METHYLENE DIANILINE TOXICITY TO BILIARY EPITHELIAL CELLS
Principal Investigator: Vicente Santa Cruz
Abstract: 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.
Funding Period: 2000-06-01 - 2001-04-20
more information: NIH RePORT