College of Pharmacy

Department: Department of Pharmaceutical Sciences
Location: OSU

College of Pharmacy
Oregon State University
203 Pharmacy Building
Corvallis, OR 97331-3507
Phone: 541-737-9534
fred.stevens@oregonstate.edu
Affiliations: Linus Pauling Institute
Mass Spectrometry Facility Web site

Table of Contents:

• Education
• Position
• Research Area
• Research
• Selected Publications

Education

Institute of Plant Biochemistry, Halle, Germany; Postdoctoral Research Associate, 2000–2002.
Free University of Amsterdam; Postdoctoral Research Associate, 1999–2000.
Oregon State University; Postdoctoral Research Associate, 1995–1999.
University of Groningen, The Netherlands; Ph.D. 1995, Pharmacy license 1990; M.Sc. 1988.

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Position

Associate Professor of Medicinal Chemistry
Principal Investigator, Linus Pauling Institute

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Research Area

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Research

Our research group has interests in the areas of bio-organic chemistry, natural products chemistry and toxicology. Mass spectrometry is an important technique in our laboratory for studying small organic molecules in complex biological matrices such as blood plasma, cell lysates, tissue homogenates and plant extracts.

Bioconjugation of oxidized lipids
This research project aims to determine how vitamin C interacts with lipid peroxidation products and how vitamin C prevents cellular damage to proteins caused by oxidized lipids. We are interested in these interactions because lipid peroxidation contributes to the development and progression of chronic inflammatory and age-related diseases, such as atherosclerosis. Our laboratory has identified vitamin C (ascorbic acid) as a biological nucleophile able to form Michael adducts with lipid-derived 2-alkenals. This reaction may be of interest as a detoxification pathway for 2-alkenals. The tools that we use for our research include liquid chromatography coupled to mass spectrometry for analysis of lipid conjugates in complex biological matrices, synthesis of (labeled) lipids and their conjugates, cell culture for investigating the biological properties of oxidized lipids and their conjugates and animal models for studying the in vivo formation, metabolism and excretion of oxidized lipids.

In collaboration with Professor Claudia Maier of OSU’s Chemistry Department, we are developing quantitative methods based on isotope dilution mass spectrometry to examine the nature and the extent of protein modifications by lipid peroxidation products in cultured cells and animal models of oxidative stress. One of our main findings is that vitamin C, at physiologically relevant concentrations, prevents adduct formation of oxidized lipids with cellular proteins. The significance of this finding is that vitamin C may help maintain proper function of metabolizing and transporter proteins, thus mitigating the deleterious effects of oxidized lipids.

Structure elucidation and biological activity of natural products
Our laboratory has also interests in the field of natural products isolation and structure elucidation. We have explored the chemistry and biology of prenylated flavonoids of the hop plant (Humulus lupulus) since 1995. We were the first to report that the principal prenylated flavonoid in hops, xanthohumol, exerts anti-inflammatory and cancer chemopreventive activities. Our current aim is to determine whether and how xanthohumol improves dysfunctional lipid and glucose metabolism in humans diagnosed with metabolic syndrome.
Another research project in our laboratory is focused on the chemistry and biology of natural products from the oilseed crop, meadowfoam (Limnanthes alba). The Oregon oilseed industry produces a high-quality oil from meadowfoam seeds that is used in personal care products. Considered useless in the past, the seed waste may prove of value as a natural herbicide in organic farming. We have developed a fermentation procedure for enhancing the herbicidal activity of the seed waste by converting inactive seedmeal glucosinolates into degradation products with herbicidal activity.

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Selected Publications

Kirkwood, J.S., Lebold, K.M., Miranda, C.L., Wright, C.L., Miller, G.W., Tanguay, R.L., Barton, C.L., Traber, M.G., Stevens, J.F. Vitamin C deficiency activates the purine nucleotide cycle in zebrafish. J. Biol. Chem. 2011 Dec 13. [Epub ahead of print]

Zasada, I.A., Weiland, J.E., Reed, R.L., and Stevens, J.F. Activity of meadowfoam (Limnanthes alba) seed meal glucolimnanthin degradation products against soilborne pathogens. J. Agric. Food Chem. 2011 Dec 16. [Epub ahead of print].

Legette, L., Ma, L., Reed, R.L., Miranda, C.L., Christensen, J.M., Proteau, R.R. and Stevens, J.F. Pharmacokinetics of xanthohumol and metabolites in rats after oral and intravenous administration. Molecular Nutrition and Food Research 2011 Dec 7. [Epub ahead of print]

Wu_, J., Stevens, J.F. and Maier, C.S. (2011). Mass spectrometry-based quantification of myocardial protein adducts with acrolein in an in vivo model of oxidative stress. Molecular Nutrition and Food Research, 55, 1401-1410.

