临床前药物安全性评价中关于肝细胞肥大的探讨
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摘要
临床前药物安全性评价研究中常常发现药物可诱导实验动物的肝细胞肥大,可能并伴有肝脏质量增加或血清生化中肝损伤指标的变化。近年来研究表明,众多化合物可以通过激活核内激素受体组成型雄甾烷受体(CAR)或过氧化物酶体激活受体α(PPARα)的机制诱导肝细胞肥大,并且该作用机制具有啮齿类动物的种属特异性,与人类缺乏相关性。然而,如何判定肝细胞肥大是不良反应还是非不良反应(适应性反应)是病理学家与毒理学家面临的挑战。该文从肝细胞肥大的定义、肝脏质量、临床病理学变化以及组织病理学变化等全面阐述了肝细胞肥大的特点,并依据证据权重分析方法探讨评估肝细胞肥大的预测风险。
Preclinical drug safety evaluation studies have often found that drugs can induce hepatocyte hypertrophy in experimental animals,which may be accompanied by increased lver weight or changes of the indicators of liver injury in serum.Recent studies have shown that hepatocyte hypertrophy may be induced by many xenobiotics through a common mechanism of activation of the nuclear receptors CAR(constitutive androstane receptor) or PPARα(peroxisome activated receptor alpha),and the machanism is rodent-specific and is not related to humans.However,it is a common challenge for pathologists and toxicologists to clearly define what is considered adverse or non-adverse(adaptive response) in the context of hepatocellular hypertrophy.In this paper,the characteristics of hepatocellular hypertrophy were discussed from the definition,liver weights,clinical pathology and histopathology changes,and the predictive risk of hepatocellular hypertrophy was evaluated by weight of evidence analysis.
Preclinical drug safety evaluation studies have often found that drugs can induce hepatocyte hypertrophy in experimental animals,which may be accompanied by increased lver weight or changes of the indicators of liver injury in serum.Recent studies have shown that hepatocyte hypertrophy may be induced by many xenobiotics through a common mechanism of activation of the nuclear receptors CAR(constitutive androstane receptor) or PPARα(peroxisome activated receptor alpha),and the machanism is rodent-specific and is not related to humans.However,it is a common challenge for pathologists and toxicologists to clearly define what is considered adverse or non-adverse(adaptive response) in the context of hepatocellular hypertrophy.In this paper,the characteristics of hepatocellular hypertrophy were discussed from the definition,liver weights,clinical pathology and histopathology changes,and the predictive risk of hepatocellular hypertrophy was evaluated by weight of evidence analysis.
引文
[1]Ennulat D,Magid-Slav M,Rehm S,et al.Diagnostic performance of traditional hepatobiliary markers of druginduced liver injury in the rat[J].Toxicol Sci,2010,116(2):397-412.
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[12]Peterson R L,Casciotti L,Block L,et al.Mechanistic toxicogenomic analysis of way-144122 administration in sprague-dawley rats[J].Toxicol Appl Pharmacol,2004,196(1):80-94.
[13]FDA.Guidance for industry:Drug-induced liver injury:Premarketing clinical evaluation[EB/OL].(2011-07-29).http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm174090.pdf.
[14]Robertson D G,Loewen G,Walsh K M,et al.Subacute and subchronic toxicology studies of CL-986,a novel anti-inflammatory compound[J].Fundam Appl Toxicol,1993,20(4):446-455.
[15]Clayton N P,Yoshizawa K,Kissling G E,et al.Immunohistochemical analysis of expressions of hepatic cytochrome P450 in F344 rats following oral treatment with kava extract[J].Exp Toxicol Pathol,2007,58(4):223-236.
[16]Sirica A E,Jicinsky J K,Heyer E K.Effect of chronic phenobarbital administration on the gamma-glutamyl transpeptidase activity of hyperplastic liver lesions induced in rats by the Solt/Farber initiation:selection process of hepatocarcinogenesis[J].Carcinogenesis,1984,5(12):1737-1740.
[17]Hall A P,Elcombe C R,Foster J R,et al.Liver hypertrophy:A review of adaptive(adverse and nonadverse)changes-conclusions from the 3rd international ESTP expert workshop[J].Toxicol Pathol,2012,40(7):971-994.
[18]Liu S,Kawamoto T,Morita O,et al.Discriminating between adaptive and carcinogenic liver hypertrophy in rat studies using logistic ridge regression analysis of toxicogenomic data:The mode of action and predictive models[J].Toxicol Appl pharmacol,2017,318:79-87.
[19]Thoolen B,Ten Kate F J,van Diest P J,et al.Comparative histomorphological review of rat and human hepatocellular proliferative lesions[J].Toxicol Pathol,2012,25(3):189-199.
