism ; Gene expression {{custom_keyword}} ;
表1 各组小鼠血清TBA、ET、AST、ALT比较(n=10, |
| 组别 | 血清TBA (c/μmol·L-1) | 血清ET (c/U·L-1) | 血清AST (z/μg·L-1) | 血清ALT (z/μg·L-1) |
|---|---|---|---|---|
| A组 | 6.10±0.22 | 0.17±0.05 | 65.96±8.47 | 50.02±1.02 |
| B组 | 6.47±0.35 | 0.20±0.06 | 67.46±7.41 | 52.14±3.23 |
| C组 | 6.96±0.41 | 0.23±0.04 | 72.01±6.21 | 54.25±3.13 |
| D组 | 8.12±1.02 | 0.45±0.12 | 101.01±8.51 | 63.45±3.45 |
| [1] |
Elevated low-density lipoprotein-cholesterol (LDL-C) is a causal factor for the development of atherosclerotic cardiovascular disease (ASCVD); accordingly, LDL-C lowering is associated with a decreased risk of progression of atherosclerotic plaques and development of complications. Currently, statins play a central role in any ASCVD management and prevention strategies, in relation to their lipid-lowering action and potentially to pleiotropic effects. After coronary artery disease, stroke is the most frequent cause of ASCVD mortality and the leading cause of acquired disability, a major public health problem. There is often a tendency to aggregate all types of stroke (atherothrombotic, cardioembolic, and haemorrhagic), which have, however, different causes and pathophysiology, what may lead to bias when interpreting the results of the studies. Survivors of a first atherothrombotic ischemic stroke are at high risk for coronary events, recurrent stroke, and vascular death. Although epidemiological studies show a weak relationship between cholesterol levels and cerebrovascular disease as a whole compared with other ASCVD types, statin intervention studies have demonstrated a decrease in the risk of stroke in patients with atherosclerosis of other territories and a decrease in all cardiovascular events in patients who have had a stroke. The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial demonstrated the benefit of high doses of atorvastatin in the secondary prevention of ischemic stroke. In this review, we discuss the evidence, use and recommendations of statins in the primary and secondary prevention of stroke, and their role in other scenarios such as the acute phase of ischemic stroke, cerebral hemorrhage, cardioembolic stroke, small vessel disease, and cognitive impairment.
{{custom_citation.content}}
{{custom_citation.annotation}}
|
| [2] |
Evidence is emerging that statins may reduce liver-related adverse outcomes in individuals with chronic liver disease. In this issue of the American Journal of Gastroenterology, Kamal et al. found in their meta-analysis that statin use was associated with a reduced risk of fibrosis progression, decompensated cirrhosis, and mortality. These encouraging findings suggest beneficial liver effects of statins. However, the overall quality of the evidence is low because 9 of the 10 studies included in the meta-analysis were observational. More robust studies, including randomized trials and research on safety in patients with advanced liver disease, are needed before statins can be routinely recommended for prevention of liver-related morbidity and mortality.
{{custom_citation.content}}
{{custom_citation.annotation}}
|
| [3] |
朱纪斌. 阿托伐他汀所致不良反应及临床合理用药分析[J]. 中国医药科学, 2019, 9(9):71-73.
{{custom_citation.content}}
{{custom_citation.annotation}}
|
| [4] |
{{custom_citation.content}}
{{custom_citation.annotation}}
|
| [5] |
Adverse drug reactions (ADRs) represent an important cause of morbidity and mortality worldwide. Statins are a class of drugs whose main adverse effects are drug-induced liver injury (DILI) and myopathy. Some of these may be predictable, due to their pharmacokinetic and pharmacodynamic properties, while others, unfortunately, are idiosyncratic. Genetic factors may also influence patient susceptibility to DILI and myopathy in the case of statins. This review will first discuss the role of statins in cardiovascular disease treatment and prevention and the underlying mechanisms of action. Furthermore, to explore the susceptibility of statin-induced adverse events such as myopathy and hepatotoxicity, it will then focus on the recent Genome-Wide Association Studies (GWAS) concerning the transporter genes, Cytochrome P450 (CYP), organic anion-transporting polypeptide (OATP) and ABCB1 and ABCC1, which seem to play a role in the development of clinically relevant adverse events. Finally, we appraise the evidence for and against the use of statins in metabolic syndrome and in HCV-infected patients, in terms of their safety and efficacy in cardiovascular events.Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.