Kuiper, H.C., Bruno, R.S., Traber, M.G., and Stevens, J.F. (2011). Vitamin C supplementation lowers urinary levels of 4-hydroperoxy-2-nonenal metabolites in humans. Free Radical Biology and Medicine 50, 848-853.

Traber, M.G. and Stevens, J.F. (2011). Vitamins C and E: Beneficial effects from a mechanistic perspective. Free Radical Biology and Medicine 51, 1000-1013.

Kuiper, H.C. and Stevens, J.F. (2011). LC-MS/MS Quantification of Mercapturic Acid Conjugates of Lipid Peroxidation Products as Markers of Oxidative Stress. Current Protocols in Toxicology 45: 17.14.1-17.14.16.

Kesinger, N.G., Langsdorf, B.L., Yokochi, A.F., Miranda, C.L. and Stevens, J.F. (2010). Formation of a vitamin C conjugate of acrolein and its paraoxonase-mediated conversion into 5,6,7,8-tetrahydroxy-4-oxooctanal. Chemical Research in Toxicology 23, 836-844.

Peluso, M.R., Miranda, C.L., Hobbs, D.J., Proteau, R.R. and Stevens, J.F. (2010). Xanthohumol and related prenylated flavonoids inhibit inflammatory cytokine production in LPS-activated THP-1 monocytes: Structure-activity relationships and in silico binding to myeloid differentiation protein-2 (MD-2). Planta Medica 76, 1536-1543.

Stevens, J.F. and Reed, R.L. (2011). Chapter 10: Glucosinolate degradation products in fermented meadowfoam seed meal and their herbicidal activities. In: Recent Advances in Phytochemistry, Vol. 41 (Gang, D.R., Ed.), pp. 141-157. Springer. ISBN: 978-1-4419-6961-3.

Chavez, J., Chung, W.G., Miranda, C.L., Singhal, M., Stevens, J.F. and Maier, C.S. (2010). Site-specific protein adducts of 4-hydroxy-2(E)-nonenal in human THP-1 monocytic cells: Protein carbonylation is diminished by ascorbic acid. Chemical Research in Toxicology 23, 37-47.

Kuiper HC, Langsdorf BL, Miranda CL, Joss J, Jubert C, Mata JE, Stevens JF. Quantitation of mercapturic acid conjugates of 4-hydroxy-2-nonenal and 4-oxo-2-nonenal metabolites in a smoking cessation study. Free Radical Biology and Medicine 2010; 48: 65-72.

Kesinger NG, Stevens JF. Covalent interaction of ascorbic acid with natural products. Phytochemistry 2009; 70: 1930-1939.

Miranda CL, Reed RL, Kuiper HC, Alber S, Stevens JF. Ascorbic acid promotes detoxification and elimination of 4-hydroxy-2(E)-nonenal in human monocytic THP-1 cells. Chemical Research in Toxicology 2009; 22: 863-874.

Stevens JF, Reed RL, Alber S, Pritchett L, Machado S. Herbicidal activity of glucosinolate degradation products in fermented meadowfoam (Limnanthes alba) seed meal. Journal of Agricultural and Food Chemistry 2009; 57: 1821-1826.

Kuiper HC, Miranda CL, Sowell JD, Stevens JF. Mercapturic acid conjugates of 4-hydroxy-2-nonenal and 4-oxo-2-nonenal metabolites are in vivo markers of oxidative stress. Journal of Biological Chemistry 2008; 283: 17131-17138.

Stevens JF, Reed RL, Morré JS. Characterization of Phytoecdysteroid Glycosides in Meadowfoam (Limnanthes alba) Seed Meal by Positive and Negative Ion LC-MS/MS. Journal of Agricultural and Food Chemistry 2008; 56: 3945-3952.

Stevens JF, Maier CS. Acrolein: Sources, metabolism, and biomolecular interactions relevant to human health and disease. Molecular Nutrition and Food Research 2008; 52: 7-25.

Nagel J, Culley LK, Liu E, Lu Y, Matthews P, Stevens JF, Page JE. EST analysis of hop (Humulus lupulus L.) glandular trichomes identifies an O-methyltransferase that catalyzes the biosynthesis of xanthohumol. Plant Cell 2008; 20: 186-200.

Han B, Stevens JF, Maier CS. Design, synthesis, and application of a hydrazide-functionalized isotope-coded affinity tag for the quantification of oxylipid-protein conjugates. Anal Chem. 2007; 79(9): 3342-54.

Colgate, E.C., Miranda, C.L. Stevens, J.F., Bray, T.M. and Ho, E. Xanthohumol, a prenylflavonoid derived from hops induces apoptosis and inhibits NF-κB activation in prostate epithelial cells. Cancer Letters 2007, 246: 201-209.

Marley K, Mooney DT, Clark-Scannell G, Tong TT, Watson J, Hagen TM, Stevens, JF, Maier CS. Mass tagging approach for mitochondrial thiol proteins. Journal of Proteome Research. 2005;4:1403-1412.

