Abstract

The objective of this proposal is to eucidate the mechanism by which certain potential myelotoxins cause bone marrow damage. We will use as the prototype bone marrow injury induced by chloramphenicol (CAP). Two types of bone marrow toxicity from CAP will be further investigated: 1. Reversible bone marrow suppression. Further studies here will include: 1. detailed investigation of the metabolic effects of CAP on bone marrow mitochondria. b. A study of CAP-marrow cell interaction using in vitro marrow culture techniques the mechanism of the protective effect of colony stimulating factor on CFU-C and the possible protection by other modulators of granulopoiesis from the CAP effect will be explored. 2. CAP-induced Aplastic Anemia. Two possible pathogenetic mechanisms will be considered and pursued. a. A biochemical predisposition - the role of the P-NO2 group of CAP will be explored. The possibililty that bone marrow aplasia results from irreversible binding of CAP to mitochondrial ribosomes will be tested. Comparative studies with marrow obtained from susceptible subjects will be carried out. b. Immune Mechanisms - The possible role of humoral and cellular immune mechanism in marrow injury from CAP will also be investigated.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis, Diabetes, Digestive and Kidney Diseases (NIADDK)
Type
Research Project (R01)
Project #
5R01AM026218-07
Application #
3151603
Study Section
Hematology Subcommittee 2 (HEM)
Project Start
1984-09-30
Project End
1987-08-31
Budget Start
1985-09-01
Budget End
1986-08-31
Support Year
7
Fiscal Year
1985
Total Cost
Indirect Cost

  Institution

Name
University of Miami School of Medicine
Department
Type
Schools of Medicine
DUNS #
City
Miami
State
FL
Country
United States
Zip Code
33101

  Publications

Isildar, M; Abou-Khalil, W H; Jimenez, J J et al. (1988) Aerobic nitroreduction of dehydrochloramphenicol by bone marrow. Toxicol Appl Pharmacol 94:305-10
Yunis, A A (1988) Chloramphenicol: relation of structure to activity and toxicity. Annu Rev Pharmacol Toxicol 28:83-100
Isildar, M; Jimenez, J J; Arimura, G K et al. (1988) DNA damage in intact cells induced by bacterial metabolites of chloramphenicol. Am J Hematol 28:40-6
Abou-Khalil, W H; Yunis, A A; Abou-Khalil, S (1988) Stability of chloramphenicol metabolites in human blood and liver as determined by high-performance liquid chromatography. Pharmacology 36:272-8
Abou-Khalil, S; Abou-Khalil, W H; Masoud, A N et al. (1987) High-performance liquid chromatographic determination of chloramphenicol and four analogues using reductive and oxidative electrochemical and ultraviolet detection. J Chromatogr 417:111-9
Jimenez, J J; Arimura, G K; Abou-Khalil, W H et al. (1987) Chloramphenicol-induced bone marrow injury: possible role of bacterial metabolites of chloramphenicol. Blood 70:1180-5
Abou-Khalil, S; Abou-Khalil, W H; Whitney, P L et al. (1987) Importance of the mitochondrial amino acid pool in the sensitivity of erythroid cells to chloramphenicol: role of glycine and serine. Pharmacology 35:308-16
Yunis, A A; Arimura, G K; Isildar, M (1987) DNA damage induced by chloramphenicol and its nitroso derivative: damage in intact cells. Am J Hematol 24:77-84
Abou-Khalil, S; Abou-Khalil, W H; Yunis, A A (1986) Mechanism of interaction of ticlopidine and its analogues with the energy-conserving mechanism in mitochondria. Biochem Pharmacol 35:1855-9
Abou-Khalil, S; Abou-Khalil, W H; Yunis, A A (1986) Swelling of mitochondria by the platelet antiaggregating agent ticlopidine. Biochem Pharmacol 35:1849-53

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