UTMB Department of Pathology

Directory lookup

Small Intestinal Injury Produced by Nonsteroidal Anti-Inflammatory Drugs

Research in my laboratory focuses on the small intestinal injury produced by nonsteriodal anti-inflammatory drugs [NSAIDs]. This drug complication, known as NSAID enteropathy, is typically found in about 40 percent of arthritics and others on chronic therapy with classical NSAIDs [e.g, naproxen, diclofenac]. In contrast to the vast attention given to gastric complications of NSAIDs, little is known about either the mechanistic basis of NSAID enteropathy or strategies to prevent this problem. We are addressing these clinically relevant unknowns using diclofenac, one of the most widely prescribed classical NSAIDs, as a representative drug for investigation.

We have established rodent models for the enteropathy of diclofenac, produced the first experimental evidence for an aging influence on the gastrointestinal toxicity of NSAIDs, and identified two new strategies to attenuate the enteropathy of diclofenac. Our observations indicate that the formation of drug-protein adducts is a casual factor in diclofenac enteropathy. Collaborative studies with colleagues in Mexico and Singapore are using this model to assess new formulations of NSAIDs. The schematic puts our hypothesis about the role of drug-protein adducts into the context of other known events in the enteropathy of diclofenac.

Techniques currently employed include immuno-histochemistry for localization of drug-protein adducts. Western blots for characterization of adducted proteins, image analysis for measurement of ulcer areas, Mrp 2 exporter deficient rats for discrimination of effects on bioactivation/biliary secretion versus intestinal vulnerability, and cell culture for wound healing by restitution.

