Abstract

My long term objectives are to clarify the biologic relevance of toxin-induced, acute changes in phase II-conjugation/detoxication enzymes, particularly the glutathione S-transferases (GSH S-t).
Specific aims of this application concern the rapid decrease in liver cytosol GSH S-t which I have recently observed in fasted animals given the model hepatotoxin 1,1-dichloroethylene (1,1-DCE). Time-course studies with I4C-1,1-DCE will determine if the decrease in GSH S-t activities precedes (1) decreased biliary excretion of detoxified GSH conjugates of the toxin, and 2) injurious covalent binding of reactive intermediates of the toxin to cell constituents. GSH S-t isozyme will be separated, and examined for changes in apparent Vmax and Km, and for covalent binding of 1,1-DCE metabolites. 14 C-lysine will be given to determine if 1,1-DCE induces rapid synthesis of GSH S-t. Possible effects of 1,1-DCE on GSH in microsomes and mitochondria will be evaluated. In addition, I will determine if acetaminophen also rapidly decreases liver GSH S-t activities. This study should clarify the selectivity mechanism and consequences of toxin-induced rapid changes in GSH S-t.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Unknown (R23)
Project #
5R23ES003368-02
Application #
3447642
Study Section
Toxicology Study Section (TOX)
Project Start
1984-04-01
Project End
1987-03-31
Budget Start
1985-04-01
Budget End
1986-03-31
Support Year
2
Fiscal Year
1985
Total Cost
Indirect Cost

  Institution

Name
University of Texas Medical Br Galveston
Department
Type
Schools of Medicine
DUNS #
041367053
City
Galveston
State
TX
Country
United States
Zip Code
77555

  Publications

Moslen, M T; Kanz, M F (1993) Biliary excretion of marker solutes by rats with 1,1-dichloroethylene-induced bile canalicular injury. Toxicol Appl Pharmacol 122:117-30
Kanz, M F; Whitehead, R F; Ferguson, A E et al. (1992) Biliary function studies during multiple time periods in freely moving rats. A useful system and set of marker solutes. J Pharmacol Toxicol Methods 27:7-15
Moslen, M T; Dunsford, H A; Karnasuta, C et al. (1989) Histochemical and immunocytochemical evidence of early, selective bile canaliculi injury after 1,1-dichloroethylene in rats. Am J Pathol 134:1099-112
Moslen, M T; Whitehead, R F; Ferguson, A E et al. (1989) 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 248:157-63
Moslen, M T; Harper, B L; Roy, D (1988) Effects of a cysteine precursor, L-2-oxothiazolidine-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
Moslen, M T; Legator, M S (1988) Advantages of a combined testing protocol (CTP) with multiple endpoints: the reverse tier approach. Mutat Res 205:91-7
Moslen, M T; Kanz, M F; Ferguson, A E (1988) A stable colorimetric assay to measure toxin elevation of inorganic phosphate in bile. Anal Biochem 168:405-10
Kanz, M F; Whitehead, R F; Ferguson, A E et al. (1988) Potentiation of 1,1-dichloroethylene hepatotoxicity: comparative effects of hyperthyroidism and fasting. Toxicol Appl Pharmacol 95:93-103
Chieco, P; Normanni, P; Moslen, M T (1988) Localization of high benzaldehyde dehydrogenase activity in rat upper gastrointestinal tract mucosa: a quantitative histochemical study. J Histochem Cytochem 36:245-52
Au, W W; Ward Jr, J B; Ramanujam, V M et al. (1988) Genotoxic effects of a sub-acute low-level inhalation exposure to a mixture of carcinogenic chemicals. Mutat Res 203:103-15

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