Albert Girotti
Research and Selected Publications

Research Interests

Interest in the cytopathological effects of oxidative stress has grown dramatically in recent years. Photodynamic action, a process involving molecular oxygen and a light-activated sensitizing agent (either applied or naturally occurring), is one of many physical and/or chemical processes that can generate cytotoxic oxidative stress. Two general reaction pathways are possible in photodynamic action: (a) Type I in which a sensitizer in the triplet excited state reacts directly with a substrate other than O2, resulting in formation of free radicals, and (b) Type II, in which the excited sensitizer transfers energy to O2 to generate highly reactive singlet oxygen (1O2). Cell membrane lipids are important targets of photodynamic attack, leading to formation of free radical-derived or 1O2-derived lipid hydroperoxide (LOOH) intermediates. LOOHs may (i) undergo Fe(II)-mediated reduction to free radical species, which propagate further peroxidative damage (one-electron pathway), or (ii) be detoxified to alcohols by glutathione-dependent selenoperoxidases (two-electron pathway).

Photodynamic stress can have pathological consequences, as for example, in premature skin aging or carcinogenesis. However, the discovery that light-driven reactions can be exploited for therapeutic purposes, as in antitumor photodynamic therapy (PDT), has also captured great interest. An important example is PDT with 5-aminolevulinic acid (ALA). In ALA-PDT, administered ALA is metabolized to protoporphyrin IX, which, upon photoexcitation, can generate 1O2 which damages and inactivates tumor cells. Through longstanding support of the NIH (National Cancer Institute), our work focuses on five important issues related to PDT antitumor action: (i) primary photochemical mechanisms at the cellular level; (ii) cell membrane damage, e.g. lipid peroxidation and its role in cell killing; (iii) prooxidant and antioxidant effects of iron and nitric oxid on cell killing; (iv) cytoprotective/repair processes which contribute to cell resistance; (v) dissemination of peroxidative injury and stress signaling via LOOH intermembrane transfer.

Training Opportunities:Postdoctoral positions are available for studies dealing with (i) selenoperoxidase-mediated LOOH detoxification; (ii) nitric oxide inhibition of LOOH-induced chain peroxidative damage; (iii) LOOH translocation.

"Lipid hydroperoxide generation, turnover, and effector activity in biological systems", (Review) A.W. Girotti, J. Lipid Res., 39, 1529-1542 (1998).

"Lipid hydroperoxide analysis by high performance liquid chromatography with mercury cathode electrochemical detection", W. Korytowski, P.G. Geiger, and A.W. Girotti, Methods Enzymol., 300, 23-33 (1999).

"Singlet oxygen adducts of cholesterol: Photogeneration and reductive turnover in membrane systems", W. Korytowski and A.W. Girotti, Photochem. Photobiol., 70, 484-489 (1999).

"Radiolabeled cholesterol as a reporter for assessing one-electron turnover of lipid hydroperoxides", W. Korytowski, M. Wrona, and A.W. Girotti, Anal. Biochem., 270, 123-132 (1999).

"Cholesterol as a singlet oxygen detector in biological systems", A.W. Girotti and W. Korytowski, Methods Enzymol., 319, 85-100 (2000).

"Nitric oxide inhibition of free radical-mediated cholesterol peroxidation in liposomal membranes", W. Korytowski, M. Zareba, and A.W. Girotti, Biochemistry 39, 6918-6928 (2000).

"Dissemination of peroxidative stress via intermembrane transfer of lipid hydroperoxides: model studies with cholesterol hydroperoxides", A. Villa, W. Korytowski, and A.W. Girotti, Arch. Biochem. Biophys., 380, 208-218 (2000).

"Inhibition of free radical-mediated cholesterol peroxidation by diazeneiumdiolate-derived nitric oxide: effect of release rate on mechanism of action in a membrane system", W. Korytowski, M. Zareba, and A.W. Girotti, Chem. Res. Toxicol. 13, 1265-1274 (2000).

"Photosensitized oxidation of membrane lipids: reaction pathways, cytotoxic effects, and cytoprotective mechanisms.", A.W. Girotti, J. Photochem. Photobiol. B. 63(1-3), 103-113 (2001).

"Hyperresistance to cholesterol hydroperoxide-induced peroxidative injury and apoptotic death in a tumor cell line that overexpresses glutathione peroxidase isotype-4.", R. Hurst, W. Korytowski, T. Kriska, R.S. Esworthy, F.F. Chu, A.W. Girotti Free Radic. Biol. Med. 31(9), 1051-1065 (2001).

"Spontaneous intermembrane transfer of various cholesterol-derived hydroperoxide species: kinetic studies with model membranes and cells.", A. Vila, W. Korytowski, and A.W. Girotti, Biochemistry 40, 14715-14726 (2001).

"Hyperresistance to photosensitized lipid peroxidation and apoptotic killing in 5-aminolevulinate-treated tumor cells overexpressing mitochondrial GPX4.", T. Kriska, W. Korytowski, and A.W. Girotti, Free Radic. Biol. Med. 33, 1389-1402 (2002).

"Spontaneous transfer of phospholipid and cholesterol hydroperoxides between cell membranes and low-density lipoprotein: assessment of reaction kinetics and prooxidant effects.", A. Vila, W. Korytowski, and A.W. Girotti, Biochemistry 41, 13705-13716 (2002).

"Nitric oxide inhibition of free radical-mediated lipid peroxidation in photodynamically treated membranes and cells.", M. Niziolek, W. Korytowski, and A.W. Girotti, Free Radic. Biol. Med. 34, 997-1005 (2003).

"Chain-breaking antioxidant and cytoprotective action of nitric oxide on photodynamically stressed tumor cells.", M. Niziolek, W. Korytowski, and A.W. Girotti, Photochem.Photobiol. 78, 262-270 (2003).

Last modified on: Monday, 10-Nov-2003 16:32:56 CST