Methylene dianiline (4,4'-diaminodiphenylmethane, DAPM) is a compound widely used in the production of epoxy resins and polyurethanes which are currently used to make items such as intra-aortic balloons and tubing of artificial dialysis machines. DAPM produces selective toxicity to biliary epithelial cells (BEC) of rats by an unknown mechanism. Previous studies of low dose DAPM have shown alterations in BEC mitochondrial ultrastructure and abnormally high levels of glucose in bile. Because BECs are responsible for glucose absorption from bile, I hypothesize that DAPM damages surface glucose receptors and/or alters high energy phosphate metabolism which regulates ATP-dependent, Na+- dependent glucose absorption.
Aim 1 will develop an in vitro system to study primary rat BECs. BECs will be isolated and cultured on microcarrier beads to confluency. Beads will then be perfused in 1 ml columns to simulate in vivo conditions. This perfusion system will provide 1) control over the effects Of specific DAPM metabolites, 2) specificity for our target population, BECs, and 3) a model for future studies to assess transport mechanisms.
Aims 2 and 3 will use this system to assess the effects of DAPM and its metabolites on the absorption of radioactive sugars dependent on glucose receptors, and on mitochondrial injury which can have subsequent effects on glucose absorption. The proposed aims will provide further insight into the mechanisms of injury induced by DAPM, and specific knowledge regarding glucose transport processes in BEC.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31ES005831-03
Application #
6178305
Study Section
Special Emphasis Panel (ZRG2-SSS-F (06))
Program Officer
Shreffler, Carol K
Project Start
2000-06-01
Project End
2001-04-20
Budget Start
2000-06-01
Budget End
2001-04-20
Support Year
3
Fiscal Year
2000
Total Cost
$17,396
Indirect Cost
Name
University of Texas Medical Br Galveston
Department
Pathology
Type
Schools of Medicine
DUNS #
041367053
City
Galveston
State
TX
Country
United States
Zip Code
77555
Santa Cruz, Vicente; Liu, Hanlin; Kaphalia, Lata et al. (2007) Effects of methylenedianiline on tight junction permeability of biliary epithelial cells in vivo and in vitro. Toxicol Lett 169:13-25
Kanz, Mary F; Dugas, Tammy R; Liu, Hanlin et al. (2003) Glutathione depletion exacerbates methylenedianiline toxicity to biliary epithelial cells and hepatocytes in rats. Toxicol Sci 74:447-56