Todd D. Porter, Ph.D.
Associate Professor

Division of Pharmaceutical Sciences, College of Pharmacy
Gill Heart Institute Markey Cancer Center

Graduate Center for Nutritional Sciences

Director of Graduate Studies for Graduate Center for Toxicology

Phone:
office: (859) 257-1137
lab: (859) 257-2566

Fax:
(859) 257-7564

e-mail:
tporter@uky.edu

World Wide Web:
http://www.uky.edu/
Pharmacy/ps/porter/

The committed pathway for cholesterol synthesis, from squalene to cholesterol, is relatively poorly characterized, despite its importance to physiology and medicine.  Several enzymes in this pathway, including squalene monooxygenase and sterol 4α methyl oxidase, are inhibited by substances found in food and vitamin supplements.  My laboratory uses recombinant DNA techniques, enzymology, and structural biology and proteomics approaches to characterize these enzymes and the mechanism of inhibition by these substances. 

Squalene monooxygenase, the second and rate-limiting step in this pathway, is inhibited by selenium and tellurium metabolites, and by chemicals found in garlic and green tea extracts.  Tellurium, an element used in semiconductor manufacturing, causes a peripheral neuropathy and demyelination in young rats when fed in excess; selenium, a common nutritional supplement and a required trace element, also causes a peripheral neuropathy and is toxic at levels only five-fold greater than that found in supplements.  Garlic and green tea also inhibit squalene monooxygenase and cholesterol synthesis; we have been characterizing the mechanism of this inhibition using cell culture techniques, mass spectrometry, cDNA cloning, heterologous expression and purification of the relevant enzymes.

The overall goal of my research is to identify the factors that modulate the downstream pathway for cholesterol synthesis, both at the regulatory level and through toxic and potentially therapeutic interactions with these cholesterolgenic enzymes.  

Research Publications

Mokashi, V., Li, L., and Porter, T.D.  (2003) Cytochrome b₅ reductase and cytochrome b₅ support the CYP2E1-mediated activation of nitrosamines in a recombinant Ames test.  Arch. Biochem. Biophys. 412, 147-152 [abstract].

Singh, D.K., Mokashi, V., Elmore, C.L., and Porter, T.D.  (2003) Phosphorylation of supernatant protein factor enhances its ability to activate microsomal squalene monooxygenase.  J. Biol. Chem. 278, 5646-5651 [abstract]

Porter, T.D.  (2003) Supernatant protein factor and tocopherol-associated protein: An unexpected link between cholesterol synthesis and vitamin E  (Invited review).  J. Nutr. Biochem. 14, 3-6. [abstract]

Porter, T.D.  (2002) The Roles of Cytochrome b₅ in Cytochrome P450 Reactions (Invited review).  J. Biochem. Mol. Toxicol. 16, 311-316.  [abstract]

Elmore, C.L., and Porter, T.D.  (2002) Modification of the nucleotide-cofactor binding site of cytochrome P450 reductase to enhance turnover with NADH in vivo.  J. Biol. Chem. 277, 48960-48964. [abstract]

Gupta, N., and Porter, T.D.  (2002) Inhibition of human squalene monooxygenase by selenium compounds.  J. Biochem. Mol. Toxicol. 16, 18-23.  [abstract]

Cooper, M.T. and Porter, T.D.  (2001) Cytochrome b₅ coexpression increases the CYP2E1-dependent mutagenicity of dialkylnitrosamines in methyltransferase-deficient strains of Salmonella typhimurium.  Mutation Res. 484, 61-68.  [abstract]

Gupta, N., and Porter, T.D.  (2001) Garlic and garlic-derived compounds inhibit human squalene monooxygenase.  J. Nutrition 131, 1662-1667.  [abstract]

Laden, B.P., and Porter, T.D.  (2001) Resveratrol inhibits human squalene monooxygenase.  Nutrition Res. 21, 747-753.  

Laden, B.P., and Porter, T.D.  (2001) Inhibition of human squalene monooxygenase by tellurium compounds: Evidence of interaction with vicinal sulfhydryls.  J. Lipid Res. 42, 235-240.  [abstract]