UTMB Department of Pathology

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Mechanisms of Environmental Diseases: Chemically Induced Cellular Lesions and Cancer

The molecular mechanisms of environmentally induced diseases were studied with an emphasis on the evaluation of the initial molecular and functional signals following the interaction of environmental chemicals with cellular molecules. These interactions start by the bio-activation of chemicals to reactive intermediates, interruption of the homeostasis of the antioxidant balance, induction of oxidative stress and formation of oxidative damage to biological molecules such as DNA and proteins. The ability of cells to withstand chemically-induced DNA damage was evaluated by determining the magnitude of DNA repair processes in the cell using base excision repair (BER) assay. BER was up regulated in cells exposed to low concentrations of several environmental chemicals according to biological phenomena known as hormesis which means the rapid response of the cell to a sub-toxic concentrations of a toxic substances. However, BER was down regulated at higher concentrations and longer exposure periods. Our studies indicate that some environmental chemicals provoke oxidative stress that sends signals to incite up or down regulation of gene expression of base excision repair enzymes. The associations of human diseases with impaired DNA repair mechanisms, such as in neurodegenerative diseases and cancer, graphically illustrates the importance of DNA repair processes in disease progression. Environmentally- induced disruption of BER may lead to diminished defense mechanisms against various types of environmental insults. Currently, our goal is to narrowly explore the sequence of the undesirable signals, induced by drinking water disinfectant byproducts (DBP) that regulate BER and how to obstruct their progression.

Our studies continue to investigate the mechanism of fetal bases for adverse pregnancy outcome (APO) and neurodegeneration following inutero exposure to DBP. Utmost priority is given to the development of mechanism based pre-clinical biomarkers for the DPB-induced APO to avert its progression.

1. Jacob S, Ahmed AE: Acrylonitrile induces oxidative stress and 8-hydroxydeoxyguanosine formation in normal human astrocytes. Toxicology Mechanisms & Meth, 13, 169-179, 2003
2. Jacob S, and Ahmed AE, Effect of route of administration on the Disposition of Acrylonitrile: Quantitative Whole Body Autoradiographic Study in Rats, Pharmacological Research, 48, 479-488, 2003
3. Chen K-H, Sreevastava K, Singhal RK, Jacob S, AHMED AE, Wilson SH: Modulation of base excision repair by low density lipoprotein, oxidized low density lipoprotein and antioxidants in mouse monocytes. Carcinogenesis. 21,106-110, 2001
4. AHMED AE, Aronson J, Jacob S: Dichlonacetonitrile; a water disinfectant by-product induces oxidative stress as the mediator of apoptosis or necrosis in mouse peritoneal macrophages; Toxicology in vitro., 14,199-210,2000
5. AHMED AE, Jacob S, Nouraldeen AM: Chloroacetonitrile (CAN) induces glutathione depletion and 8-Hydroxylation of guanine bases in gastric mucosal DNA of rats. J Biochem Toxicol 13(3): 1999
6. Hamada EM, Abdel-Aziz AH, Abd-Allah AR, AHMED AE: Possible functional immunotoxicity of acrylonitrile. Pharmacol Res 37(2): 123-129, 1998
7. Jacob S, Abdel-Aziz AH, Shouman SA, AHMED AE: Effect of glutathione modulation on the distribution and transplacental uptake of 2-[14C] chloroacetonitrole (CAN). Quantitative whole-body autoradiographic study in pregnant mice. Toxicol Indus Health 14(4): 533-546, 1998
8. Muntaz MM, Farooqui MY, AHMED AE: Propionitrile whole-body autoradiography, conventional toxicokinetics and metabolism studies in rats. Toxicol Industrial Health 13(1): 27-41, 1997
9. Saleh MA, AHMED AE, Kamel A, Dary C: Determination of the distribution of malathion in rats following various routes of administration by whole-body electronic autoradiography. Toxicol Industrial Health 13(6): 751-758, 1997
10. AHMED AE, Jacob S, Giovanella BC, Kosielski AJ, Liehr JG, Stehlin JS Jr.: Comparative disposition of the antineoplastic agent 9-nitro camptothecin and inactive isomer 12-nitro camptothecin in CASE-bearing nude mice: effect of route of administration on tissue distribution. Cancer, Chemother Pharmacol 41: 29-36, 1997
11. Abdel-Aziz AH, Abdel-Naim AB, Hamada FM, AHMED AE: In-vitro testicular bioactivation of acrylonitrile. Pharmacological Res 35(2): 129-134, 1997
12. AHMED AE, Jacob S, Ghanayem BI: Comparative disposition of acrylonitrile and methacrylonitrile: a quantitative whole body autoradiographic study in rats. Fund Applied Toxicol 33: 49-59, 1996
13. Au WW, AHMED AE, Chiewchanwit T, Hsie AW, Ma H, Moslen MT: Toxicity and genotoxicity of 2-methoxyethanol in vitro and in vivo. Occup Hyg Risk Mgt 92: 132-141, 1996.
