Terrence J Monks, PhD
Head and Professor
Department:
Pharmacology and Toxicology
(520) 626-9906
Secondary Phone:
(520) 626-2823
Fax:
(520) 626-2466
E-mail:
Location:
Pharmacy 341F
Bio / Research:
Molecular Basis of ROS-induced Cell Death: Mechanisms of cell death are usually classified into two pathways, apoptosis and necrosis. The American Society of Toxicologic Pathologists uses the term oncosis, with its root meaning of “swelling,” as the alternate descriptor of cell death occurring by non-apoptotic pathways. Necrosis more accurately describes the consequences of oncotic cell death, usually the death of a large number of cells resulting in moderate to severe tissue injury.
Oncotic cell death typically occurs in response to toxic injury induced by chemical exposure and reactive oxygen species (ROS). ROS contribute to a variety of human diseases and toxicities associated with chemical exposure. Understanding factors that regulate the cellular stress response to ROS and the molecular mechanisms by which they interact with cellular constituents, and the consequences of such interactions, are important fundamental goals of biomedical research. Responses to stress that usually result in oncotic cell death (and tissue necrosis) may be manipulated, at the genetic and pharmacological level, to produce a potentially favorable (survivable) tissue response. Basic knowledge of the mechanisms by which ROS induce cell death may yield strategies for clinical interventions in pathologies in which ROS play a prominent role. The laboratory is investigating the cellular and molecular mechanisms by which ROS induce both apoptotic and oncotic/necrotic cell death.
Neurotoxicology of Ecstasy: 3,4-(±)-Methylenedioxymethamphetamine (MDMA; Ecstasy, XTC, E) is a Schedule 1 synthetic, psychoactive drug possessing stimulant and hallucinogenic properties. The subjective effects of MDMA have contributed to its popularity as a “party drug” amongst adolescents and young adults who frequent late night “raves” or “techo-parties.” Several adverse effects are associated with the use of MDMA, the most worrisome of which is long-term serotonergic toxicity. MDMA use and abuse therefore has the potential to give rise to a major public health problem. The neurotoxic effects of MDMA are dependent on the route and frequency of drug administration. Direct injection of either MDMA into the brain fails to reproduce the neurotoxicity following peripheral administration, indicating that the parent amphetamines are unlikely to be solely responsible for the neurotoxic effects. The alarming increase in the recreational use of MDMA and the multitude of adverse effects resulting from its misuse therefore necessitates a complete understanding of the neuropharmacology and neurotoxicology of this unusual amphetamine derivative.
Proteomics in Toxicology (in collaboration with Dr. Lau):
Identifying protein targets of environmental chemicals that produce acute tissue toxicities and cancer has been a nearly impossible task. Recent developments in mass spectrometry (MS) ionization methods and instrumentation now make possible the rapid, high-throughput analysis of proteins. MS has become the method of choice for sequencing peptides and proteins with limited amounts of available sample. These analytical capabilities have driven the growth of proteomics, the study of the protein complement of the genome. The long-term goal of this project is to
(i) develop mass spectrometric methods to identify protein targets of environmental chemicals,
(ii) ascertain those features that predispose certain proteins, or motifs within proteins (“electrophile binding motifs”, or EBMs) to chemical adduction, and
(iii) determine the potential biological/toxicological consequences of adduction to rationally selected “electrophilins.”
A critical area in functional proteomics is the detection of chemical-induced post-translational modifications (PTMs) that may either indirectly alter cell signaling pathways or directly alter the structure and function of the modified protein. Such chemical-induced PTMs are usually of low abundance and thus not detectable by standard proteomic protocols.
Education:BSc, Hatfield Polytechnic, Hatfield, U.K., 1975, Biochemistry
PhD, St. Mary's Hospital Medical School, University of London, London, U.K., 1978, Biochemical Pharmacology
Post-doctoral Training, National Institutes of Health, Bethesda, Maryland, 1979-1984, Chemical Toxicology
As Principal Investigator
Oncotic/necrotic cell death
Jeong, J.K., Stevens, J.L., Lau, S.S., and Monks, T.J. Quinone-thioether-mediated DNA damage, growth arrest, and gadd153 expression in renal proximal tubular epithelial cells. Molec. Pharmacol., 50:592-598, 1996.
Jeong, J.K., Huang, Q., Lau, S.S., and Monks, T.J. The response of renal epithelial cells to physiological-and chemical-induced growth arrest. J. Biol.Chem., 272:7511-7518, 1997.
Jeong, J.K., Dybing, E., S¿derlund, E., Brunborg, G., Holme, J.A., Lau, S.S., and Monks, T.J. DNA damage, gadd153 expression, and cytotoxicity in plateau phase renal proximal tubular epithelial cells treated with a quinol-thioether. Arch. Biochem. Biophys., 341:300-308, 1997.