1. Treinen-Moslen M, Kaphalia L, and Kanz M. Consequences of MRP2 deficiency: Lessons from rats with a mutation in this exporter. Comments on Toxicology 9: 229-249, 2004
2. Jones JA, Kaphalia L, Treinen-Moslen M, and Liebler DC. Proteomic Characterization of metabolites, protein adducts and biliary proteins in rats exposed to 1,1-dicloroethylene and diclofenac. Chemical Research in Toxicology 16:1306-1317, 2003
3. Daiker DH, Shipp BK, Schoenfeld HA, Klimpel GR, Witz G, Moslen MT and Ward JB. Effect of cyp2e1 induction by ethanol on the immunotoxicity and genotoxicity of extended low-level benzene exposure. J Toxicol Environ Health 59:101-116, 2000
4. Atchison CR, West AB, Balakumaran A, Hargus SJ, Pohl LR, Daiker DH, Aronson JF, Hoffmann WE, Shipp BK, Treinen-Moslen M. Evidence for drug-enterocyte adducts as causal factors for diclofenac enteropathy in rats. Gastroenterology 119: 1537-1547, 2000
5. Atchison CR, Balakumaran A, West AB, Hoffmann WE, and Treinen-Moslen, M. Aging enhances susceptibility of diclofenac-treated rats to gastric ulceration, while attenuating the enteropathy. Digestive Dis Sci 45: 614-620, 2000
6. Daiker DH, Ward JB, Schoenfeld HA, Witz G and Moslen MT. Characterization of a dietary ethanol protocol for Cyp2e1 induction in the CD-1 mouse without evident hepatic toxicity or genotoxicity. Int J Toxicol 18:327-335, 1999
7. Woodard, SH and Moslen, MT. Decreased biliary secretion of proteins and phospholipids by rats with 1,1-dichloroethylene-induced bile canalicular injury. Toxicol Appl Pharmacol 152:295-301, 1998
8. Balakumaran A, Campbell GA, Moslen MT. Calcium channel blockers induce thymic apoptosis in vivo rats. Tox Appl Pharmacol 139: 122-127, 1996
9. Daiker DH, Moslen MT, Carr J, Ward J. Repeated, oral benzene exposure alters enzymes involved in benzene metabolism. J Tox Environ Hlth 48: 439-451, 1996
10. Balasubramanian J, Kaphalia L, Campbell GA, Moslen MT. Induction of apoptosis in the rat thymus by 2-methoxyethanol is decreased by phenobarbital pretreatment. Occupational Hyg 2: 275-281, 1996
11. Moslen MT, Kaphalia L, Balasubramanian H, Yin LM, Au WW. Species differences in testicular and hepatic biotransformation of 2-methoxyethanol. Toxicology 96: 217-224,1995
12. Kanz MF, Kaphalia L, Moshin S, Taj Z, Moslen MT. Hyperthyroidism increases covalent binding and biliary excretion of 1,1 dichloroethylene in rats. J Tox Environ Hlth 41: 187-206, 1994
13. Moslen MT, Kanz MF, Bhatia J, Smith CV, Rassin DK. Biliary glutathione and some amino acids are markedly diminished when biliary pressure is elevated. Exp Molec Pathol 61: 1-15, 1994
14. Corcoran GB, Fix L, Jones DP, Moslen MT, Nicotera P, Oberhammer FA, Buttyan R. Apoptosis: Molecular control point in toxicity. Toxicol Appl Pharmacol 128: 169-181, 1994
15. Moslen MT, Kanz MF. Biliary excretion of marker solutes by rats with 1,1-dichloroethylene-induced bile canalicular injury. Toxicol Appl Pharmacol 122: 117 130, 1993
16. Bhatia J, Moslen MT, Haque A, McCleery R, Rassin DK. Total parenteral nutrition associated alterations in hepatobiliary function and histology in rats: Is light exposure a clue? Pediatrics Res 33: 487-492, 1993
17. Klein GL, Goldblum RM, Moslen MT, Pyron DL, Mann PA, Lee TC, Alfrey A.C. Increased biliary transferrin excretion following parenteral aluminum administration to rats. Pharmacol Toxicol 72: 373 376, 1993.
18. Zimniak P, Ziller SA, Panfil I, Radaminska A, Wolters H, Kuipers F, Sharma R, Saxena M, Moslen MT, Vore M, Vonk R, Awasthi YC, Lester R. Identification of an anion-transport ATPase that catalyzes glutathione-conjugate dependent ATP hydrolysis in canalicular plasma membranes from normal rats and rats with conjugated hyper-bilirubinemia (GY mutant). Arch Biochem Biophys 292: 534 538, 1992.
19. Bhatia J, Moslen MT, Kaphalia L, Rassin DK. Glutathione and tissue mino acid responses to light-exposed parenteral nutrients. Toxicol Lett 3: 79-89, 1992
20. Bhatia J, Rivera A, Moslen MT, Rassin DK. Hepatic function during short-term total parental nutrition: Effect of light exposure of parenteral nutrients. Res Commun Chem Pathol Pharmacol 78: 321-340, 1992
21. Moslen MT, Kanz MF, Bhatia J, Kaphalia L, Goldblum RM. Biliary endogenous PI, D-glucose, IgA and transferrin are differentially altered by hydrostatic pressure. J Hepatol 16: 89-97, 1992.