[20]Lake B G.Human relevance of rodent liver tumour formation by constitutive androstane receptor(CAR)activators[J].Toxicol Res,2018,7(4):697-717.doi:10.1039/c8tx00008e.
[2]Maronpot R R,Yoshizawa K,Nyska A,et al.Hepatic enzyme induction:Histopathology[J].Toxicol Pathol,2010,38(5):776-795.
[3]Thoolen B,Maronpot R R,Harada T,et al.Proliferative and nonproliferative lesions of the rat and mouse hepatobiliary system[J].Toxicol Pathol,2010,38(7Suppl):5s-81s.
[4]Sellers R S,Morton D,Michael B,et al.Society of toxicologic pathology position paper:Organ weight recommendations for toxicology studies[J].Toxicol Pathol,2007,35(5):751-755.
[5]Ennulat D,Walker D,Clemo F,et al.Effects of hepatic drug-metabolizing enzyme induction on clinical pathology parameters in animals and man[J].Toxicol Pathol,2010,38(5):810-828.
[6]Allen D G,Pearse G,Haseman J K,et al.Prediction of rodent carcinogenesis:An evaluation of prechronic liver lesions as forecasters of liver tumors in ntp carcinogenesis studies[J].Toxicol Pathol,2004,32(4):393-401.
[7]Carmichael N G,Enzmann H,Pate I,et al.The significance of mouse liver tumor formation for carcinogenic risk assessment:Results and conclusions from a survey of ten years of testing by the agrochemical industry[J].Environ Health Perspect,1997,105(11):1196-1203.
[8]Li X,Elwell M R,Ryan A M,et al.Morphogenesis of postmortem hepatocyte vacuolation and liver weight increases in sprague-dawley rats[J].Toxicol Pathol,2003,31(6):682-688.
[9]Rothacker D L,Kanerva R L,Wyder W E,et al.Effects of variation of necropsy time and fasting on liver weights and liver components in rats[J].Toxicol Pathol,1988,16:22-26.
[10]Boll M,Weber L W,Font M,et al.The enzyme inducers 3-methylcholanthrene and phenobarbital affect the activities of glucocorticoid hormone-regulated enzymes in rat liver and kidney[J].Toxicology,1998,126(1):127-136.
[11]Lake B G,Evans J G.Effect of pretreatment with some mixedfunction oxidase enzyme inducers on the acute hepatotoxicity of coumarin in the rat[J].Food Chem Toxic,1993,31(12):963-970.
[12]Peterson R L,Casciotti L,Block L,et al.Mechanistic toxicogenomic analysis of way-144122 administration in sprague-dawley rats[J].Toxicol Appl Pharmacol,2004,196(1):80-94.
[13]FDA.Guidance for industry:Drug-induced liver injury:Premarketing clinical evaluation[EB/OL].(2011-07-29).http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm174090.pdf.
[14]Robertson D G,Loewen G,Walsh K M,et al.Subacute and subchronic toxicology studies of CL-986,a novel anti-inflammatory compound[J].Fundam Appl Toxicol,1993,20(4):446-455.
[15]Clayton N P,Yoshizawa K,Kissling G E,et al.Immunohistochemical analysis of expressions of hepatic cytochrome P450 in F344 rats following oral treatment with kava extract[J].Exp Toxicol Pathol,2007,58(4):223-236.
[16]Sirica A E,Jicinsky J K,Heyer E K.Effect of chronic phenobarbital administration on the gamma-glutamyl transpeptidase activity of hyperplastic liver lesions induced in rats by the Solt/Farber initiation:selection process of hepatocarcinogenesis[J].Carcinogenesis,1984,5(12):1737-1740.
[17]Hall A P,Elcombe C R,Foster J R,et al.Liver hypertrophy:A review of adaptive(adverse and nonadverse)changes-conclusions from the 3rd international ESTP expert workshop[J].Toxicol Pathol,2012,40(7):971-994.
[18]Liu S,Kawamoto T,Morita O,et al.Discriminating between adaptive and carcinogenic liver hypertrophy in rat studies using logistic ridge regression analysis of toxicogenomic data:The mode of action and predictive models[J].Toxicol Appl pharmacol,2017,318:79-87.
[19]Thoolen B,Ten Kate F J,van Diest P J,et al.Comparative histomorphological review of rat and human hepatocellular proliferative lesions[J].Toxicol Pathol,2012,25(3):189-199.
[20]Lake B G.Human relevance of rodent liver tumour formation by constitutive androstane receptor(CAR)activators[J].Toxicol Res,2018,7(4):697-717.doi:10.1039/c8tx00008e.