Stevens JF, Page JE. Molecules of Interest. Xanthohumol and related prenylflavonoids in hops and beer: to your good health! Phytochemistry. 2004; 65:1317-1330 (invited review; fourth most cited Phytochemistry article in the period 2004-2009).

Stevens JF, Miranda CL, Frei B, Buhler DR. Inhibition of peroxynitrite-mediated LDL oxidation by prenylated flavonoids: The a,ß-unsaturated keto functionality of 2'-hydroxychalcones as a novel antioxidant pharmacophore. Chemical Research in Toxicology. 2003;16:1277-1286.

Wollenweber E, Stevens JF, Klimo K, Knauft J, Frank N, Gerhäuser C. Cancer chemopreventive in vitro activities of isoflavones isolated from Iris germanica. Planta Medica. 2003;69:15-20.

Stevens JF, Miranda CL, Wolthers KR, Schimerlik M, Deinzer ML, Buhler DR. Identification and in vitro biological activities of hop proanthocyanidins: Inhibition of nNOS activity and scavenging of reactive nitrogen species. Journal of Agriculture and Food Chemistry. 2002;50:3435-3443.

Rodriguez RJ, Miranda CL, Stevens JF, Deinzer ML, Buhler DR. Influence of prenylated and non-prenylated flavonoids on liver microsomal lipid peroxidation and oxidative injury in rat hepatocytes. Food and Chemical Toxicology. 2001;39:437-445.

Yilmazer M, Stevens JF, Buhler DR. In vitro glucuronidation of xanthohumol, a flavonoid in hop and beer, by rat and human liver microsomes. FEBS Letters. 2001;491:252-256.

Yilmazer M, Stevens JF, Deinzer ML, Buhler DR. In vitro biotransformation of xanthohumol, a flavonoid from hops (Humulus lupulus), by rat liver microsomes. Drug Metabolism and Disposition. 2001;29:223-231.

Miranda CL, Aponso GLM, Stevens JF, Deinzer ML, Buhler DR. Prenylated chalcones and flavanones as inducers of quinone reductase in mouse Hepa 1c1c7 cells. Cancer Letters. 2000;149:21-29.

Henderson MC, Miranda CL, Stevens JF, Deinzer ML, Buhler DR. In vitro inhibition of human P450 enzymes by prenylated flavonoids from hops, Humulus lupulus. Xenobiotica. 2000;30:235-251.

Stevens JF, Taylor AW, Nickerson GB, Ivancic M, Henning J, Haunold ML, Deinzer ML. Prenylflavonoid variation in Humulus lupulus: distribution and taxonomic significance of xanthogalenol and 4'-O-methylxanthohumol. Phytochemistry. 2000;53:759-775.

Miranda CL, Stevens JF, Ivanov V, McCall M, Frei B, Deinzer ML, Buhler DR. Antioxidant and prooxidant actions of prenylated and nonprenylated chalcones and flavanones in vitro. Journal of Agriculture and Food Chemistry. 2000;48:3876-3884.

Miranda CL, Yang Y-H, Henderson MC, Stevens JF, Santana-Rios G, Deinzer ML, Buhler DR. Prenylflavonoids from hops inhibit the metabolic activation of the carcinogenic heterocylcic amine, 2-amino-3-methylimidazo[4,5-f]quinoline, mediated by cDNA-expressed human CYP1A2. Drug Metabolism and Disposition. 2000;28:1297-1302.

Milligan SR, Kalita JC, Pocock V, Van De Kauter V, Stevens JF, Deinzer ML, Ron H, De Keukeleire D. The endocrine activities of 8-prenylnaringenin and related hop (Humulus lupulus) flavonoids. Journal of Clinical Endocrinology & Metabolism. 2000;85:4912-4915.

Stevens JF, Taylor AW, Deinzer ML. Quantitative analysis of xanthohumol and related prenylflavonoids in hops and beer by liquid chromatography-tandem mass spectrometry. Journal of Chromatography A. 1999;832:97-107.

Miranda CL, Stevens JF, Helmrich A, Henderson MC, Rodriguez RJ, Yang Y-H, Deinzer ML, Barnes DW, Buhler DR. Antiproliferative and cytotoxic effects of prenylated flavonoids from hops (Humulus lupulus) in human cancer cell lines. Food and Chemical Toxicology. 1999;37:271-285.

Stevens JF, Ivancic M, Deinzer ML, Wollenweber E. A novel 2-hydroxyflavanone from Collinsonia canadensis. Journal of Natural Products. 1999;62:392-394.

Stevens JF, Ivancic M, Hsu VL, Deinzer ML. Prenylflavonoids from Humulus lupulus. Phytochemistry. 1997;44:1575-1585.

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