Photo of Dennis R Koop, Ph.D.

Dennis R Koop Ph.D.

  • 5034947803
    • Professor of Physiology and Pharmacology School of Medicine
The cytochrome P450 system is essential in most organisms for the biosynthesis of endogenous compounds such as steroids, fatty acids, prostaglandins and pheromones. However, the largest number of P450 substrates are foreign chemicals that include drugs, plant metabolites, environmental pollutants and food additives. In general, the role of P450 is to detoxify chemicals and increase elimination from the body. However, in some cases the oxidized products can initiate cell toxicity, including chemical carcinogenesis, mutagenesis and teratogenesis. The detrimental properties of this enzyme family underscore the importance of understanding the regulation of the individual members of the gene family.Research in my laboratory is focused on characterizing the regulation and catalytic activity of P450 2E1 (CYP2E1), and examining the effect of antioxidants on stress signaling pathways and P450-dependent metabolism. The level of CYP2E1 is increased by alcohol consumption, and it is hypothesized that many ethanol-associated toxicities are due to the induction of this enzyme in hepatic and extrahepatic tissues. For example, an increased hepatotoxicity of acetaminophen is thought to be due to metabolism of this commonly used over-the-counter pain medication to a reactive metabolite by higher levels of CYP2E1. The induction of CYP2E1 also is associated with an increased generation of active oxygen species that can initiate cellular damage. Since the degree of damage is related to the level of the enzyme, it is important to find those factors that control its intracellular concentration and to identify compounds that can alter its metabolic activity and expression. The research in my laboratory utilizes ce ll lines expressing the normal CYP2E1 and selectively modified forms of the enzyme to identify those regions important in its degradation. In addition, the expression is monitored in genetic models of iron overload where induction of CYP2E1 could exacerbate drug-induced toxicity. The effect of constituents of natural products such as those found in herbal tinctures and alcoholic beverages on P450 dependent expression and metabolism are also being investigated. The metabolic activity of CYP2E1 and other P450s toward endogenous compounds such as lipids, sterols and steroids is being investigated using state-of-the art LC/MS.

Memberships and associations

  • SOM-Physiology &Pharmacology DepartmentPhysiology &PharmacologyProgram in Molecular &Cellular Biosciences

