Experimental Production of Mallory Bodies in Mice by Diet Containing 3,5-Diethoxycarbonyl-1,4-Dihydrocollidine

Yokoo, Hidejiro; Harwood, Thomas R.; Racker, Darlene K.; Arak, Saima

doi:10.1016/s0016-5085(82)80293-x

Cited by 55 publications

(29 citation statements)

References 10 publications

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“…The liquid diet composition and preparation have been described previously. 7 The liquid diet (1 kcal/mL) was fed to drug-primed mice continuously through a syringe pump system at the rate of 180 mL/kg/d. A volume of 8% (wt/vol) ethanol solution was infused into 11 mice in an amount to maintain a high blood-ethanol level.…”

Section: Methodsmentioning

confidence: 99%

Mallory body formation by ethanol feeding in drug-primed mice

Zhang‐Gouillon

Yuan

et al. 1998

Hepatology

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Drug-primed mice, created by a 5-month feeding of diethyl-1,4-dihydro-2,4,6-trimethyl-3,5-pyridinedicarboxylate (DDC), followed by a 1-month withdrawal, were refed ethanol or isocaloric dextrose (control) diets intragastrically for 7 days. The formation of Mallory bodies (MBs) was monitored by immunofluorescence and immunoperoxidase microscopy using antibodies to cytokeratin and ubiquitin, and also by electron microscopy. The changes in cytokeratin 55 (CK55), ubiquitin conjugate, nuclear factor B (NFB) p65, NFB p50, inhibitor B␣, c-myc, tumor necrosis factor ␣, and cytochrome P450 2E1 (CYP2E1) contents were determined by Western blotting using appropriate antibodies. The messenger RNA (mRNA) for CYP2E1, cytokeratin, ubiquitin, hepatocyte growth factor activator, and tissue transglutaminase was quantitated. MBs were present at 5 to 7 days' postfeeding with ethanol, but not with dextrose. They developed in clusters of ''empty hepatocytes,'' where the cytokeratin antibody failed to recognize the typical filament structures seen in normal hepatocytes. MBs were larger and more numerous in the subcapsular region. Northern blots showed that CK55 mRNA was decreased by the ethanol treatment, but protein levels were increased, suggesting a decreased turnover of the cytokeratin. Likewise, the increase in CYP2E1 protein in the face of a lack of an increase in mRNA for CYP2E1 could be explained by a decreased turnover of this cytochrome. This is the first report of MB formation induced by ethanol ingestion in an experimental model. (HEPATOLOGY 1998;27:116-122.)The association between alcohol abuse and Mallory body (MB) formation in liver goes back to Mallory' s first report in 1911. 1 Mouse is the only species other than man in which MBs can be induced in response to a continuous feeding of various agents like griseofulvin and diethyl-1,4-dihydro-2,4,6-trimethyl-3,5-pyridinedicarboxylate (DDC). However, attempts to induce MBs by ethanol feeding in mice have been as yet unsuccessful, perhaps because of inappropriate experimental conditions. In recent years, we set up a drug-primed mouse model to study MB formation that involved a first feeding of the drug (griseofulvin or DDC) for 5 months, followed by drug withdrawal for 1 month, and a 7-day drug refeeding. [2][3][4] Most of the MBs disappear after the drug withdrawal, leaving only small dot-like MBs at the hepatocyte periphery. However, while it takes at least 3 months of continuous drug feeding before MBs appear in naive mice, 3,4 MBs reappear after only 3 days of refeeding in drug-primed mice. We have used this mouse model to show that heat shock performed in vivo leads to MB formation. 5 Therefore, it was of major interest to determine the response of these drug-primed mice to ethanol feeding. The experimental protocol included feeding via an intragastric indwelling tube to achieve good nutrition and to maintain high blood alcohol levels. 6 The results show for the first time that alcohol ''abuse'' can induce MBs in mice in a few days using a drug-primed model. MATERIALS...

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Section: Methodsmentioning

confidence: 99%

Mallory body formation by ethanol feeding in drug-primed mice

Zhang‐Gouillon

Yuan

et al. 1998

Hepatology

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“…This has led to a hypothesis of tanglement of cytokeratins due to a primary microtubular disturbance, with subsequent trapping of microtubule-associated proteins so that cytoplasmic tubulin dimers cannot form a tubular structure (15). Other MB-inducing chemicals include colchicine (2211, dieldrin (222) and 3,5-diethoxycarbonyl-l,4-dihydrocollidine (223). Many such drugs are carcinogens.…”

Section: Mbs and Chemicals So Far Mbs Have Only Beenmentioning

confidence: 99%

“…In mice fed dieldrin, a chlorated hydrocarbon compound, MBs and both benign and malignant hepatic tumors develop within 2 yr (224). 3,5-Diethoxycarbonyl-1,4-dihydrocollidine requires 2 to 6 mo to produce MBs in most cells (223). In discontinuation of these drugs, MBs often disappear, but some may persist for as long as 6 mo (70,225).…”

Section: Mbs and Chemicals So Far Mbs Have Only Beenmentioning

confidence: 99%

The Mallory Body: Morphological, Clinical and Experimental Studies (Part 1 of A Literature Survey)

