Contributions to the Research & Society
Acquired forms of cholestatic liver disease such as primary
biliary cirrhosis, hepatitis, primary sclerosing cholangitis,
and cholestasis of pregnancy result in a substantial clinical
burden. Additionally, cholestasis secondary to sepsis is
an essential component of multiple organ dysfunction syndrome
which is the leading cause of death in critically ill patients.
Clinically, a common treatment regimen for cholestasis includes
the administration of phenobarbital which does not relieve
cholestasis or any of its various causes, but rather is used
to reduce the appearance of side effects such as hepatotoxicity.
It is likely that the induction of drug transporters by phenobarbital
as a compensatory transport and excretion pathway is the
mechanism for this clinical observation. We are investigating
alternative means to activate this molecular defense mechanism
which may represent an important advance in the clinical
management of cholestasis.
Regulation of the processes by which chemicals exit the
cell during chemical exposure and cholestasis, especially
metabolites produced by Phase I and Phase II biotransformation
is not well understood. Understanding of the mechanisms that
control drug transporter-mediated excretion of organic anions
can potentially serve the scientific and medical community
in our objective to create safe and biologically active drugs
that alleviate specific transport deficiencies or up-regulate
the excretion of chemicals in patients or exposed individuals.
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