A Minimally Toxic Dose of Methylene Dianiline Injures Biliary Epithelial Cells in Rats

Mf, Kanz; Gh, Gunasena; Kaphalia, Lata; Dk, Hammond; Ya, Syed

doi:10.1006/taap.1998.8382

Cited by 28 publications

(21 citation statements)

References 35 publications

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“…3B). These ultrastructural alterations are consistent with those observed for the 50 mg/kg dose, where mitochondrial abnormalities, loss of lumenal microvilli and dilation of rough endoplasmic reticulum cisternae were also evident (Kanz et al, 1998).…”

Section: Model Of Bec Injury Without Evident Hepatocyte Injurysupporting

confidence: 88%

“…Prior studies have suggested that DAPM is a selective BEC toxicant (Bailie et al, 1993;Kanz et al, 1998;Santa Cruz et al, 2005), but evidence that the alterations in biliary parameters induced by DAPM are characteristic of BEC injury rather than hepatocellular injury has been equivocal. Thus, we examined aspects of BEC function in rats given a dose of DAPM (25 mg/ kg) that is reported to be below the threshold of injury (Bailie et al, 1993).…”

Section: Discussionmentioning

confidence: 99%

“…For DAPM-injury experiments, rats were anesthetized with pentobarbital (50 mg/ml, 1 ml/kg) and bile duct, duodenal and peritoneal cannulas were implanted by established procedures (Kanz et al, 1998). Body temperatures of anesthetized rats were maintained at ~37ºC by a homeothermic blanket unit (Harvard Bioscience, Natick, MA).…”

Section: Experimental Protocolsmentioning

confidence: 99%

“…For electron microscopy studies, rats were anesthetized with pentobarbital 3 h after treatment with DAPM or vehicle. Livers were perfusion-fixed and sectioned as previously described (Kanz et al, 1998).…”

Section: Experimental Protocolsmentioning

confidence: 99%

“…Minimally toxic doses (50 mg/ kg) induce prominent increases in biliary inorganic phosphate (P i ) and glucose but have only minor effects on hepatocellular constituents such as bilirubin and bile acids in serum and bile (Kanz et al, 1998;Dugas et al, 2001). The mechanism(s) by which DAPM causes BEC injury and alterations in biliary constituents is unknown; however, elevations in biliary P i are typically regarded as an indicator of tight junction (TJ) leakage.…”

Section: Introductionmentioning

confidence: 99%

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Effects of methylenedianiline on tight junction permeability of biliary epithelial cells in vivo and in vitro

Cruz¹,

Liu²,

Kaphalia³

et al. 2007

Toxicology Letters

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Methylenedianiline (DAPM) is considered a cholangiodestructive toxicant in vivo. Increases in biliary inorganic phosphate (P i ) and glucose occur prior to biliary epithelial cell (BEC) injury, which could be due to increased paracellular permeability and/or impairment of P i and glucose uptake by BEC. To evaluate these possibilities, we induced mild injury [loss of BEC from major bile ducts (6 h), ultrastructural alterations in BEC mitochondria and Golgi cisternae (3 h), and striking increases in biliary P i and glucose (3-6 h)] with 25 mg DAPM/kg and then assessed temporal alterations in tight junction (TJ) permeability by measuring bile to plasma (B:P) ratios of [ 3 H]-inulin. Parameters maintained by hepatocytes in bile were unchanged (bile flow, bile acids, bilirubin) or only transiently perturbed (protein, glutathione). Minimal elevations in B:P ratios of inulin occurred temporally later (4 h) in DAPM-treated rats than increases in biliary P i and glucose. To confirm a direct effect of DAPM on BEC TJs, we measured transepithelial resistance (TER) and bi-ionic potentials of BEC monolayers prior to and after exposure to pooled (4 to 6) bile samples collected from untreated rats (Basal Bile) or rats treated with 50 mg DAPM/ kg (DAPM-Bile). BEC TJs were found to be cation selective. Exposure to DAPM-Bile for 1 h decreased TERs by ~35% and decreased charge selectivity of BEC TJs while exposure to Basal Bile had no effects. These observations indicate that DAPMBile impairs paracellular permeability of BEC in vitro. Further, our in vivo model suggests that increases in paracellular permeability induced by DAPM are localized to BEC because bile flow and constituents excreted by hepatocytes were unchanged; BEC damage was temporally correlated with increases in biliary P i and glucose; and elevations in B:P ratios of inulin were delayed and minimal.

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Section: Model Of Bec Injury Without Evident Hepatocyte Injurysupporting

confidence: 88%