Huang, Q., Lau, S.S., and Monks, T.J. Induction of gadd153 mRNA by nutrient deprivation is overcome by glutamine. Biochem. J., 341:225-231, 1999.
Jeong, J.K., Wogan, G.N., Lau, S.S., and Monks, T.J. Quinol-glutathione conjugate-induced mutation spectra in the supf gene replicated in human AD293 cells and bacterial MBL50 cells. Cancer Res., 59:3641-3645, 1999.
Tikoo, K., Lau, S.S., and Monks, T.J. Histone H3 phosphorylation is coupled to poly (ADP-ribosylation) and reactive oxygen species-induced cell death in renal proximal tubular epithelial cells. Molec. Pharmacol. 60:394-402, 2001.
Ramachandiran, S., Huang, Q., Dong, J., Lau, S.S., and Monks, T.J. Mitogen activated protein kinases contribute to reactive oxygen species-induced cell death in renal proximal tubule epithelial cells. Chem. Res, Toxicol., 15, 1635-1642, 2002.
Dong, J., Everitt, J., Lau, S.S., and Monks, T.J. Induction of ERK1/2 and histone H3 phosphorylation within the outer stripe of the outer medulla of the Eker rat by 2,3,5-tris-(glutathion-S-yl)hydroquinone. Toxicol Sci. 80, 350-357, 2004. (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15129024)
Apoptotic cell death
Bratton, S.B., Lau, S.S., and Monks, T.J. Identification of quinol-thioethers in bone marrow of hydroquinone/phenol treated rats and mice, and their potential role in benzene-mediated hematotoxicity. Chem. Res. Toxicol., 10:859-865, 1997.
Bratton, S.B., Lau, S.S., and Monks, T.J. The putative benzene metabolite, 2,3,5-tris-(glutathion-S-yl)hydroquinone, depletes glutathione, stimulates sphingomyelin turnover, and induces apoptosis in Hl-60 cells. Chem. Res, Toxicol., 13:550-556, 2000.
Neurotoxicity of Ecstasy
Miller, R.T., Lau, S.S., and Monks, T.J. Metabolism of 5-(glutathion-S-yl)-a-methyldopamine following intracerebroventricular administration to male Sprague Dawley rats. Chem. Res. Toxicol., 8:634-641, 1995.
Miller, R.T., Lau, S.S., and Monks, T.J. Effects of 5-(glutation-S-yl)-a-methyldopamine on dopamine, serotonin, and norepinephrine concentrations following intracerebroventricluar administration to male Sprague Dawley rats. Chem. Res. Toxicol., 9:457-465, 1996.
Miller, R.T., Lau, S.S., and Monks, T.J. 2,5-bis-(Glutathion-S-yl)-a-methyldopamine, a putative metabolite of (±)-3,4-methylenedioxyamphetamine, produces long-term decreases in brain serotonin concentrations. Eur. J. Pharmacol., 323:173-180, 1997.
Monks, T.J., Ghersi-Egea, J-F., Philbert, M.A., Cooper, A.J.L., and Lock, E.A. The role of glutathione in neuroprotection and neurotoxicity. Toxicol. Sci., 51:161-177, 1999.
Bai. F., Lau, S.S., and Monks, T.J. Glutathione and N-acetylcysteine conjugates of a-methyldopamine produce serotonergic neurotoxicity. Possible role in methylenedioxyamphetamine-mediated neurotoxicity. Chem. Res. Toxicol., 12:1150-1157, 1999.
Bai, F., Lau, S.S., and Monks, T.J. The serotonergic neurotoxicity of 3,4-(±)-methylenedioxy-amphetamine and 3,4-(±)-methylenedioxymetamphetamine (ecstasy) is potentiated by inhibition of g-glutamyl transpeptidase. Chem. Res. Toxicol. 14: 863-870, 2001.
Monks, T.J.,Bai, F., Miller, R.T., Lau, S.S. Serontonergic neurotoxicity of of methylenedioxy-amphetamine and methylenedioxymetamphetamine. Adv. Exp. Med. Biol., 500, 397-406, 2001.
Monks, T.J., Jones, D.C., Bai, F., and Lau, S.S. The role of metabolism in 3,4-(±)-methylenedioxy-amphetamine and 3,4-(±)-methylenedioxymethamphetamine (ecstasy) neurotoxicity. Ther. Drug Monitoring, 26, 132-136, 2004.
Jones, D.C., Lau, S.S., and Monks, T.J. Thioether metabolites of 3,4-(±)-methylenedioxy-amphetamine and 3,4-(±)-methylenedioxymethamphetamine inhibit hSERT function and simultaneously stimulate dopamine uptake into hSERT-expressing SK-N-MC cells. J Pharmacol Exp Ther. 2004 May 28 [Epub ahead of print] PMID: 15169827.