{{custom_citation.content}}
{{custom_citation.annotation}}
|
| [6] |
付俣萧, 黄旭, 吕童, 等. 阿托伐他汀在致死型约氏疟原虫感染的肝脏病理损伤中的作用研究[J]. 中国免疫学杂志, 2019, 35(9):1042-1046.
{{custom_citation.content}}
{{custom_citation.annotation}}
|
| [7] |
王可欣. 阿托伐他汀对阿霉素致大鼠肝脏损伤的保护作用及其机制研究[D]. 石家庄: 河北医科大学, 2018.
{{custom_citation.content}}
{{custom_citation.annotation}}
|
| [8] |
苏萍, 陈影, 张广平, 等. 阿托伐他汀的肝毒性机制研究[J]. 药物评价研究, 2019, 42(11):2174-2179.
{{custom_citation.content}}
{{custom_citation.annotation}}
|
| [9] |
于红红, 高晓燕. 护肝片对药物性肝损伤的防治作用[J]. 中国现代应用药学, 2019, 36(18):2271-2274.
{{custom_citation.content}}
{{custom_citation.annotation}}
|
| [10] |
喻明丽, 陈洁, 陈永刚, 等. 他汀类药物致肝损伤的生化特征[J]. 昆明医科大学学报, 2018, 39(8):13-17.
{{custom_citation.content}}
{{custom_citation.annotation}}
|
| [11] |
宋佳, 王春霞, 张育才. 肝损伤新型生物学标记物的研究进展[J]. 中国小儿急救医学, 2019, 26(7):523-526.
{{custom_citation.content}}
{{custom_citation.annotation}}
|
| [12] |
A major disadvantage that may occur in association with atorvastatin (ATV) therapy is elevation of serum transaminases. This study was designed to evaluate the effects of treatment of rats with various doses of ATV (2, 5, and 10 mg/kg/day) on liver function, oxidative stress, and histology and on the severity of acetaminophen (APAP) hepatotoxicity. ATV administration for 21 days resulted in a dose-dependent significant rise in serum activities of alkaline phosphatase, aspartate aminotransferase, and alanine aminotransferase. Only ATV at 10 mg/kg/day decreased reduced glutathione (GSH) levels and superoxide dismutase (SOD) activity, increased malondialdehyde (MDA) levels, and elicited histopathological changes in the liver. In rats challenged with APAP (500 mg/kg), the livers showed centrilobular necrosis with evident oxidative stress and liver dysfunction after 24 h. Rats challenged with APAP after pretreatment with ATV 2 or 5 mg/kg/day showed significantly lower activities of serum enzymes, higher hepatic GSH levels and SOD activities, lower MDA levels and milder histopathological changes compared with rats challenged with APAP after pretreatment with ATV 10 mg/kg/day or without drug pretreatment. In conclusion, the effect of ATV on the liver is dose dependent. Our results showed that ATV, at the highest dose used, induced hepatic lipid peroxidation and injury, suggesting a role for oxidative stress in ATV-induced hepatotoxicity. However, lower doses of ATV attenuated APAP-induced hepatotoxicity via a mechanism related, at least in part, to a reduction of APAP-induced hepatic oxidative stress. These results are of practical interest as both drugs may be used concurrently in clinical practice. © The Author(s) 2014.
{{custom_citation.content}}
{{custom_citation.annotation}}
|
| [13] |
{{custom_citation.content}}
{{custom_citation.annotation}}
|
| [14] |
Treatment with statins is known all over the world. They are generally considered safe at therapeutic doses. Nevertheless, clinical trials are not enough to assess their scarce adverse effects such as idiosyncratic drug induced liver injury (DILI). Due to some conditions, such as concomitant usage (drug-drug interaction using an identical metabolising enzyme) and genetic polymorphisms, there is an increasing concern about their safety. Hepatotoxicity and rhabdomyolysis have begun to appear in published studies. Most of investigations have focused on both these adverse effects and mechanisms of drug induced toxicity. The present review has attempted to compile almost all of the existing studies on the hepatotoxicity of statins but not rhabdomyolysis. The aim of our study is to provide an overview of the studies on the statin-associated hepatotoxicity and to discuss the published studies. The researchers are of the opinion that the research on this topic is incomplete but extremely necessary.