14. AHMED AE, Jacob S, Giovanella BC, Kozielski AJ, Stehlin JS Jr, Liehr JG: Influence of route of administration on [3H]-camptothecin distribution and tumor uptake in CASE-bearing nude mice: whole-body autoradiographic studies. Cancer, Chemother and Pharmacol 39: 122-130, 1996
15. Liehr JG, AHMED AE, Giovanella BC: Pharmacokinetics of camptothecins administered orally. Ann of NY Acad Sci 803: 157-63, 1996
16. AHMED AE, Nouraldeen AM, Abdel-Rahman SZ, Rajaraman S. Role of glutathione modulation in acrylonitrile-induced gastric DNA damage in rats. Arch Toxicol 70: 620-627, 1996
17. Subruamanian U, AHMED AE: Intestinal toxicity of acrylonitrile: In vitro metabolism by intestinal cytochrome P450 2E1. Toxicol and Appl Pharmacol, 135: 1-8, 1995
18. Nouraldeen AM, AHMED AE: Studies on the mechanisms of haloacetonitriles-induced genotoxicity. IV: In vitro interaction of haloacetonitriles with DNA. Toxicology in vitro 0:1-10, 1995
19. Abdel-Rahman SZ, Nouraldeen AM, AHMED AE: Acrylonitrile-induced reversible inhibition of uridine uptake by isolated rat intestinal epithelial cells. Toxicology In Vitro 8: 139-143, 1994
20. AHMED AE, Jacob S, Au W: Quantitative whole body autoradiographic disposition of glycol ether in mice. Effect of route of administration. Fundam Appl Toxicol 22: 266-276, 1994
21. Burka LT, Sanchez IM, AHMED AE, Ghanayem BI: Comparative metabolism and disposition of acrylonitrile and methacrylonitrile in rats. Arch Toxicol 68: 611-618, 1994
22. Abdel-Rahman SZ, Nouraldeen AM, AHMED AE: Molecular interaction of [2,3 14C]-acrylonitrile with DNA in gastric tissue of rat. J Biochem Toxicol 9: 191-198, 1994
23. AHMED AE, Jacob S, Soliman S, Ahmed N, Osman K, Loh JP, Romero N: Whole body autoradiographic disposition, elimination and placental transport of [14C]-Tri-ortho-cresyl phosphate in mice. J Appl Toxicology 13(4): 259-267, 1993
24. Abdel-Aziz AH, Abdel-Rahman SZ, Nouraldeen AM, Loh JP, AHMED AE: Effect of glutathione modulation on molecular interaction of chloroacetonitrile with maternal and fetal DNA. Rep Toxicol 7: 263-272, 1993
25. AHMED AE, Hussein G, Loh JP: Studies on the mechanism of acetonitrile toxicity I: Distribution and whole body autoradiography. Pharmacol Toxicol 70: 322-330, 1992
26. AHMED AE, Abdel Rahman, Al-Deen A Nour: Interaction of acrylonitrile with testicular DNA. Biochem Toxicology 7: 5-11, 1992
27. AHMED AE, Abdel Aziz A, Abdel-Rahman AZ, Al-Deen A Nour: Pulmonary toxicity of acetonitrile: covalent interaction and effect on replicative and unscheduled DNA synthesis in the lung. Toxicology 76: 1-14, 1992
28. AHMED AE, Ansari GAS, Dencker L, Ullberg S: Differential distribution and placental transport of 2-and 3-t[methyl-14C]butyl-4-hydroxyanisole (BHA) in pregnant mice. Fundamental and Appl Toxicol 16: 356-364, 1991.
29. AHMED AE, Jacob S, Loh JP, Samra SK, Nokra M, Pollard RB: Comparative disposition and whole body autoradiographic distribution of AZT and thymidine in mice. J Pharmacol Exp Ther 257: 479-486, 1991
30. Ghanayem BI, Farooqui MYH, Elshabrawy O, Mumtaz MM, AHMED AE: Assessment of the acute acrylonitrile-induced neurotoxicity in rats. Neurotoxicol Teratol 13: 499-502, 1991.
31. Farooqui MYH, Mumtaz MM, Ghanayem BI, AHMED AE: Hemoglobin degradation, lipid peroxidation and inhibition of Na+/K+-atpase in rat erythrocytes exposed to acrylonitrile. Biochem Toxicol 5: 221-227, 1991.