In collaboration with Dr. Serrine Lau
Molecular basis of renal carcinogenesis
Peters, M.M., Jones, T.W., Monks, T.J. and Lau, S.S. Cytotoxicity and cell proliferation induced by the nephrocarcinogen hydroquinone, and its nephrotoxic metabolite 2,3,5-tris-(glutathion-S-yl)hydroquinone. Carcinogenesis, 18:2393-2401, 1997.
Towndrow, K.M., Mertens, J.J.W.M., Jeong, J.K., Weber, T.J., Monks, T.J., and Lau, S.S. Stress- and growth related gene expression are independent of chemical-induced prostaglandin E2 synthesis in renal epithelial cells. Chem. Res. Toxicol., 13:111-117, 2000
Lau, S.S., Monks, T.J., Everitt, J.I., Kleymenova, E., and Walker, C.W. Carcinogenicity of a nephrotoxic metabolite of the Ònon-genotoxicÓ carcinogen hydroquinone. Chem. Res. Toxicol., 14:25-33, 2001.
Yoon, H.S., Walker, C.L., Monks, T.J., and Lau, S.S. Transformation of kidney epithelial cells by quinol-thioethers via inactivation of the tuberous sclerosis-2 tumor suppressor gene. Molec. Carcinogenesis, 31:37-45, 2001.
Weber, T.J., Huang, Q., Monks, T.J., and Lau, S.S. Differential regulation of redox responsive transcription factors by the nephrocarcinogen, 2,3,5-tris-(glutathion-S-yl)hydroquinone. Chem. Res. Toxicol. 14: 814-821, 2001.
Yoon, H.S., Monks, T.J., Everitt, J.I., Walker, C.L., and Lau, S.S. Cell proliferation is insufficient but loss of tuberin is necessary for chemically induced nephrocarcinogenicity. Am. J. Physiol. Renal Physiol. 283: F262-F270, 2002.
Habib, S.L., Phan, M.F., Monks, T.J., and Lau, S.S. Reduced constitutive 8-oxogaunine-DNA glycosylase expression and impaired induction following oxidative DNA damage in the tuberin deficient Eker rat. Carcinogenesis, 24, 573-582, 2003.
Patel, S.K., Ma, N., Monks, T.J., and Lau, S.S. Changes in gene expression during chemical-induced nephrocarcinogenesis in the Eker rat. Molec. Carcinogenesis, 38, 141-154, 2003.
Yoon, H-S., Ramachandiran, S., Chacko, M.A.S., Monks, T.J., and Lau, S.S. The tuberous sclerosis-2 tumor suppressor modulates ERK and b-Raf activity in transformed renal epithelial cells. Am. J. Physiol. Renal Physiol., 286, F417-F424, 2004.
Proteomics in Toxicology
Person, M.D., Monks, T.J., and Lau, S.S. An integrated approach to identifying chemically induced post-translational modifications using comparative MALDI-MS and targeted HPLC-ESI-MS/MS. Chem. Res, Toxicol., 16, 598-608, 2003.
Person, M.D., Mason, D.E., Liebler, D.C., Monks, T.J., and Lau, S.S. Alkylation of cytochrome c by (glutathion-S-yl)-1,4-benzoquinone and iodoacetamide demonstrates compound dependent site specificity. Chem. Res. Toxicology, Accepted pending revision, 6/30/04.
Prostaglandin-mediated Cytoprotection
Weber, T.J., Lau, S.S., and Monks, T.J. PGE2 Ðmediated cytoprotection in renal epithelial cells. Evidence for a pharmacologically distinct receptor. Amer. J. Physiol., 273 (Renal Physiol. 42):F507-F515, 1997.
Weber, T.J., Monks, T.J., and Lau, S.S. DDM-PGE2-mediated cytoprotection in renal epithelial cells by a thromboxane A2 receptor coupled to NF-kB. Amer. J. Physiol. Renal Physiol, 278:F270-F278, 2000.
Towndrow, K.M., Jia, Z., Lo, H-H., Person, M.D., Monks, T.J., and Lau, S.S. 11-Deoxy-16,16-dimethylprostaglandin E2 induces specific proteins in association with its ability to protect against oxidative stress. Chem. Res, Toxicol., 16, 312-319, 2003.
Person, M.D., Lo, H-H., Towndrow, K.M., Jia, Z., Monks, T.J., and Lau, S.S. Comparative identification of prostanoid-inducible proteins by LC-ESI MS/MS and MALDI-TOF mass spectrometry. Chem. Res, Toxicol., 16, 757-767, 2003.
Jia, Z., Person, M.D., Shen, J., Hensley, S.C., Stevens, J.L., Monks, T.J., and Lau, S.S. GRP78/Bip is essential for 11-deoxy-16,16-dimethylprostaglandin mediated cytoprotection in renal epithelial cells. Am. J. Physiol. Renal Physiol. 287, F000-F000, 2004 Jun 29 [Epub ahead of print] PMID: 15226156