Jensen¹,

Gluud²

1994

Hepatology

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To aid understanding of markers of disease and predictors of outcome in alcohol-exposed systems, we undertook a literature survey of more than 700 articles to view the morphological characteristics and the clinical and experimental epidemiology of the Mallory body. Mallory bodies are filaments of intermediate diameter that contain intermediate filament components (e.g., cytokeratins) observable by conventional light microscopy or immunohistochemical methods, identical in structure regardless of initiating factors or putative pathogenesis. Although three morphological types can be identified under electron microscopy (with fibrillar structure parallel, random or absent), they remain stereotypical manifestations of hepatocyte injury. A summary of the conditions associated with Mallory bodies in the literature and their validity and potential etiological relationships is presented and discussed, including estimates on the combined light microscopic and immunohistochemical prevalences and kinetics. Emphasis is placed on proper confounder control (in particular, alcohol history), which is highly essential but often inadequate. These conditions include (mean prevalence of Mallory bodies in parentheses): Indian childhood cirrhosis (73%), alcoholic hepatitis (65%), alcoholic cirrhosis (51%), Wilson's disease (25%), primary biliary cirrhosis (24%), nonalcoholic cirrhosis (24%), hepatocellular carcinoma (23%), morbid obesity (8%) and intestinal bypass surgery (6%). Studies in alcoholic hepatitis strongly suggest a hit-and-run effect of alcohol, whereas other chronic liver diseases show evidence of gradual increase in prevalence of Mallory bodies with severity of hepatic pathology. Mallory bodies in cirrhosis do not imply alcoholic pathogenesis. Obesity, however, is associated with alcoholism and diabetes, and Mallory bodies are only present in diabetic patients if alcoholism or obesity complicates the condition. In addition, case studies on diseases in which Mallory bodies have been identified, along with pharmacological side effects and experimental induction of Mallory bodies by various antimitotic and oncogenic chemicals, are presented. Mallory bodies occur only sporadically in abetalipoproteinemia, von Gierke's disease and focal nodular hyperplasia and during hepatitis due to calcium antagonists or perhexiline maleate. Other conditions and clinical drug side effects are still putative. Finally, a variety of experimental drugs have been developed that cause Mallory body formation, but markedly different cell dynamics and metabolic pathways may raise questions about the relevance of such animal models for human Mallory body formation. In conclusion, the Mallory body is indicative but not pathognomonic of alcohol involvement. A discussion on theories of development and pathological significance transcending the clinical frameworks will be presented in a future paper.

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“…The pathogenesis of Mallory body formation is unknown although theoretical mechanisms have included microtubular failure, vitamin A deficiency, and prolonged cholestatis (33-35). In experimental animals, Mallory bodies have been induced in the liver of mice fed griseofulvin (36, 37) or 3,5-diethoxycarbonyl-1,4-dihydrocollidine (35). However, the induction period for Mallory bodies in the Armenian hamster by DES (within 1 to 2 weeks) is much shorter than that observed in mice fed griseofulvin (5 months) or 3,5-diethoxycarbonyl-1,4-dihydrocollidine (40 days).…”

Section: Discussionmentioning

confidence: 98%

Diethylstilbestrol-Induced Jaundice in the Chinese and Armenian Hamster

1983

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An unusual and impressive hyperbilirubinemia was induced in Chinese hamsters by administration of diethylstilbestrol (DES). This icterus was dose-dependent and affected females more severely than males. However, a similar mortality was detected in both sexes. Another hamster, the Armenian hamster, was even more susceptible to the icteric and lethal effects of DES. The hamster model of DES-induced icterus showed many clinical dissimilarities when compared to the human estrogen-induced jaundice, simple cholestatic jaundice. Furthermore, hepatic pathology was distinctly different as canalicular cholestasis was absent although other degenerative and regenerative hepatocellular changes were present. Livers of Armenian hamsters were more severely affected than were livers from Chinese hamsters and contained Mallory bodies even within 1 week after DES treatment. A modest, nonlethal jaundice also was detected in European hamsters after DES injection, whereas Syrian hamsters were not affected even after larger doses. This unique sensitivity to DES, and the spectrum of sensitivity within these related hamsters (Armenian > Chinese > European vs. resistant Syrian) provide an interesting model for study of DES effect on hepatic function.Idiopathic jaundice of pregnancy and more recently, jaundice associated with oral contraceptives are two human diseases in which hepatic function is clinically impaired by estrogenic components (1, 2). A genetic predisposition is apparently necessary and responsible for this estrogen-induced jaundice (3, 4), although a minor impairment of biliary excretion can be detected (by bromosulfophthalein excretion, etc.) in normal patients receiving estrogens (5) or in late pregnancy (61, and this estrogen effect is enhanced in the diseased liver (7). Hepatic injury has been reported occasionally in human males treated with synthetic estrogen therapy [ stilbestrol or diethylstilbestrol (DES)] for prostatic carcinoma. Such injury has been manifested by abnormalities of tests of hepatic function (8), jaundice with intrahepatic cholestasis (9-13), alcoholic hepatis-like injury (14), and peliosis hepatitis (13, 15). A case of hepatocellular jaundice resulting from an allergic reaction to DES also has been reported (16).Early studies on toxic effects from administration of natural and synthetic estrogens indicated the presence of hepatotoxicity (fatty degeneration and interstitial hepatitis) although a species susceptibility (dog vs. rat) was quite distinct (17-19). In various experimental animal models, injection of estrogens has been shown to impair biliary excretion (as measured by bromosulfophthalein) (20-22) but the production of severe hepatic dysfunction was uncommon. The present report defines the extraordinary jaundice and hepatic pathology induced by DES in the Chinese hamster. This novel response to DES was even more impressive in the Armenian hamster and present to some degree in the European hamster. On the other hand, Syrian hamsters were not affected even after larger doses of DES. Although t...

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Experimental Production of Mallory Bodies in Mice by Diet Containing 3,5-Diethoxycarbonyl-1,4-Dihydrocollidine

Cited by 55 publications

References 10 publications

Mallory body formation by ethanol feeding in drug-primed mice

Mallory body formation by ethanol feeding in drug-primed mice

The Mallory Body: Morphological, Clinical and Experimental Studies (Part 1 of A Literature Survey)

Diethylstilbestrol-Induced Jaundice in the Chinese and Armenian Hamster

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