Fetal Ascites—Liver Giant-Cell Transformation

FLETCHER, CHARLES B.

doi:10.1001/archpedi.1964.02090010556016

Cited by 5 publications

(1 citation statement)

References 3 publications

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“…For these chemically induced MNHs, it is considered that the MNHs originate from single hepatocytes with disturbed cell division because the chemicals affect the nuclear components (Richey et al 1977; Scampini et al 1993), and mitosis, or polyploidization, considered to be caused by karyokinesis in the absence of cytokinesis (van Zwieten and Hollander 1997), is frequently found (Malarkey et al 1995; Pohjanvirta et al 1995; Rachmilewitz et al 1950). On the other hand, several hepatocytic abnormalities found in infants such as giant cell hepatitis (Bird et al 1963), fetal ascites (Fletcher et al 1964), liver cell adenoma/carcinoma (McDougal and Gatzimos 1957; Roth and Duncan 1955; Wheeler et al 1986), idiopathic iron storage (Goldfisher et al 1981), and rubella (Plotkin et al 1965) are known to induce MNHs. Since a wide variety of causative factors can induce MNHs in infant liver, it has been considered a nonspecific response to injury (Richey et al 1977; Scampini et al 1993; Wheeler et al 1986).…”

Section: Discussionmentioning

confidence: 99%

Characterization of Multinuclear Hepatocytes Induced in Rats by Mitemcinal (GM-611), an Erythromycin Derivative

Hayashi¹,

Fujii²,

Kato³

et al. 2008

Toxicol Pathol

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Mitemcinal is an erythromycin derivative with motilin agonistic action, developed as a gastrointestinal motor-activating agent. The characteristics of mitemcinal-induced multinuclear hepatocytes (MNHs, hepatocytes with three or more nuclei per cell) from detailed morphological observations together with the results of a study on the mechanisms of MNH formation by combining cytocentrifuge preparations with 5-bromo-2'-deoxyuridine cumulative labeling are reported. MNHs were observed only in rats in the high-dose groups of the subchronic study, with a higher incidence in females and reversibility after twenty-eight days of drug withdrawal, but not observed in dogs. In the chronic study, the incidence increased relative to the dose. Histopathologically, MNHs were preferentially observed in the centrilobular zone, without nuclear atypia or mitotic figures. In the cell kinetic study, the labeling pattern of MNHs included all-positive, all-negative, and mixed labeling patterns of nuclei. The all-negative pattern indicated that the cells were formed by fusion of nondividing cells. The current results indicate that the cell kinetic approach effectively demonstrated the mechanism of mitemcinal-induced MNHs as fusion of hepatocytes and that drug-induced disturbance of mitosis is not involved in the multinucleation of MNHs by mitemcinal.

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Section: Discussionmentioning

confidence: 99%

Characterization of Multinuclear Hepatocytes Induced in Rats by Mitemcinal (GM-611), an Erythromycin Derivative

Hayashi¹,

Fujii²,

Kato³

et al. 2008

Toxicol Pathol

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Ascites in the Newborn Associated with Hepatitis

Deckelbaum

Weizman

Bauer

1980

Clin Pediatr (Phila)

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Multinucleated Hepatocytes Induced by Rifabutin in Rats

Scampini¹,

Nava²,

Newman³

et al. 1993

Toxicol Pathol

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AESTRAC~Rifabutin is an antibiotic of the rifamycin class, which is particularly active against mycobacteria, including those that occur in AIDS patients. Because clinical use will include long-term therapy, an extensive battery of long-term toxicity studies was carried out by the oral route, including carcinogenicity studies. An interesting feature was the occurrence of multinucleated hepatocytes (MNHs) in the rat. In some instances, as many as 25 nuclei occurred in a single cell. Light microscopy revealed a large hepatocyte with normal eosinophilic staining. The multiple nuclei stained like those present in the surrounding normal cells. Electron microscopy showed no abnormalities of the nuclei and no cell membranes within the cytoplasm. The customary organelles were present. MNHs were dose-and sex-related, starting from 10 mg/kg/day and being more evident in males. They began to appear after 5 wk of treatment and persisted over long periods of recovery ( I 2 mo), without showing any tendency for cell proliferation. The life-span of MNHs was similar to that of normal hepatocytes. MNHs were present in the carcinogenicity study, but there was no increase in liver tumors.MNHs did not occur in mice or monkeys treated with rifabutin, nor did they occur in response to treatment with rifampin. The effect appears to be specific to the rat.Keywords. Liver; antibiotic . INTRODUC~ION Rifabutin is an antibiotic of the rifamycin class, which is particularly active against mycobacteria including those that occur in AIDS patients. Because clinical use will include long-term therapy, an extensive battery of long-term toxicity studies was carried out by the oral route, including carcinogenicity studies.At the beginning of the customary safety experiments in the rat, the presence in the liver of multinucleated hepatocytes (MNHs) was discovered. In this article, we report the details of our extensive investigation of the phenomenon. MATERIALS AND MITHODSThe customary toxicity studies for safety evaluation were carried out in rats, mice, and monkeys.The majority of the studies, particularly those of rats, were carried out at Farmitalia Carlo Erba, whereas a proportion of those in mice and monkeys were performed under the supervision of Farmitalia Carlo Erba in independent contract laboratories. Materials, methods, and results are to be reported separately (4). The details of the studies are given in Table I. In these, the customary investigations were performed including the recording of body weight, clinical signs, ophthalmoscopy, food and water consumption, hematology, and clinical biochemistry. At termination, a full necropsy was carried out, the customary organs were weighed, and pumerous tissues were examined for histopathologYFor these studies, rifabutin of pharmaceutical grade and 96.48% purity was obtained from the Department , . .... of R&D/Galenics, Farmitalia (Milan) and, similarly, rifampin of 94.6% purity was supplied by SPA (Milan).Because MNHs were seen to occur in the liver of rats with evidence of a dose-related e...

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Fetal Ascites—Liver Giant-Cell Transformation

Cited by 5 publications

References 3 publications

Characterization of Multinuclear Hepatocytes Induced in Rats by Mitemcinal (GM-611), an Erythromycin Derivative

Characterization of Multinuclear Hepatocytes Induced in Rats by Mitemcinal (GM-611), an Erythromycin Derivative

Ascites in the Newborn Associated with Hepatitis

Multinucleated Hepatocytes Induced by Rifabutin in Rats

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