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Thomas A. Kocarek, Ph.D. |
RESEARCH INTERESTS:
The enzymes of the cytochrome P450 superfamily of hemoprotein monooxygenases are responsible for the oxidative metabolism of a diverse assortment of substrates, both endogenous and xenobiotic. P450s are most abundant in the liver, particularly the hepatocyte, where the amount of each P450 is controlled by a complex combination of intracellular and extracellular signals. A remarkable property of many P450s is inducibility, whereby the presence of a chemical inducer evokes an increase in the amount of one or more P450s, which often results in metabolism of the inducer. P450 induction has important implications for drug-drug interactions or toxicity in humans if the rate-limiting step in a drug’s elimination or bioactivation is catalyzed by an inducible P450.
Emerging evidence suggests that certain of the xenobiotic-inducible P450s are regulated by the same processes that control metabolism of a cell's own endogenous lipophilic chemicals. Metabolites of the cholesterol biosynthetic pathway are now recognized to function not only as chemical intermediates, but also as intracrine regulators of hepatocyte physiology, which act by modifying the activities of nuclear receptors. The focus of Dr. Kocarek's research is to understand the linkage between hepatocellular sterol metabolism and P450 expression. This research will lead to greater understanding of the mechanisms whereby the hepatocyte recognizes, responds to, and metabolizes foreign chemicals.
Selected Recent Publications
Duniec-Dmuchowski Z, Ellis E, Strom SC and Kocarek TA. Regulation of CYP3A4 and CYP2B6 Expression by Liver X Receptor Agonists. Biochem Pharmacol 74:1535-1540, 2007. PMID: 17825266
Jackson NM and Kocarek TA. Suppression of CYP2B induction by alendronate-mediated farnesyl diphosphate synthase inhibition in primary cultured rat hepatocytes. Drug Metab Dispos 36:2030-2036, 2008. PMID: 18617600
Duniec-Dmuchowski Z, Fang HL, Strom SC, Ellis E, Runge-Morris M and Kocarek TA. Human pregnane X receptor activation and CYP3A4/CYP2B6 induction by 2,3-oxidosqualene:lanosterol cyclase inhibition. Drug Metab Dispos 37:900-908, 2009. PMID: 19158313
Cook IT, Duniec-Dmuchowski Z, Kocarek TA, Runge-Morris and Falany CN. 24-Hydroxycholesterol sulfation by human cytosolic sulfotransferase: Formation of monosulfates and disulfates, molecular modeling, sulfatase sensitivity, and inhibition of liver X receptor activation. Drug Metab Dispos 37:2069-2078, 2009. PMID: 19589875
Runge-Morris M and Kocarek TA. Regulation of sulfotransferase and UDP-glucuronosyltransferase expression by the PPARs. PPAR Res 2009:728941, 2009. PMID: 19680455
