Pharmacology

Erin Allen

Mentor: Jonathan Doorn, PhD

Year Entered Into Program: 2006-2011

PhD Institution: University of Iowa, 2011

Affiliations

  • Medicinal and Natural Products Chemistry

Research Description

Molinate is a thiocarbamate herbicide, commonly used as a pre-emergent in rice patty fields, which has been shown to cause neurotoxicity. Molinate undergoes oxidation to molinate sulfoxide and is further oxidized to molinate sulfone, an electrophile reactive toward thiols. Previous work demonstrated a decrease in aldehyde dehydrogenase (ALDH) activity in rats treated with molinate. These findings suggest the sulfone metabolite of molinate, and perhaps the sulfoxide metabolite, to be an inhibitor of ALDH, potentially modifying the active-site cysteine. ALDH is an enzyme important in the catabolism of many neurotransmitters, and inhibition of these catabolic processes may lead to the accumulation of neurotoxic metabolites such as 3,4-dihydroxyphenylacetaldehyde (DOPAL). The hypothesis of my current research is molinate and both metabolites inhibit ALDH through modification of the active-site cysteine, and molinate sulfone is the most potent inhibitor. To test this hypothesis, molinate sulfoxide and molinate sulfone were synthesized, and various model systems were used, including rat brain ALDH, rat striatal mitochondria, synaptosomes, and human recombinant ALDH. The enzyme activity was monitored in each of these model systems and the relative potency of each inhibitor determined. Preliminary results demonstrate molinate, molinate sulfone, and molinate sulfoxide inhibit ALDH activity, causing an increase of the endogenous neurotoxin, DOPAL, and molinate sulfone is the most potent ALDH inhibitor. Future work will include elucidating the mechanism of ALDH inhibition for each of these inhibitors, and analyzing the effects of these inhibitors on dopaminergic PC6-3 cells.

Publication(s)

Gagan, E.M., Hull, M.W., Schultz, T.W., Poch, G., Dawson, D.A.:  Time dependence in mixture toxicity with soft electrophiles: 1. Combined effects of selected SN2- and SNAr- reactive agents with a nonpolar narcotic.  Archives of Environmental and Contamination Toxicology, 52(3):283-293, 2007.  PMID: 17253098 Roberts, R.A., Laskin, D.L., Smith, C.V., Robertson, F.M., Allen, E.M., Doorn, J.A., and Slikker, W.: Nitrative and Oxidative Stress in Toxicology and Disease. Toxicological Sciences, 112(1), 4-16, 2009.  PMCID: PMC2769059 E.M.G. Allen, D.G.R. Anderson, V.R. Florang, T.D. Hurley, and J.A. Doorn.:  Relative Inhibitory         Potency of Molinate and Metabolites with Aldehyde Dehydrogenase: Implications for the Mechanism of    Enzyme Inhibition. Chemical Research in Toxicology, 23(11):1843-1850, 2010. PMCID: PMC2989800 Y. Jinsmaa, V.R. Florang, J.N. Rees, L.M Mexas, L.L. Eckert, E.M.G. Allen, D.G. Anderson, J.A. Doorn (2011). Dopamine-derived biological reactive intermediates and protein modifications: Implications for Parkinson’s disease. Chem Biol Interact, 192(1-2):118-21, 2011.  PMCID: PMC3109112 E.M.G. Allen, J.J. Mieyal.:  Protein-thiol oxidation and cell death: regulatory role of glutaredoxins. Antioxidant and Redox Signaling, Invited review, 17(12):1748-1763, 2012. PMID: 22530666 E.M.G. Allen, V.R. Florang, L.L. Eckert, Y. Jinsmaa, J.A. Doorn.:  Cellular localization of dieldrin and structure-activity relationship of dieldrin analogs in dopaminergic cells. Chemical Research in Toxicology, 26(7):1043-1054, 2013. PMCID: PMC4327868 D.A. Dawson, E.M. Allen, J.L. Allen, H.J. Baumann, H.M. Bensinger, N. Genco, D. Guinn, M.W. Hull, Z.J. Il’Giovine, C.M. Kaminski, J.R. Peyton, T.W. Schultz, G. Pöch.:  Time-dependence in mixture toxicity prediction. Toxicology, 326:153-163, 2014. PMCID: PMC4280022

Award(s)

  • Fellowship appointment on the Pharmacological Sciences Training Grant (NIH T32 GM067795), University of Iowa, 2007-2009
  • Graduate Student Poster Presentation Finalist, Clinical and Administrative Pharmacy Research Day, 2008
  • American Foundation for Pharmaceutical Education Predoctoral Fellowship, 2008-2011
  • Graduate Student Senate Travel Funds Award, University of Iowa, Iowa City, IA, 2008, 2009, and 2010
  • Executive Coun cil of Graduate and Professional Students (ECGPS) Travel Award, 2008 and 2009
  • Iowa Women of Innovation Student Finalist, 2009
  • Society of Toxicology Graduate Student Travel Award, 2010
  • Women in Toxicology Student Achievement Award, Honorable Mention, 2010
  • Winner: Outstanding Poster Presentation Award, Interdisciplinary Health Research Day, 2009 and 2010
  • Winner: Outstanding Poster Presentation Award, Interdisciplinary Health Research Day, Nov 2010
  • Elected Graduate Student Representative, Central States Society of Toxicology, 2010-2011
  • Winner: Outstanding Poster Presentation Award, Central States Society of Toxicology, 2007, 2009, and 2010
  • Received travel award to attend the Society for Neuroscience Annual Meeting, 2010
  • Awarded the College of Pharmacy Dissertation Fellowship, Spring 2011
  • Winner: 2010 Graduate Student Poster Session, Carver College of medicine, April 2010
  • Received travel award to attend the Society of Toxicology's 49thh Annual Meeting, March 2010
  • Third Place for Outstanding Written Submission, Jakobsen Conference, 2011
  • Winner: Outstanding Graduate Student Poster Prewsentation Award, Health Sciences Research Week, 2010 and 2011
  • College of Pharmacy Dissertation Fellowship, 2011