Research Interests
Toxicology, biliary drug excretion, metal toxicity, metallothionein, transgenic animals, gene expression
Research in this laboratory is involved in basic regulatory mechanisms in toxicology. Our research has two main aims: (1) to determine the role of cellular membrane transporters in the toxicity of chemicals, (2) and examine how chemicals produce thyroid tumors. In both of these projects we are investigating the role ligand-activated transcription factors play in regulating chemical elimination, examining both transport and biotransformation of chemicals.
All organisms are exposed to foreign chemicals (xenobiotics). Xenobiotics are natural ingredients in food, fungal toxins in food, as well as man-made chemicals such as drugs, pesticides and industrial chemicals. Many of these chemicals are lipid soluble and are biotransformed into more water soluble chemicals. The water soluble metabolites must be exported out of cells, into urine or bile. A number of xenobiotics increase the biotransformation of chemicals by increasing the transcription of biotransformation enzymes, by binding to various transcription factors, such as PXR, CAR, AhR, PPARa and Nrf2.
Our laboratory is involved in determining whether these nuclear receptors not only enhance the biotransformation of chemicals, but also the transport of their metabolites into bile and urine. This would then enhance the elimination of xenobiotics which would be desirable, but might shorten the duration of drugs, which might be undesirable, and enhance the elimination of thyroid hormones, which might be responsible for producing thyroid tumors.
Models used in our laboratory include knock-out mice, and techniques include surgery, enzyme assays, histology, mRNA analysis by northern blotting and bDNA, western blotting, pharmacokinetics, immunohistochemistry, EMSA, etc.
Cheng, X. and Klaassen, C.D.: Regulation of mRNA expression of xenobiotic transporters by the Pregnane-X receptor (PRX) in mouse liver, kidney and intestine. Drug Metab. Dispos. 34: 1863-1867, 2006.
Buckley, D.B. and Klaassen, C.D.: Tissue- and gender-specific mRNA expression of UDP-glucuronosyltransferases (UGTs) in mice. Drug Metab. Dispos. 35: 121-127, 2007.
Tanaka, Y., Maher, J.M., Chen, C., and Klaassen, C.D.: Hepatic ischemia-reperfusion induces renal heme oxygenase-1 (HO-1) via NF-E2 related factor 2 (Nrf2) in rats and mice. Mol. Pharmacol. 71: 817-825, 2007.
Chen, C., Cheng, X., Dieter, M.Z., Tanaka, Y., and Klaassen, C.D.: Activation of cyclic AMP (cAMP)-dependent signaling pathway induces mouse organic anion transporting polypeptide 2 (Oatp2) expression. Mol. Pharmacol. 71: 1159-1164, 2007.
Alnouti, Y.M., Shelby, M.K., Chen, C., and Klaassen, C.D.: Influence of phenobarbital on morphine metabolism and disposition: LC-MS/MS determination of morphine (M) and morphine-3-glucuronide (M3G) in Wistar-Kyoto rat serum, bile, and urine. Curr Drug Metab 8: 79-89, 2007.
Petrick, J.S. and Klaassen, C.D.: Importance of hepatic induction of constitutive androstane receptor (CAR) and other transcription factors that regulate xenobiotic metabolism and transport. Drug Metab. Dispos. 35:1806-1815, 2007.
Maher, J.M., Dieter, M.Z., Aleksunes, L.M., Slitt, A.L., Guo, G., Tanaka, Y., Scheffer, G.L., Chan, J.Y., Manautou, J.E., Chen, Y., Dalton, T.P., Yamamoto, M., and Klaassen, C.D.: Oxidative and electrophilic stress induces multidrug resistance-associated protein transporters via the nuclear factor-E2-related factor-2 transcriptional pathway. Hepatology 46: 1597-1610, 2007.
Lu, H. and Klaassen, C.D.: Gender differences in mRNA expression of ABC efflux and bile acid transporters in kidney, liver and intestine of 5/6 nephrectomized rats. Drug Metab. Dispos. 36:16-23, 2007.
Knight, T.R., Choudhuri, S. and Klaassen, C.D.: Constitutive mRNA expression of various glutathione S-transferase isoforms in different tissues of mice. Toxicol. Sci. 100: 513-524, 2007.
Cheng, X., Buckley, D. and Klaassen, C.D.: Regulation of hepatic bile acid transporters Ntcp and Bsep expression. Biochem. Pharmacol. 74: 1665-1676, 2007.
Alnouti, Y. and Klaassen, C.D.: Regulation of sulfotransferase enzymes by prototypical microsomal enzyme inducers in mice. J. Pharmacol. Exp. Ther. 324: 612-621, 2007.
Tanaka, Y., Chen, C., Maher, J.M. and Klaassen, C.D.: Ischemic-reperfusion of rat livers decreases liver and increases kidney multidrug resistance-associated protein 2 (Mrp2). Toxicol. Sci. 101: 171-178, 2008.
Alnouti, Y. and Klaassen, C.D.: Tissue distribution, ontogeny, and regulation of aldehyde dehydrogenase (Aldh) enzymes mRNA by prototypical microsomal enzyme inducers in mice. Toxicol. Sci. 101: 51-64, 2008.
Tanaka, Y., Aleksunes, L.M., Yeager, R.L., Gyamfi, M.A., Esterly, N., Guo, G.L., and Klaassen, C.D.: NF-E2-related factor 2 (NRF2) inhibits lipid accumulation and oxidative stress in mice fed a high-fat diet. J. Pharmacol. Exp. Ther. 325:655-664, 2008.
Lu, H., Choudhuri, S., Ogura, K., Csanaky, I.L., Lei, X., Cheng, X., Song, P., and Klaassen, C.D.: Characterization of organic anion transporting polypeptide 1b2-null mice: essential role in hepatic uptake/toxicity of phalloidin and microcystin-LR. Toxicol. Sci. 103: 35-45, 2008.
Curtis D. Klaassen
University Distinguished Professor and Chair
Department of Pharmacology, Toxicology and Therapeutics
The University of Kansas Medical Center
MS1018
3901 Rainbow Boulevard
Kansas City, KS 66160
Phone: (913) 588-7500
Fax: (913) 588-7501
E-mail: cklaasse@kumc.edu
Curriculum Vitae in PDF Format
Updated 9/5/08
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The University of Kansas Medical Center