22. Kanz MF, Whitehead RF, Ferguson AE, Kaphalia L, Moslen MT. Biliary function studies during multiple time periods in freely-moving rats: A useful system and set of marker solutes. J Pharmacol Methods 27: 7-15, 1992.
23. Kanz MF, Taj Z, Moslen MT. 1,1-Dichloroethylene hepatotoxicity: Effects of hypothyroidism on distribution, covalent binding and injury in the rat. Toxicology 70: 213-229, 1991
24. Kanz MF, Vanoye-Trevino C, Moslen MT. The use of a silastic shield to protect an externalized biliary cannula. Lab Animals 23: 36-38, 1989
25. Harper BL, Ward JB Jr, Ramanujam S, Ammenheuser MM, Au WW, Moslen MT, Legator MS. A combined testing protocol for assessing genotoxicity in individual animals: Application to environmental Toxicology. J Appl Toxicol 9: 97-102, 1989
26. Moslen MT, Dunsford HA, Karnasta C, Chieco P, Kanz MF. Immunocytochemical and histochemical evidence of early selective bile canaliculi injury after 1,1-dichloroethylene in fasted rats. Am J Pathol 134: 1099-1112, 1989
27. Moslen MT, Whitehead RF, Ferguson, AE, Kanz MF. Protection by L-2-oxothiazolidine-4-carboxylate, a cysteine prodrug, against 1,1 dichloroethylene hepatotoxicity in rats is associated with decreases in toxin metabolism and cytochrome P-450. J Pharmacol Exp Ther 248: 157 163, 1989
28. Au WW, Harper BL, Moslen MT, Ward JB Jr, Legator MS. Genotoxic effects of a subacute low level inhalation exposure to a mixture of carcinogenic chemicals. Mutation Res 203: 103-115, 1988
29. Moslen MT, Kanz MF, Ferguson AE. A stable calorimetric assay to measure toxin elevation of inorganic phosphate in bile. Anal Biochem 168: 405-410, 1988
30. Moslen MT, Legator MS. Advantages of a combined testing protocol (CTP) with multiple endpoints: The reverse tier approach. Mutation Res 205: 91-97, 1988
31. Chieco P, Normanni P, Moslen MT. Localization of high benzaldehyde dehydrogenase activity in rat upper gastrointestinal tract mucosa: A quantitative histochemical study. J Histochem Cytochem 36: 245-252, 1988
32. Moslen MT, Kanz MF, Bhatia J, Catarau EM. Two cannula method for parenteral infusion and serial blood sampling in the freely moving rat. J Ent Parent Nutr 12: 633-638, 1988
33. Moslen MT, Harper BL, Roy D. Effects of a cysteine precursor, L-2-oxothiazolidine-4-carboxylate, nutritional status and sex on tissue glutathione and hepatic GSH-utilizing enzymes of CD-1 mice. Res Commun Chem Pathol Pharmacol. 61: 49-63, 1988
34. Kanz MF, Whitehead RF, Ferguson AE, Moslen MT. Hyperthyroidism potentiates 1,1-dichloroethylene hepatotoxicity by different pathways than fasting. Toxicol Appl Pharmacol 95: 93-103, 1988
35. Chieco P, Normanni P, Moslen MT, Maltoni C. Quantitative histochemistry of benzaldehyde dehydrogenase in hepatocellular carcinomas of vinyl chloride-treated rats. J Histochem Cytochem 34: 151-185, 1986
36. Moslen MT, Ahluwaha MB, Farber E. 1,2-Dibromoethane initiation of hepatic nodules in Sprague-Dawley rats selected with Solt-Farber System. Arch Toxicol 58: 118-119, 1986
37. Moslen MT, Poisson LR, Reynolds ES. Cholestasis and increased biliary excretion of inulin in rats given 1,1-dichloroethylene. Toxicol 34: 201-209, 1985
38. Moslen MT, Reynolds ES. Rapid, substrate-specific, and dose-dependent deactivation of liver cytosolic glutathione S-transferase in vivo by 1,1-dichloroethylene. Res Commun Chem Pathol Pharmacol 47: 59-72, 1985
39. Reynolds ES, Treinen RJ, Farrish HH, Moslen MT. Metabolism of 14Carbon tetrachloride to exhaled, excreted and bound metabolites: Dose-response, time-course and pharmacokinetics. Biochem Pharmacol 33: 363-3374, 1984
40. Reynolds ES, Kanz MF, Chieco P, Moslen MT. 1,1-Dichloro\ethylene: An apoptotic hepatotoxin? Envir Hlth Persp 57: 313-320, 1984
41. Moslen MT. Increased incidence of foci and nodules in the livers of rats given one or two doses of 1,2-dibromoethane followed by partial hepatectomy and phenobarbital. Toxicologic Pathol 12: 307-314, 1984
42. Reynolds ES, Treinen RJ, Farrish HH, Moslen MT. Relationships between the pharmacokinetics of CCl4 conversion to CO2 and CHCl3 and liver injury. Arch Toxicol Suppl 7: 303-306, 1984
43. Botti-Cacciari B, Moslen MT, Reynolds ES, Vannini V. Single step method or separation of rat liver cytosolic glutathione S-trans-ferase isozymes. Arch Toxicol Suppl 7: 517-20, 1984