Publications

  • "Longitudinal study on the use of dried blood spots for home monitoring in children after kidney transplantation." Pediatric Transplantation In: , 2017.
  • "A comparison of salivary testosterone measurement using immunoassays and tandem mass spectrometry." Psychoneuroendocrinology In: , Vol. 71, 01.09.2016, p. 180-188.
  • "Diphenylether-Modified 1,2-Diamines with Improved Drug Properties for Development against Mycobacterium tuberculosis." ACS Infectious Diseases In: , Vol. 2, No. 7, 08.07.2016, p. 500-508.
  • "A role for adenine nucleotides in the sensing mechanism to purine starvation in Leishmania donovani." Molecular Microbiology In: , Vol. 101, No. 2, 01.07.2016, p. 299-313.
  • "Polyphenon E, non-futile at neuroprotection in multiple sclerosis but unpredictably hepatotoxic : Phase I single group and phase II randomized placebo-controlled studies." Journal of the neurological sciences  In: , Vol. 358, No. 1-2, 15.11.2015, p. 46-52.
  • "A phase II study of sulforaphane-rich broccoli sprout extracts in men with recurrent prostate cancer." Investigational New Drugs  In: , Vol. 33, No. 2, 01.04.2015, p. 480-489.
  • "Threshold levels of ABL tyrosine kinase inhibitors retained in chronic myeloid leukemia cells determine their commitment to apoptosis." Cancer Research In: , Vol. 73, No. 11, 01.06.2013, p. 3356-3370.
  • "Analysis of tacrolimus and creatinine from a single dried blood spot using liquid chromatography tandem mass spectrometry." Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences  In: , Vol. 926, 01.05.2013, p. 54-61.
  • "Effect of the ethinylestradiol/levonorgestrel combined oral contraceptive on the activity of cytochrome P4503A in obese women." British Journal of Clinical Pharmacology  In: , Vol. 74, No. 3, 09.2012, p. 510-514.
  • "Naloxone pro-drug rescues morphine induced respiratory depression in Sprague-Dawley rats." Respiratory Physiology and Neurobiology In: , Vol. 180, No. 1, 15.01.2012, p. 52-60.
  • "The effects of nitrogen-heme-iron coordination on substrate affinities for cytochrome P450 2E1." Chemico-Biological Interactions In: , Vol. 193, No. 1, 15.08.2011, p. 50-56.
  • "Ubiquitin-dependent proteasomal degradation of human liver cytochrome P450 2E1 : Identification of sites targeted for phosphorylation and ubiquitination." Journal of Biological Chemistry  In: , Vol. 286, No. 11, 18.03.2011, p. 9443-9456.
  • "Optimization of endochin-like quinolones for antimalarial activity." Experimental Parasitology In: , Vol. 127, No. 2, 02.2011, p. 545-551.
  • "Interstrain differences in the liver effects of trichloroethylene in a multistrain panel of inbred mice." Toxicological Sciences  In: , Vol. 120, No. 1, 2011, p. 206-217.
  • "Mechanism for prevention of alcohol-induced liver injury by dietary methyl donors." Toxicological Sciences  In: , Vol. 115, No. 1, 05.2010, p. 131-139.
  • "Pharmacokinetic study of acid in multiple sclerosis : Comparing mice and human pharmacokinetic parameters." Multiple Sclerosis In: , Vol. 16, No. 4, 04.2010, p. 387-397.
  • "Paired assessment of volatile anesthetic voncentrations with synaptic actions recorded in vitro." PLoS One In: , Vol. 3, No. 10, e3372, 08.10.2008.
  • "Soluble epoxide hydrolase gene deletion is protective against experimental cerebral ischemia." Stroke In: , Vol. 39, No. 7, 07.2008, p. 2073-2078.
  • "Isoflurane differentially modulates inhibitory and excitatory synaptic transmission to the solitary tract nucleus." Anesthesiology In: , Vol. 108, No. 4, 04.2008, p. 675-683.
  • "Polymorphisms in the human soluble epoxide hydrolase gene EPHX2 linked to neuronal survival after ischemic injury." Journal of Neuroscience In: , Vol. 27, No. 17, 25.04.2007, p. 4642-4649.
  • "Alcohol metabolism's damaging effects on the cell : A focus on reactive oxygen generation by the enzyme cytochrome P450 2E1." Alcohol Research and Health In: , Vol. 29, No. 4, 2006, p. 274-280.
  • "Effect of pregnancy on the pharmacokinetics of paclitaxel : A case report." Clinical Breast Cancer In: , Vol. 7, No. 4, 2006, p. 342-344.
  • "Steatohepatitis induced by intragastric overfeeding in mice." Hepatology  In: , Vol. 42, No. 4, 10.2005, p. 905-914.
  • "Use of CYP2E1-transfected human liver cell lines in elucidating the actions of ethanol." Alcoholism: Clinical and Experimental Research In: , Vol. 29, No. 9, 09.2005, p. 1726-1734.
  • "Centella asiatica accelerates nerve regeneration upon oral administration and contains multiple active fractions increasing neurite elongation in-vitro." Journal of Pharmacy and Pharmacology In: , Vol. 57, No. 9, 09.2005, p. 1221-1229.
  • "Hepatoprotective mechanisms of Yan-gan-wan." Hepatology Research  In: , Vol. 32, No. 4, 08.2005, p. 202-212.
  • "Cytochrome P450 CYP2E1, but not nicotinamide adenine dinucleotide phosphate oxidase, is required for ethanol-induced oxidative DNA damage in rodent liver." Hepatology  In: , Vol. 41, No. 2, 02.2005, p. 336-344.
  • "A phase I study of 5-fluorouracil, leucovorin, and celecoxib in patients with incurable colorectal cancer." Prostaglandins and Other Lipid Mediators In: , Vol. 75, No. 1-4, 01.2005, p. 169-172.
  • "Proteasome-dependent degradation of cytochromes P450 2E1 and 2B1 expressed in tetracycline-regulated HeLa cells." Toxicology and Applied Pharmacology In: , Vol. 199, No. 3, 15.09.2004, p. 332-343.
  • "ω-Hydroxylation of farnesol by mammalian cytochromes P450." Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids In: , Vol. 1682, No. 1-3, 01.06.2004, p. 18-27.

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