32. AHMED AE, Hussein GI, Loh JP, Abdel-Rahman SZ: Studies on the mechanism of haloacetonitrile-induced gastrointestinal toxicity: Interaction of dibromoacetonitrile with glutathione and glutathione-S-transferase in rats. J Biochem Toxicol 6(2): 115-121, 1991
33. Nokta M, Loh JP, Douidar SM, AHMED AE, Pollard RB: Metabolic interaction of recombinant interferon- and zidovudine in AIDS patients. J Interferon Res 11: 159-164, 1991
34. AHMED AE, Jacob S, Loh JP: Studies on the mechanism of haloacetonitriles toxicity: Quantitative whole body autoradiographic distribution of [2-14C]-chloroacetonitrile in rats. Toxicol 67: 279-302, 1991
35. Mumtaz MM, Farooqui MYH, Ghanayem BI, AHMED AE: The urotoxic effects of N,N'-Dimethylaminopropionitrile: In vivo and in vitro metabolism. Toxicol Appl Pharmacol 110: 61-69, 1991
36. Mumtaz MM, Farooqui MYH, Ghanayem BI, Rajaraman S, Frankenberg L, AHMED AE: Studies on the mechanism of urotoxic effects of N,N'-Dimethylaminopropionitrile in rats and mice. 1. Biochemical and morphologic characterization of the injury and its relationship to metabolism. J Toxicol Environ Hlth 33: 1-17, 1991
37. Saydjari R, Townsend CM, Barranco SC, AHMED AE, Thompson JC: The effects of cyclosporin and -difluoromethylornithine on the induction of ornithine decarboxylase activity in colon cancer cells in vitro. Clin Chem Enzymol Comm 2: 87-95, 1990
38. Loh JP, AHMED AE: Determination of Camptothecin in biological fluids using reversed-phase high performance liquid chromatography with fluorescent detection. J of Chromatography 530: 367-376, 1990.
39. Bhat HK, AHMED AE, Ansari GAS: Toxicokinetics of monochloroactic acid; a whole-body autoradiography study. Toxicology 63: 35-43, 1990
40. Calhoun K, AHMED AE, Stanley D, Steinberg R: Vitamin A and E - Chemoprotection of oral tumors. Arch Otolaryngology 115: 484-488, 1989.
41. AHMED AE, Soliman SA, Loh JP: Studies on the mechanisms of haloacetonitrile toxicity: Inhibition of rat hepatic glutathione S-transferase in vitro. Toxicol Appl Pharmacol 100: 271, 1989.
42. Jenkins VK, Perry RR, AHMED AE: Role of metabolism in effects of diflubenzuron on growth of B16 melanomas in mice. Investigational New Drugs 4: 325 335, 1987
43. Upreti RK, Farooqui MYH, AHMED AE, Ansari GAS: Toxicokinetics and molecular interaction of [14C]-formaldehyde in rats. Arch Environ Contam Toxicol 16: 263 273, 1987.
44. Douidar SM, AHMED AE: A novel mechanism for the enhancement of acetaminophen hepatotoxicity by phenobarbital. J Pharm Exp Ther 240: 578-583, 1987
45. Kretschmer N, Boor PJ, el-Azhary R, AHMED AE, Reynolds ES: Studies on the mechanism of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU)-induced hepatotoxicity. III. Ultrastructural characterization of bile duct injury. Canc Chem Pharmacol 19: 109-117, 1987
46. AHMED AE, el-Azhary R, Boor PJ, Haque A, Costanzi J: Studies on the mechanism of 1-(2- chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU)-induced hepato-toxicity. II. Biochemical and morphological characterization of the injury and its prevention by phenobarbital. Canc Chem Pharmacol 19: 103-108, 1987
47. Farooqui MYH, Upreti RK, AHMED AE, Ansari GAS: Influence of intraperitoneally administered formaldehyde on bile production and glutathione levels in rats. Res Commun Chem Pathol Pharmacol 53: 233-236, 1986.
