The effects of dieldrin on the subcellular structure and function of mammalian liver cells

Wright, A. N.; Potter, Dorothy A.; Wooder, M.F.; Donninger, C.; Greenland, Robert D.

doi:10.1016/s0015-6264(72)80251-7

Cited by 63 publications

(9 citation statements)

References 52 publications

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“…The MBs in nontumorous livers were confined to the central region of the hepatic lobule. This is noteworthy in that, although previous papers on the carcinogenicity of dieldrin did not mention MBs (18, [24][25][26][27], the hepatocellular carcinomas which developed were believed to arise in the centrilobular region (18,24). The site of origin of the hepatic tumors produced in this experiment was not determined, although the histologic appearance of the tumors was similar to that previously reported (18,(24)(25)(26)(27).…”

Section: Discussionmentioning

confidence: 97%

Dieldrin–Induced Mallory Bodies in Hepatic Tumors of Mice of Different Strains

et al. 1983

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Mallory bodies (MBs) were induced in hepatic tumors by administration for up to 85 weeks of a diet containing 10 ppm dieldrin to 50 C3H/He and 62 C57BL/6J x C3H/He B6C3F1 male mice. MBs were seen in 15 of 28 (54%) mice which developed benign hepatic tumors and 33 of 45 (73%) mice with hepatocellular carcinoma, but in only 3 of 39 (8%) mice without hepatic tumors. In mice with tumors, the MBs were predominantly confined to tumor tissue and persisted in a carcinoma transplanted into a nude mouse. MBs were not observed, however, in hepatic tumors of 67 C57BL/ 6J, 49 C3H/He, or 81 B6C3F1 mice given 12 pg diethylnitrosamine i.p. on Days 0,3,9, and 15. Thirtyone of 195 control mice of all three strains had hepatic tumors. Only one of the controls had a tumor with an MB, and no MBs were seen in nontumor-bearing livers of control animals. These observations, coupled with the results of a previous study in which MBs were observed in hepatocytes of dieldrin-treated C57BL/6J mice, indicate that mice treated with dieldrin are a reliable animal model for the study of MBs.Mallory bodies (MBs) are cytoplasmic inclusion bodies which were first described in the hepatocytes of patients with alcoholic liver disease (1). They are also seen in several other hepatic diseases including hepatocellular carcinoma (2, 3) and have been reported in pulmonary alveolar epithelial cells of patients with asbestosis and radiation pneumonitis (4) and in pulmonary adenocarcinoma (5). In animal studies, MBs have been reported in the livers of mice treated with griseofulvin and also in liver tumors which developed in these mice (6), and in cultured hepatocytes isolated from diethylnitrosamine (DEN)-induced hepatocellular carcinomas of rats (7, 8). Electron microscopic and immunohistochemical studies have characterized MBs as composed of filaments related to the tonofdament subclass of intermediate-sized filaments (9-11) which, along with microfilaments and microtubules, are part of the cytoskeletal network. Human and mouse MBs have antigenic determinants which cross-react with antibodies to human MBs (2,10,11) and prekeratin antibodies (2).At the present time, there are three principal theories regarding the significance of MBs or events leading to their formation. One is that MBs form as the result of microtubular dysfunction which leads to ineffective dispersal or increased synthesis of intermediate-filament protein-producing aggregates visible microscopically (3, 8, 12). Colchicine, griseofulvin, and ethanol are agents which have been postulated to function in this manner (3, 8, 12). A second theory is that MBs form as a manifestation of vitamin A deficiency and actually represent a pathologic and largely hepatocyte-specific form of keratinization (2). This view is supported by immunologic and electrophoretic data relating MB filaments to prekeratin-like polypeptides. A third theory is that MBs represent a change in altered cells which are progressing in the direction of neoplasia (7, 8, 13). The abnormal accumulation of intermediate filaments is...

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Section: Discussionmentioning

confidence: 97%

Dieldrin–Induced Mallory Bodies in Hepatic Tumors of Mice of Different Strains

et al. 1983

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“…The de-ethylation is induced about 40-fold measured in vitro and expressed relative to cytochrome P-450. Working, some years ago, with CFE rats which had a low basal level of the enzyme, a 600-fold induction was measured [7]. At low doses of chlorfenvinphos (2.5 mg/kg) little change in the metabolic profile was found in vivo; however, at higher doses, giving clinical signs of intoxication in control animals, dieldrin-pretreated rats produced five times more metabolite 2 ( Fig.…”

Section: Rate Of De-ethylationmentioning

confidence: 99%

Enzyme-mediated selective toxicity of an organophosphate and a pyrethroid: some examples from a range of animals

Hutson

Millburn

1991

Biochemical Society Transactions

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“…A variety of xenobiotic compounds are known to induce characteristic changes in the livers of laboratory animals. These changes include: (i) liver enlargement, usually as a result of cell enlargement, polyploidisation or cell replication, (ii) induction of drugmetabolising enzymes, and (iii) proliferation of the smooth endoplasmic reticulum (1)(2)(3)(4)(5)(6). Such changes are not usually accompanied by evidence of liver damage, and are reversible upon withdrawal and elimination of the compound (5,6).…”

Section: Introductionmentioning

confidence: 99%

“…Phenobarbitone, DDT, butylated hydroxytoluene (BHT) and a-HCH have also been shown to promote the formation of rat liver tumours from lesions previously initiated by hepatocarcinogens (13 -16). By analogy, it has been suggested that microsomal enzyme inducers do not exert an intrinsically carcinogenic effect on mouse liver, but function by enhancing the effect of a pre-existing oncogenic factor, which may be of environmental or genetic origin (5,7).…”

Section: Introductionmentioning

confidence: 99%

Quantitative aspects of enhanced liver tumour formation in CF-1 mice by dieldrin

1985

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The dose-response characteristics of dieldrin-mediated enhancement of liver tumour formation in CF-1 mice were analysed, using existing tumour data from chronic feeding studies at six levels of continuous exposure, involving a total of greater than 1500 animals. The dose-response relationship can be expressed as: Dx X Tx = D0 X T0 = constant, where T0 = the median liver tumour induction period in control CF-1 mice, Tx = the median liver tumour induction period in dieldrin-treated mice at a dose level Dx, D0 = the background dose equivalent for the induction of 'spontaneous' liver tumours, Dx = the sum of background dose (D0) and actual dieldrin dose (delta x). The relationship, which is a Druckrey equation (D X Tn = constant) where n = 1, indicates that: (i) the velocity of liver tumour development is proportional to the daily dose level (Dx), (ii) the total tumourigenic dose is constant across all doses, (iii) the effects of dieldrin on the neoplastic process in mouse liver are essentially irreversible and cumulative, and (iv) there is no evidence for a threshold level. However, when delta x much less than D0, the actual contribution of dieldrin to tumour formation is expected to be negligible.

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The effects of dieldrin on the subcellular structure and function of mammalian liver cells

Cited by 63 publications

References 52 publications

Dieldrin–Induced Mallory Bodies in Hepatic Tumors of Mice of Different Strains

Dieldrin–Induced Mallory Bodies in Hepatic Tumors of Mice of Different Strains

Enzyme-mediated selective toxicity of an organophosphate and a pyrethroid: some examples from a range of animals

Quantitative aspects of enhanced liver tumour formation in CF-1 mice by dieldrin

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