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ToxSci Advance Access published online on December 15, 2004
Toxicological Sciences, doi:10.1093/toxsci/kfi061
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Toxicological Sciences © Society of Toxicology 2004; all rights reserved.
Received October 26, 2004
Accepted December 9, 2004

In Vitro Toxicology

Mitochondrial Dysfunction Occurs Before Transport or Tight Junction Deficits in Biliary Epithelial Cells Exposed to Bile from Methylenedianiline-Treated Rats

Vicente Santa Cruz 1, Tammy R. Dugas 2, and Mary F. Kanz 3*

1 Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555-0609; Chevron Phillips Chemical Co. LP, 10001 Six Pines Drive, Suite 4103, The Woodlands, TX 77380
2 Department of Pharmacology, Louisiana State University Health Science Center - Shreveport, Shreveport, LA 71130-39
3 Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555-0609

* To whom correspondence should be addressed.
Mary F. Kanz, E-mail: mkanz{at}utmb.edu


  Abstract

Methylenedianiline (DAPM) rapidly injures biliary epithelial cells (BEC) in vivo. Prior to evident BEC injury, biliary glucose and inorganic phosphate appreciably rise which could stem from loosened tight junctions (TJ). Concurrently, ultrastructural abnormalities in BEC mitochondria of DAPM-treated animals are observed, suggesting other impairments. Our objective was to develop an in vitro BEC model to assess the time course of impairments in TJ integrity, glucose uptake, and mitochondrial function following DAPM exposure. We exposed monolayers of primary, polarized rat BEC to bile collected from rats prior to (Basal Bile) or after oral treatment (DAPM-Bile) with 50 mg DAPM/kg. DAPM-Bile collected during 0-60 min (1st Hr) and during 61-120 min (2nd Hr) after treatment was pooled from 4-6 rats. When monolayers were exposed to 1st Hr DAPM-Bile for 120 min, metabolic activity (XTT assay) decreased ~75% and transepithelial resistance decreased ~16% in agreement with an ~65% increase in leakage of a glucose analog, methyl-{alpha}-D-glucopyranoside (AMG), from apical to basolateral media. By 60 min, AMG uptake was decreased ~40%. Mitochondrial function was very rapidly compromised with ~120% increases in mitochondrial membrane potential at 15 min and ~55% decreases in ATP levels at 30 min. This sequence of events indicates that DAPM impairs BEC mitochondria prior to impairments in glucose uptake or TJ integrity. Thus, our in vitro primary rat BEC/ bile exposure model mimics in vivo observations and yields basic information about the time course of events that occur during DAPM-induced injury.

Keywords: methylenedianiline; biliary epithelial cells; bile; mitochondria; tight junctions; glucose transport.
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