48. Ghanayem B, AHMED AE: Prevention of acrylonitrile-induced gastrointestinal bleeding by prior treatment with SH modifiers. Res Commun Chem Pathol Pharmacol 53: 141-144, 1985
49. AHMED AE, Farooqui MYH: Molecular interactions of acrylonitrile at target sites of carcinogenicity in rats. Arch Toxicol Suppl 7, 1985
50. Ghanayem B, Boor PJ, AHMED AE: Acrylonitrile-induced gastric mucosal necrosis: Role of gastric glutathione. J Pharm Exp Ther 232: 570, 1985
51. Gad el Karim M, Sodagopa VM, AHMED AE, Legator MS: Benzene myeloclasto- genicity: A function of its metabolism. Am J Indust Med 340: 715, 1985
52. Fanini D, Trieff N, Sadagopa R, AHMED AE, Adams PM: Effect of acute acrylonitrile exposure on metrazol-induced seizures in the rat. Neurotoxicology 6: 29, 1985
53. Douidar SM, Boor PJ, AHMED AE: Potentiation of the hepatotoxic effect of acetaminophen by prior administration of salicylate1. J Pharm Exp Ther 223: 242, 1985
54. el-Azhary RA, AHMED AE: Heme metabolism in liver and spleen of 1-(2-chloroethyl)-3-cyclohexyl-1- nitrosourea (CCNU)-treated rats. Biochem Pharmacol 33: 3171-3175, 1984
55. Farooqui MYH, AHMED AE: Circadian periodicity of tissue glutathione and its relationship with lipid peroxidation in rats. Life Sci 34: 2413-2418, 1984.
56. Ghanayem B, AHMED AE, Boor PJ: Acetyl salicylic acid-induced gastric mucosal lesions: no role of gastric glutathione. Res Comm Chem Path Pharm 45: 1, 1984.
57. Farooqui MYH, AHMED AE: In vivo interactions of acrylonitrile with macromolecules in rats. Chem-Biol Interact 47: 363-371, 1983
58. Ghanayem B, AHMED AE: Acrylonitrile-induced gastrointestinal hemorrhage and the effects of metabolism modulation in rats. Toxicol Appl Pharmacol 68: 290, 1983.
59. AHMED AE, Sye W-F, Coppenhaver DH, Baron S: Mouse interferon: Rapid purification by adsorption on controlled pore glass and high performance liquid chromatography. J Chromatogr 259: 169, 1983.
60. Elshabrawy O, AHMED AE, Adams P: Brain distribution and behavioral effects of acrylonitrile in the rat. Neurotox Neurobiol 4, 1983
61. Willcockson W, Khalid M, AHMED AE, Hillman G: Structure activity studies on N-chloroethyl acetylcholine analogs on schistosoma mansoni and vertebrate neuromuscular preparations. Exp Parasitol 56: 70, 1983
62. Farooqui MYH, AHMED AE: The effects of acrylonitrile on hemoglobin and red cell metabolism. J Toxicol Env Hlth 21: 695-707, 1983
63. AHMED AE, Koenig M, Farrish HH: Studies on the quantitation of chlorambucil in plasma by reversed-phase high-performance liquid chromatography. J Chromatogr 233: 392, 1982
64. AHMED AE, Hsu TF, el-Azhary RA, Moawad H, Costanzi J: Macromolecular interactions of 14C-(ring) melphalan in blood. Biochem Pharmacol 31: 1615, 1982
65. AHMED AE, Hsu TF, el-Azhary RA, Moawad H, Farrish HH, Costanzi J: Tissue distribution and macromolecular interactions of 14C-(ring) melphalan in the rat. Canc Chemother Pharmacol 8: 271, 1982
66. AHMED AE, Farooqui MYH: Comparative toxicities on aliphatic nitriles. Tox Lett 12: 157, 1982
67. AHMED AE, Farooqui MYH, Upreti RK, Elshabrawy O: Distribution and covalent interactions of 1-14C-acrylonitrile in the rat. Toxicology 23: 159, 1982
68. AHMED AE, Farooqui MYH, Upreti RK, Elshabrawy O: Comparative toxicokinetics of 2,2-14C- and 1-14C-acrylonitrile in the rat. J Appl Toxicol 3: 39, 1982
69. Ghanayem B, AHMED AE: In vivo biotransformation and biliary excretion of 1-14C-acrylonitrile in rats. Arch Toxicol 50: 175, 1982
70. Ghanayem B, AHMED AE: Quantitative determination of gastrointestinal bleeding in rats. J Pharmacol Met 8: 311, 1982
71. Willcockson W, Dotson M, Grim S, AHMED AE, Hillman G: Effects of phosphonium and chloroethyl-acetylcholine compounds on schistosome and vertebrate acetyl cholinesterase. Comp Biochem Physiol 72: 101, 1982
72. Douidar SM, AHMED AE: Studies on simultaneous determination of acetaminophen, salicylic acid and salicyluric acid in biological fluids by high performance liquid chromatography. J Clin Chem Clin Biochem 20: 791, 1982