44. Ansari GAS, Moslen MT, Reynolds ES. Evidence for in vivo covalent binding of .CCl3 derived from CCl4 to cholesterol of rat liver. Biochem Pharmacol 331: 3509 3510, 1982
45. Botti B, Moslen MT, Trieff NM, Reynolds ES. Transient decrease of hepatic cytosol glutathione S-transferase activities in rats given 1,2-dibromoethane or CCl4. Chem Biol Inter 42: 259-270, 1982
46. Bandi ZL, Moslen MT, Reynolds ES. Ion exchange chromatography of phosphatides and glycolipids on quaternary triethylammonium glycophase covalently bound to controlled pore glass. J Chromatogr 249: 93-101, 1982
47. Reynolds ES, Moslen MT, Treinen, RJ. Isopropanol enhancement of carbon tetrachloride metabolism in vivo. Life Sci 31: 661-669, 1982
48. Chieco P, Moslen MT, Reynolds ES. Histochemical evidence that plasma and mitochondria membranes are primary foci of hepatocellular injury caused by 1,1-dichloroethylene. Lab Invest 46: 413-421, 1982
49. Hu LA, Ansari GAS, Moslen MT, Reynolds ES. Efficient clean-up of fat samples by Sep-Pak cartridges for polybrominated biphenyl analysis. J Chromatogr 241: 491-422, 1982
50. Chieco P, Moslen MT, Reynolds ES. Effect of administrative vehicle on oral 1,1- dichloroethylene toxicity. Toxicol Appl Pharmacol 57: 146-155, 1981
51. Reynolds ES, Moslen MT, Boor PJ, Jaeger RJ. 1,1-Dichloroethylene hepatotoxicity: Time-course of GSH changes and biochemical aberrations. Am J Pathol 101: 31-344, 1980
52. Boor PJ, Moslen MT, Reynolds ES. Allylamine cardiotoxicity: I. Sequence of pathologic events. Toxicol Appl Pharmacol 50: 581-592, 1979
53. Reynolds ES, Moslen MT. Halothane hepatotoxicity: Enhancement by polychlorinated biphenyl pretreatment. Anesthesiology 47: 19-27, 1977
54. Moslen MT, Reynolds ES, Boor PJ, Bailey K, Szabo S. Trichloroethylene-induced deactivation of cytochrome P-450 and loss of liver glutathione. Res Commun Chem Pathol Pharmacol 16: 109-120, 1977
55. Moslen MT, Reynolds ES, Szabo S. Enhancement of the hepatotoxicity and metabolism of trichloroethylene and perchloroethylene. Biochem Pharmacol 26: 369-375, 1977
56. Jaeger RJ, Murphy SD, Reynolds ES, Szabo S, Moslen MT. Chemical modification of acute hepatotoxicity of vinyl chloride monomer in rats. Toxicol Appl Pharmacol 41: 597-607, 1977
57. Reynolds ES, Moslen MT. Damage to hepatic cellular membranes by chlorinated olefins with emphasis on synergism and antagonism. Environ Hlth Persp 21: 137-147, 1977
58. Szabo S, Jaeger RJ, Moslen MT, Reynolds ES. Modulation of 1,1-dichloroethylene hepatotoxicity by hypothyroidism. Toxicol Appl Pharmacol 42: 367-376, 1977
59. Boor PJ, Reynolds ES, Moslen MT. Neurotoxicity of digitoxin in adult and newborn rats: Drug Distribution. Arch Inter Pharmacol Ther 224: 4-12, 1976
60. Reynolds ES, Moslen MT. Metabolism of (14C-1)-halothane in vivo: Effects of multiple anesthesia, phenobarbital and CCl4 pretreatment. Biochem Pharmacol 24: 2075-2081, 1975
61. Szabo S, Reynolds ES, Moslen MT. Chemical factors in etiology of duodenal ulcer. Lancet II:73 (July 12) 1975
62. Reynolds ES, Moslen MT, Szabo S, Jaeger RJ Vinyl chloride-induced deactivation of the liver mixed function oxidase system: An in vivo study. Res Commun Chem Pathol Pharmacol 12:685-694, 1975
63. Reynolds ES, Moslen MT, Szabo S, Jaeger RJ, Murphy SD. Hepatotoxicity of vinyl chloride and 1,1-dichloroethylene: Role of mixed function oxidase system. Am J Pathol 81: 219-236, 1975
64. Reynolds ES, Moslen MT. Chemical modulation of early carbon tetrachloride injury. Tox Appl Pharmacol 29: 377-388, 1974
65. Reynolds ES, Moslen MT. In vivo covalent binding of 14C-CCl4 metabolites in liver microsomal lipids. Biochem Biophys Res Commn 55: 747-750, 1974
66. Reynolds ES, Moslen MT. Liver injury following halothane anesthesia in phenobarbital pretreated rats. Biochem Pharmacol 23: 189 195, 1974
67. Jaeger RJ, Reynolds ES, Conolly RB, Moslen MT, Szabo S, Murphy SD. Acute hepatic injury by vinyl chloride in rats pretreated with phenobarbital. Nature 252: 724-725, 1974
68. Berendzen R, Moslen MT. Manpower and employment in American astronomy. Annals NY Acad Sci 198: 46-65, 1972
69. Reynolds ES, Ree HJ, Moslen MT. Liver parenchymal cell injury. IX. Phenobarbital potentiation of endoplasmic reticulum denaturation following carbon tetrachloride. Lab Invest 26: 290-299, 1972

Search PubMed database for Mary Moslen-Treinen