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Dr. Rifkind has had a long
standing research interest in the molecular mechanisms by which the
environmental toxin 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, dioxin) produces
its toxic effects and in the role of cytochrome P4501A induction in those effects. At sublethal doses, TCDD is carcinogenic and
causes a wasting syndrome and defects in cardiac contraction. Uniquely, TCDD produces all of its toxic and
biochemical effects by activation of a cellular receptor, the aryl hydrocarbon
receptor (AhR). The AhR is increasingly
being recognized to have important regulatory roles in normal physiologic
processes as well in mediating toxicity of TCDD and related aromatic
hydrocarbons. AhR activation by TCDD
elicits transcriptional increases in cytochrome P450 (CYP) enzymes in the CYP1A
family as well as TCDD toxicities. Using
the chick embryo as a model, Dr.
Rifkind’s group discovered that human and chick CYP1A2 are highly active epoxygenases
for the membrane lipid, arachidonic acid, indicating that CYP1A may exert
biologic effects via the metabolism of endogenous substances as well as foreign
chemicals.
Dr. Rifkind’s laboratory is currently investigating transcriptional and
posttranscriptional effects of AhR activation and CYP1A induction resulting in
dysregulation of cell signaling pathways governing gluconeogenesis and lipid
metabolism (i.e. the Akt, AMPK and PGC1 pathways) and in disturbed
mitochondrial function. Her group is
using TCDD as a tool to probe the AhR. Molecular and biochemical approaches in primary
hepatocyte and cardiac myocyte cultures and in the chick embryo in ovo,
are being used to study effects of AhR activation on energy production and
nutrient homeostasis in liver and heart. Effects of TCDD resemble pathologic
changes in cancer, heart disease, diabetes mellitus, and wasting syndromes,
major human diseases. Dr. Rifkind’s research seeks to identify new
pharmacologic targets for those conditions as well as regulatory roles of the
AhR in energy metabolism.