73. el-Azhary RA, AHMED AE: Effect of melphalan on -aminolevulinic acid synthetase in the spleen, bone marrow and liver of rats. J Pharmacol Exp Ther 223: 457, 1982
74. Farooqui MYH, AHMED AE: Molecular interactions of 1-14C-acrylonitrile and K14CN in rat blood. Chem-Biol Interact 38: 145m, 1982
75. AHMED AE, Patel K: Acrylonitrile: In vivo metabolism in rats and mice. Drug Metab Disp 9: 219, 1981
76. AHMED AE, Hsu TF: Quantitative analysis of melphalan and its major hydrolysate in patients and animals by reversed-phase HPLC. J Chromatogr 222: 453, 1981
77. Willcockson WS, Khalid M, AHMED AE, Hillman GR: Effects of acetylcholine mustard analogs on schistosome and vertebrate neuromuscular preparations. J Pharmacol Exp Ther 218: 330, 1981
78. Gill D, AHMED AE: Covalent binding of 14C-benzene to cellular organelles and bone marrow nucleic acids. Biochem Pharmacol 30: 1127, 1981
79. AHMED AE, Kubic VL, Stevens J, Anders MW: Halogenated methanes: Metabolism and toxicity. In: Symposium on toxic interactions between chemicals: mechanisms and effects. Fed Proc 39: 3150, 1980
80. Abreu ME, AHMED AE: Metabolism of acrylonitrile to cyanide. In vitro studies. Drug Metab and Disp 8: 376, 1980.
81. Rabello-Gay N, AHMED AE: Acrylonitrile in vivo, cytogenic studies in mice and rats. Mut Res 79: 249, 1980
82. Boor PJ, Nelson TJ, Moslen MT, Chieco P, AHMED AE, Reynolds ES: Allylamine cardiovascular toxicity: modulation of the monoamine oxidase system and biotransformation to acrolein. International conference on industrial and environmental xenobiotics: biotransformation and kinetics, Prague, Czechoslovakia. 1980.
83. Trieff N, AHMED AE: Acrylonitrile, human health effects and hazard evaluations. EPA Criteria Document, Federal Registry. October, 1979.
84. Anders MW, Kubic VL, AHMED AE: Metabolism of halogenated methanes and macromolecular binding. J Environ Path Toxicol 1: 117, 1978
85. Anders MW, Stevens JL, Sprague RW, Shaath Z, AHMED AE: Metabolism of haloforms to carbon monoxide. II. In vivo studies. Drug Metab Disp 6: 556, 1978
86. Anders MW, Kubic VL, AHMED AE: Bio-organic mechanism of the metabolism of dihalomethane to carbon monoxide, formaldehyde, formic acid and inorganic halide. In: Proceedings of the international conference on in vivo aspects of biotransformation and toxicity of industrial and environmental xenobiotics. Prague 13 15, September, 1977
87. AHMED AE, Kubic VL, Anders MW: Metabolism of dihalomethanes to formaldehyde and inorganic halide. II. Studies on the mechanism of the reaction. Biochem Pharmacol 27: 2021, 1977
88. AHMED AE, Anders MW, Kubic VL: Metabolism of haloforms to carbon monoxide. I. In vitro studies. Drug Metab Disp 5: 198, 1977
89. AHMED AE, Hanna PE, Grund VR: Conformationally restricted analogs of histamine H1 receptor antagonists: Cis- and trans-1-benzyl-3-dimethylamino-6-phenylpiperidine. J Med Chem 19: 117, 1976
90. AHMED AE, Anders MW: Metabolism of dihalomethanes to formaldehyde and inorganic halide. 1. In vitro studies. Drug Metab Disp 4: 357, 1976
91. Anders MW, Kubic VL, AHMED AE: Metabolism of halogenated methanes and macromolecular binding. Proceedings of conference on the status of predictive tools in application of safety evaluations: present and future: Carcinogenesis and Mutagenesis, 117, Pathotox. Inc., 1976
92. AHMED AE: Synthesis and biological activity of conformationally restricted analogs of histamine H1 receptor antagonists: Cis- and trans-1-benzyl-3-dimethylamino-6-phenylpiperidine. Ph.D. Thesis, University of Minnesota, 1975.
93. Hanna PE, AHMED AE: Conformationally restricted analogs of histamine H1 receptor antagonists: Trans- and cis- 1,2-diphenyl-3-dimethylaminopyrrolidine. J Med Chem 16: 963, 1973
94. Hanna PE, AHMED AE, Grund VR, Merriman RL: 1,5-Diphenyl-3-dimethylaminopyrrolidine: A long-acting histamine antagonist. J Pharm Sci 62: 512, 1973

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