{{custom_citation.content}}
{{custom_citation.annotation}}
|
| [15] |
{{custom_citation.content}}
{{custom_citation.annotation}}
|
| [16] |
吴军. 他汀类药物临床多效性研究进展[J]. 药品评价, 2020, 17(1):24-25,53.
{{custom_citation.content}}
{{custom_citation.annotation}}
|
| [17] |
{{custom_citation.content}}
{{custom_citation.annotation}}
|
| [18] |
陈步宽. 他汀类药物致肝损伤临床特点及影响因素分析[J]. 肝脏, 2017, 22(10):885-887,903.
{{custom_citation.content}}
{{custom_citation.annotation}}
|
| [19] |
The identification of the key regulators of bile acid (BA) synthesis and transport within the enterohepatic circulation has revealed potential targets for pharmacological therapies of cholestatic liver diseases. Novel drug targets include the bile BA receptors, farnesoid X receptor and TGR5, the BA-induced gut hormones, fibroblast growth factor 19 and glucagon-like peptide 1, and the BA transport systems, apical sodium-dependent bile acid transporter and Na -taurocholate cotransporting polypeptide, within the enterohepatic circulation. Moreover, BA derivatives undergoing cholehepatic shunting may allow improved targeting to the bile ducts. This review focuses on the pathophysiological basis, mechanisms of action, and clinical development of novel pharmacological strategies targeting BA transport and signaling in cholestatic liver diseases. (Hepatology 2017;65:1393-1404).© 2016 by the American Association for the Study of Liver Diseases.
{{custom_citation.content}}
{{custom_citation.annotation}}
|
| [20] |
Progressive familial intrahepatic cholestasis (PFIC) is a genetically heterogeneous disorder of bile flow disruption due to abnormal canalicular transport or impaired bile acid (BA) metabolism, causing excess BA accumulation and liver failure. We previously reported an intrahepatic cholestasis mouse model based on loss of function of both farnesoid X receptor (FXR; NR1H4) and a small heterodimer partner (SHP; NR0B2) [double knockout (DKO)], which has strong similarities to human PFIC5. We compared the pathogenesis of DKO livers with that of another intrahepatic cholestasis model, Bsep-/-, which represents human PFIC2. Both models exhibit severe hepatomegaly and hepatic BA accumulation, but DKO showed greater circulating BA and liver injury, and Bsep-/- had milder phenotypes. Molecular profiling of BAs uncovered specific enrichment of cholic acid (CA)-derived BAs in DKO livers but chenodeoxycholate-derived BAs in Bsep-/- livers. Transcriptomic and proteomic analysis revealed specific activation of CA synthesis and alternative basolateral BA transport in DKO but increased chenodeoxycholic acid synthesis and canalicular transport in Bsep-/-. The constitutive androstane receptor (CAR)/pregnane X receptor (PXR)-CYP2B/CYP2C axis is activated in DKO livers but not in other cholestasis models. Loss of this axis in Fxr:Shp:Car:Pxr quadruple knockouts blocked Cyp2b/Cyp2c gene induction, impaired bilirubin conjugation/elimination, and increased liver injury. Differential CYP2B expression in DKO and Bsep-/- was recapitulated in human PFIC5 and PFIC2 livers. In conclusion, loss of FXR/SHP results in distinct molecular pathogenesis and CAR/PXR activation, which promotes Cyp2b/Cyp2c gene transcription and bilirubin clearance. CAR/PXR activation was not observed in Bsep-/- mice or PFIC2 patients. These findings provide a deeper understanding of the heterogeneity of intrahepatic cholestasis.
