University of Kentucky College of Pharmacy Pharmaceutical Sciences Associate ProfessorAppointed: 1991 University of Kentucky Medical Research Centers Graduate Center for Nutritional Sciences Associate ProfessorAppointed: 2001 University of Kentucky Academic Centers Graduate Center for Toxicology Associate ProfessorAppointed: 1992 |  |
QualificationsPh.D., University of Illinois at Chicago, Pharmacology, 1981. B.S., University of Illinois, Biochemistry, 1976. Expertise and Research InterestsMy laboratory is interested in the regulation and activity of enzymes involved in cholesterol synthesis. We use biochemical and recombinant DNA techniques to express and characterize these enzymes and associated proteins in E. coli and in cultured hepatoma cells. We are particularly interested in how their activity is regulated at the protein level by regulatory proteins (kinases and accessory protein factors) as well as how sterols and botanical products can modulate their activity. Current studies are directed at understanding how garlic, tea, and policosanol (a by-product of sugar cane processing) inhibit cholesterol synthesis. General areas of interest include structure-function relationships of proteins, nutritional biochemistry, and molecular toxicology. Other ExpertiseBiochemistry of the cytochrome P450 system, with emphasis on the structure and function of NADPH-cytochrome P450 reductase, the electron donor protein for this system, including studies on nitrosamine activation by CYP2E1 and P450 activity in P450 reductase-null mice. Future ResearchSqualene monooxygenase requires an electron transfer partner as a source of electrons, and this redox partner has traditionally been thought to be NADPH-cytochrome P450 reductase (CPR). Recent studies with mice that lack hepatic expression of CPR indicate that a second electron donor may be present in liver cells, and that this protein may support up to 40% of the activity of squalene monooxygenase. Current studies are directed at identifying and characterizing this unknown electron transfer protein. Mice that lack hepatic CPR expression develop fatty livers, consisting predominantly of triglycerides. It is not clear why loss of CPR expression would cause this lipidosis, as a role for CPR in triglyceride synthesis and processing has not been discovered. CPR is involved in both the synthesis and degradation of cholesterol, and so the connection may lie in disruption of this lipid homeostasis. We have replicated this lipidosis in hepatoma cell culture using an siRNA approach, facilitating investigation into this interesting and unexpected observation. Industrial RelevanceAmes mutagenicity assays with CYP2E1 and P450 reductase expressed in Salmonella tester strains. KeywordsCOS Keywords:Biochemistry, Environmental Health, Environmental Medicine, Enzymology, Escherichia Coli, Molecular Biology, Mutagenesis, Pharmaceuticals, Pharmacology, Recombinant Dna, Spectroscopy, Toxicology.Additional Terms:Cholesterol Biosynthesis, Cytochrome P450, Expression in E. Coli, Garlic, Immunoblotting, Mutagen Testing, Policosanol, Recombinant DNA, Selenium Toxicity, Squalene Epoxidase, Tellurium Toxicity.MembershipsAmerican Society for Pharmacology and Experimental Therapeutics Honors and Awards2005, Peer Review Committee,
American Heart Association (AHA),
University of Kentucky
2002, Editorial Board,
Journal of Biochemical and Molecular Toxicology
Previous Positions1986-1991, Assistant Professor,
University of Michigan,
Medical School,
Biological Chemistry
Funding Received- American Heart Association (AHA):
Characterization of human squalene monooxygenase,
$214,500,
Jan 2001
to Dec 2003.
- Alternative and Complementary Medicine, R21 AT003488:
Inhibition of cholesterol synthesis by policosanol,
$250,000,
2007
to 2009.
- National Science Foundation (NSF):
Strategies to enhance mammalian P450 systems in bacteria, MCB-9808636,
$298,948,
1999
to 2002.
- American Heart Association (AHA):
Characterization of human squalene monooxgenase,
$69,806,
1999
to 2001.
- NIH-NIEHS 5 R01 ES-06420:
Ames mutagenicity testing with recombinant human P450s,
$341,957,
1992
to 1998.
