Michael Franklin
Professor of Pharmacology and Toxicology
Title: Professor of Pharmacology and Toxicology
Email address: mfranklin@alanine.pharm.utah.edu
Education and Training:
- B.S., 1966, University of Birmingham
- Ph.D., 1969, University of London, Biochemistry
Research Interests:
Our research group centers its investigations around the enzymes and transporters responsible for the disposition of xenobiotic compounds. Xenobiotics include drugs, environmental contaminants and dietary anutrients. Many xenobiotics are capable of causing toxicity by interacting with cellular targets, either directly, or most often, after bioactivation by certain of the metabolizing enzymes. This can be prevented through further metabolism by an inactivating or protective set of metabolizing enzymes or by active excretion before the toxic interaction can occur. The laboratory is especially interested in factors which perturb the balance of activation/inactivation enzymes and more recently, has extended the studies to include changes in efflux transporters. The enzymes studied include cytochromes P450, epoxide hydrolase, quinone oxidoreductase, and UDP-glucuronosyltransferases, sulfotransferases and glutathione transferases. The transporters of interest are the ATP-binding cassette (ABC) family of transporters. Of greatest interest are changes in activities from alterations in transcription rate, and direct inhibition, and how such changes arise from the influence of hormones, administered drugs, and environmental and other chemicals.
The expertise of the research group is used in conjunction with information generated by neuroscientists in the Anticonvulsant Drug Development Program in the evaluation of antiepileptic agents. Knowledge of how promising new antiepileptic compounds affect metabolizing enzymes is critical for their future potential as therapeutic agents. In conjunction with investigators in the Division of Hematology, how variations in certain of these metabolizing enzymes and transporters contribute to the precipitation of Porphyria Cutanea Tarda is under scrutiny using both human and laboratory animal studies. How drug metabolizing and other enzymes and transporters are perturbed by selenazolidines, novel prodrug forms of L-selenocysteine that we have designed and synthesized, is being investigated during an evaluation of their efficacy as chemopreventive compounds.
Selected Publications:
Drug Metabolizing Enzyme Regulation:
- Lamb. J.G. and Franklin, M.R. (2000) Early events in the induction of rat hepatic UDP-glucuronosyl-transferase, glutathione S-transferase and microsomal epoxide hydrolase by 1,7-phenanthroline: comparison with oltipraz, tert-butyl-4-hydroxyanisole and tert-butylhydroquinone. Drug Metabolism and Disposition. 28 1018-1023.
- Franklin, M.R., Phillips, J.D. and Kushner, J.P. (2000) CYP3A inducing agents attenuate the accumulation and excretion of uroporphyrin in a rat model of porphyria cutanea tarda. Biochemical Pharmacology. 60 1325-1331.
- El-Sayed, W.M., Aboul-Fadl, T., Roberts, J.C., Lamb, J.G., and Franklin, M.R. (2006) Murine hepatoma (Hepa1c1c7) cells: A responsive in vitro system for chemoprotective enzyme induction by organoselenium compounds. Toxicology In Vitro. 21 157-164.
- Haley, S.L., Lamb, J.G., Franklin, M.R., Constance, J.E., and Dearing, D.M. (2007) Xenobiotic metabolism of plant secondary compounds in juniper (Juniperus monosperma) by specialist and generalist woodrat herbivores, genus Neotoma. Comparative Biochemistry and Physiology; Toxicology & Pharmacology. 146 552-560.
Drug Metabolizing Enzyme Inhibition:
- Chatterjee, P., and Franklin, M.R. (2003) Human cytochrome P450 inhibition and metabolic-intermediate complex formation by goldenseal extract and its methylenedioxyphenyl components. Drug Metabolism and Disposition 31 1391-1397.
- Franklin, M.R. and Constance, J.E. (2007) Comparative 1-substituted imidazole inhibition of cytochrome P450 isozyme-selective activities in human and mouse hepatic microsomes. Drug Metabolism Reviews 39 309-322.
Porphyria Cutanea Tarda Development:
- Franklin, M.R., Phillips, J.D. and Kushner, J.P. (2002) Uroporphyria in the uroporphyrinogen decarboxylase-deficient mouse: Interplay with siderosis and PCB exposure. Hepatology 36 805-811.
- Phillips, J.D., Bergonia, H.A., Reilly, C.A., Franklin, M.R., and Kushner, J.P. (2007) A porphomethene inhibitor of uroporphyrinogen decarboxylase causes porphyria cutanea tarda. Proceedings of the National Academy of Sciences. USA 104 5079-5084.
Selenium Compound Efficacy:
- El-Sayed, W.M., Hussin, W.A., and Franklin, M.R. (2007) The antimutagenicity of 2-substituted selenazolidine-4-(R)-carboxylic acids. Mutation Research. 627 136-145.
- Franklin, M.R., Moos, P.J., El-Sayed, W.M., Aboul-Fadl, T., and Roberts J.C. (2007) Pre- and post-initiation chemoprevention activity of 2-alkyl/aryl selenazolidine-4(R)-carboxylic acids against tobacco-derived nitrosamine (NNK)-induced lung tumors in the A/J mouse. Chemico-Biological Interactions 168 211-220.
