Pharmacology, Toxicology and Therapeutics : Faculty & Graduate Students : Erik K. Pacyciak
Research Interests
The human liver is responsible for the detoxification of endogenous metabolites as well as potentially toxic xenobiotics. The liver performs this function through initial uptake of the substrates into the liver from the blood. Uptake into the liver can occur via passive diffusion or via active transport. Members of the organic anion transporting polypeptide (OATP) superfamily are responsible for the hepatic uptake of some chemicals. Following uptake, metabolism and excretion of the endo-/xenobiotics occur. Nuclear receptors such as pregnane X receptor (PXR) and the constitutive androstane receptor (CAR) act as xenobiotic sensors that protect the body from a multitude of foreign chemicals (xenobiotics) as well as play a central role in the metabolism and clearance of steroids and toxic endogenous lipids (endobiotics). A structurally diverse array of chemicals including drugs, steroids, herbal extracts, pesticides and various environmental toxins activate PXR and/or CAR. The concerted action of hepatic uptake/efflux transporters and nuclear receptors act to rid the body of potentially harmful chemicals.
Polybrominated diphenyl ether (PBDE) congeners are used as flame retardants and are universally present in the environment. Researchers have detected an exponential increase of PBDE congeners in the US population over the last two decades, especially with unexpected high levels in breast milk from women. We are most commonly exposed to three PBDE congeners, BDE47 (tetraBDE), 99 (pentaBDE), and 209 (decaBDE). PBDE congeners disrupt thyroid hormone homeostasis, act as neurotoxins, and are labeled as potential carcinogens. We have little understanding of the mechanism by which PBDE congeners exert their toxicities.
My current research goal is to clarify the mechanism by which PBDE congeners induce P450 enzymes. Additionally, I am working to determine the substrate specificity of the OATP/Oatp (mouse) family for PBDEs. I have shown that PBDEs are activators of the xenobiotic nuclear receptor PXR. Current work includes determination of PBDEs as CAR activators as well as elucidating which PBDEs may be substrates for OATP/Oatp.
Pacyniak EK, Cheng X, Cunningham M, Crofton K, Klaassen CD, Guo GL.
The Flame Retardants, Polybrominated Diphenyl Ethers (PBDE), are Pregnane X Receptor (PXR) Activators. Toxicol Sci. 2007
Erik K. Pacyniak
Department of Pharmacology, Toxicology, and Therapeutics
The University of Kansas Medical Center
KLSIC, MS1018
3901 Rainbow Boulevard
Kansas City, KS 66160
Phone: (913) 588-3089
Fax: (913) 588-7501
E-Mail: epacyniak@kumc.edu
Updated 11/13/08
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The University of Kansas Medical Center