Publications- Li, L, Porter, T D (2007) Hepatic cytochrome P450 reductase-null mice reveal a second microsomal reductase for squalene monooxygenase, Arch Biochem Biophys, 461, 76-84
- Singh, D K (2006) Policosanol inhibits cholesterol synthesis in hepatoma cells by activation of AMP-kinase, J Pharmacol Exp Ther, 318, 1020-1026
- Singh, D K, Porter, T D (2006) Inhibition of sterol 4-methyl oxidase is the principal mechanism by which garlic decreases cholesterol synthesis, J Nutr, 136, 759S-764S
- Mokashi V, Porter TD, Supernatant Protein Factor Requires Phosphorylation and Interaction With
Golgi to Stimulate Cholesterol Synthesis in Hepatoma
Cells., Archives of Biochemistry and Biophysics, 435(1), 175-81, Mar 2005
 - Mokashi V, Singh DK, Porter TD, Supernatant Protein Factor Stimulates HMG-CoA Reductase in Cell Culture
and in Vitro., Archives of Biochemistry and Biophysics, 433(2), 474-80, Jan 2005
 - Mokashi V, Singh DK, Porter TD (Apr 2004) Rat supernatant protein factor-like protein stimulates squalene
monooxygenase and is activated by protein kinase A., Biochemical and Biophysical Research Communications, 316 (3), 688-92
 - Porter TD, Jud Coon: 35 Years of P450 Research, a Synopsis of P450 History., Drug Metabolism and Disposition: the Biological Fate of Chemicals, 32(1), 1-6, Jan 2004
 - Mokashi V, Li L, Porter TD, Cytochrome b5 reductase and cytochrome b5 support the CYP2E1-mediated
activation of nitrosamines in a recombinant Ames test, Archives of Biochemistry and Biophysics, 412(1), 147-52, April 2003
 - Singh DK, Mokashi V, Elmore CL, Porter TD, Phosphorylation of supernatant protein factor enhances its ability to
stimulate microsomal squalene monooxygenase, Journal of Biological Chemistry, 278(8), 5646-51, February 2003
 - Elmore CL, Porter TD, Modification of the nucleotide cofactor-binding site of cytochrome P-450
reductase to enhance turnover with NADH in Vivo, Journal of Biological Chemistry, 277(50), 48960-4, December 2002
 - Gupta N, Porter TD, Inhibition of human squalene monooxygenase by selenium compounds, Journal of Biochemical and Molecular Toxicology, 16(1), 18-23, 2002
 - Porter TD, The roles of cytochrome b5 in cytochrome P450 reactions, Journal of Biochemical and Molecular Toxicology, 16(6), 311-6, 2002
 - Cooper MT, Porter TD, Cytochrome b(5) coexpression increases the CYP2E1-dependent mutagenicity
of dialkylnitrosamines in methyltransferase-deficient strains of
Salmonella typhimurium, Mutation Research, 484(1-2), 61-8, December 2001
 - Gupta N, Porter TD, Garlic and garlic-derived compounds inhibit human squalene monooxygenase, Journal of Nutrition, 131(6), 1662-7, June 2001
 - Laden BP, Porter TD, Inhibition of human squalene monooxygenase by tellurium compounds:
evidence of interaction with vicinal sulfhydryls, Journal of Lipid Research, 42(2), 235-40, February 2001
 - Laden BP, Porter TD, Resveratrol inhibits human squalene monooxygenase, Nutrition Research, 21, 747-753, 2001
- Laden BP, Tang Y, Porter TD, Cloning, heterologous expression, and enzymological characterization of human squalene monooxygenase, Archives of Biochemistry and Biophysics, 374(2), 381-8, February 2000
 - Porter TD, Correlation between codon usage, regional genomic nucleotide composition, and amino acid composition in the cytochrome P-450 gene superfamily, Biochimica Et Biophysica Acta, 1261(3), 394-400, April 1995
 - Porter TD, Coon MJ, Cytochrome P-450. Multiplicity of isoforms, substrates, and catalytic and regulatory mechanisms, Journal of Biological Chemistry, 266(21), 13469-72, July 1991
 - Porter TD, An unusual yet strongly conserved flavoprotein reductase in bacteria and mammals, Trends in Biochemical Sciences, 16(4), 154-8, April 1991
 - Porter TD, Kasper CB, Coding Nucleotide Sequence of Rat NADPH-cytochrome P-450 Oxidoreductase
CDNA and Identification of Flavin-binding Domains., Proceedings of the National Academy of Sciences of the United States of America., 82(4), 973-7, Feb 1985

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