{{custom_citation.content}}
{{custom_citation.annotation}}
|
| [21] |
Bile duct obstruction is a potent stimulus for cholangiocyte proliferation, especially for large cholangiocytes. Our previous studies reported that conjugated bile acids (CBAs) activate the protein kinase B (AKT) and extracellular signal‐regulated kinase 1 and 2 (ERK1/2) signaling pathways through sphingosine 1‐phosphate receptor (S1PR) 2 in hepatocytes and cholangiocarcinoma cells. It also has been reported that taurocholate (TCA) promotes large cholangiocyte proliferation and protects cholangiocytes from bile duct ligation (BDL)‐induced apoptosis. However, the role of S1PR2 in bile‐acid–mediated cholangiocyte proliferation and cholestatic liver injury has not been elucidated. Here, we report that S1PR2 is the predominant S1PR expressed in cholangiocytes. Both TCA‐ and sphingosine‐1‐phosphate (S1P)‐induced activation of ERK1/2 and AKT were inhibited by JTE‐013, a specific antagonist of S1PR2, in cholangiocytes. In addition, TCA‐ and S1P‐induced cell proliferation and migration were inhibited by JTE‐013 and a specific short hairpin RNA of S1PR2, as well as chemical inhibitors of ERK1/2 and AKT in mouse cholangiocytes. In BDL mice, expression of S1PR2 was up‐regulated in whole liver and cholangiocytes. S1PR2 deficiency significantly reduced BDL‐induced cholangiocyte proliferation and cholestatic injury, as indicated by significant reductions in inflammation and liver fibrosis in S1PR2 knockout mice. Treatment of BDL mice with JTE‐013 significantly reduced total bile acid levels in serum and cholestatic liver injury. Conclusion: This study suggests that CBA‐induced activation of S1PR2‐mediated signaling pathways plays a critical role in obstructive cholestasis and may represent a novel therapeutic target for cholestatic liver diseases. (Hepatology 2017;65:2005‐2018).
{{custom_citation.content}}
{{custom_citation.annotation}}
|
| [22] |
{{custom_citation.content}}
{{custom_citation.annotation}}
|
| [23] |
Statins are standard therapy for the treatment of lipid disorders, and the field of redox biology accepts that statins have antioxidant properties. Our aim in this report was to consider the pleiotropic effects of atorvastatin, pravastatin and simvastatin administered prior to endotoxin-induced acute lung injury. Male mice were divided into 5 groups and intraperitoneally injected with LPS (10 mg/kg), LPS plus atorvastatin (10 mg/kg/day; A + LPS group), LPS plus pravastatin (5 mg/kg/day; P + LPS group) or LPS plus simvastatin (20 mg/kg/day; S + LPS group). The control group received saline. All mice were sacrificed one day later. There were fewer leukocytes in the P + LPS and S + LPS groups than in the LPS group. MCP-1 cytokine levels were lower in the P + LPS group, while IL-6 levels were lower in the P + LPS and S + LPS groups. TNF-α was lower in all statin-treated groups. Levels of redox markers (superoxide dismutase and catalase) were lower in the A + LPS group (p < 0.01). The extent of lipid peroxidation (malondialdehyde and hydroperoxides) was reduced in all statin-treated groups (p < 0.05). Myeloperoxidase was lower in the P + LPS group (p < 0.01). Elastance levels were significantly greater in the LPS group compared to the statin groups. Our results suggest that atorvastatin and pravastatin but not simvastatin exhibit anti-inflammatory and antioxidant activity in endotoxin-induced acute lung injury.Copyright © 2013 Elsevier B.V. All rights reserved.
{{custom_citation.content}}
{{custom_citation.annotation}}
|
| [24] |
康雷, 林孝威, 王国栋, 等. 药物性肝损伤药学实践探索[J]. 中国药师, 2017, 20(11):2025-2029.
{{custom_citation.content}}
{{custom_citation.annotation}}
|
| [25] |
叶晓莉, 王凌, 蒋学华. 茴三硫对利福平致药物性肝损伤的保护作用及机制[J]. 华西药学杂志, 2018, 33(5):501-503.
{{custom_citation.content}}
{{custom_citation.annotation}}
|
| [26] |
李晓玲, 孙凤霞, 王琮, 等. 多药耐药相关蛋白2及其与胆汁淤积的关系研究[J]. 国际流行病学传染病学杂志, 2018, 45(1):48-50.
{{custom_citation.content}}
{{custom_citation.annotation}}
|
| {{custom_ref.label}} |
{{custom_citation.content}}
{{custom_citation.annotation}}
|
PDF(1037 KB)
/
| 〈 |
|
〉 |
