Office: MEYR 549E
Cancer Chemoprevention. Many compounds of diverse structure are known to have biochemical properties that imbue them with cancer chemopreventive potential. These compounds tend to elevate the cell’s ability to blunt assault by carcinogenic agents of exogenous and endogenous origin. A large body of work over the last 20 years has indicated that a major transcriptional pathway for activation of the phase 2 xenobiotic metabolizing enzymes that manifest this protection is mediated by transcription factor Nrf2. The availability of Nrf2 to activate transcription is controlled by a chaperone protein – Keap1 – a cysteine-rich protein that has come under increasing scrutiny of late. Keap1 is believed to be a target for compounds with cancer chemopreventive properties. It is generally believed that the covalent modification of Keap1 by these compounds is part of the process involved in facilitating the ability of Nrf2 to activate the transcription of genes that augment cellular defense. It is generally not known for any given chemopreventive, whether it is the chemopreventive agent, or some derivative thereof that is involved in covalent modification of Keap1.
Dithiolethiones are a class of cancer chemopreventives, two of which, oltipraz and anetholedithione, have been investigated in chemoprevention clinical trials. The chemical mechanism by which these compounds activate the Nrf2 pathway is unknown. Work by the PI’s group has recently shown that the major reductive metabolite of oltipraz activates the transcription of phase 2 enzymes with a potency comparable to oltipraz itself. It has recently further been demonstrated that H2O2, which is generated from the major metabolite in a GSH-stimulated redox cycle, is an important messenger for chemopreventive phase 2 enzyme induction by the metabolite and oltipraz itself. A downstream metabolite(s) has also been shown to induce phase 2 enzymes with comparable potency, but is not a redox active species. So, it may induce in a chemically distinctly different way, in so far as it acts through the Keap1/Nrf2 pathway.
The involvement of H2O2 as a messenger for dithiolethiones generally is not certain, though preliminary experiments suggest it is in the case of anetholedithione. The target Cys on Keap1 of H2O2 and celluar oxidants in general is not known. It is also unclear whether oltipraz may interact separately with Keap1, independent of its metabolites. The contribution of each of the metabolites of oltipraz to the global gene expression induced by oltipraz is also uncertain. The group is currently working toward clarifying the mechanistic aspects by which the cancer chemopreventive effects of these compounds are manifest.
- Blans, P., Fishbein*, J.C. Determinants of Selectivity in Alkylation of Nucleosides and DNA by Secondary Diazonium Ions: Evidence for, and Consequences of, a Preassociation Mechanism. Chem. Res. Tox.,2004 17 1531-9.
- Velayutham, M., Villamena, F.A., Fishbein*, J.C. and Zweier*, J.L., Cancer Chemopreventive Oltipraz Generates Superoxide Anion Radical, Arch. Bioch. Biophys., 2005 435 83-88.
- Velayutham, M., Villamena, F.A.Navamal, M., Fishbein*, J.C. and Zweier*, J.L. Glutathione Mediated Formation of Oxygen Free Radicals by the Major Metabolite of Oltipraz, Chem Res. Tox. 2005 18 970-975.
- Perrino*, F. W.; Harvey, S.; Blans, P.; Gelhaus, S.; LaCourse, W. R.; Fishbein*, J. C., Polymerization past the N2-isopropylguanine and the N6-isopropyladenine DNA lesions with the bypass DNA polymerases η and ι and the replicative DNA polymerase α, Chem Res. Tox. 2005, 18 1451-61.
- Lu, X., Heilman, J.M., Blans, P., Fishbein*, J.C. The Structure of DNA Dictates Purine Atom Site Selectivity in Alkylation By Primary Diazonium Ions, Chem Res. Tox. 2005 18 1462-70.
- Zink, C.N., Kim, H.-J., Fishbein*, J.C., Synthesis and Aqueous Chemistry of α-Acetoxy-N-nitrosomorpholine: Reactive Intermediates and Products J. Org. Chem. 2006, 71 202-9.
- Upton, D.C., Wang, X., Blans, P., Perrino, F.W., Fishbein, J.C.*, Akman, S.A.*, Mutagenesis by exocyclic alkylamino purine adducts in Escherichia coli, Mutat. Res. 2006, in press.
- Upton, D.C., Wang, X., Blans, P., Perrino, F.W., Fishbein, J.C.*, Akman, S.A.* Replication of N 2-ethyldeoxyguanosine DNA adducts in human 293 cells, Chem. Res. Tox., 2006, in press.
- CHEM 470: Toxicological Chemistry – This course covers chemical, biochemical and to some extent biological aspects of toxicology, the science of poisons. Emphasis changes during the semester from the bigger picture of various organs that are frequent targets of toxins and why this is so, to very molecular aspects of classes of toxins. The text is heavily supplemented by readings in the primary literature, with which students become very familiar as the semester progress. In spite of what the catalogue says, the only pre-requisite is completion of CHEM 352, it is suggested with a B or better.
- CHEM 351: Organic Chemistry I
- CHEM 352: Organic Chemistry II
- CHEM 352L: Organic Chemistry Laboratory II
- CHEM 451: Mechanisms of Organic Reactions