Role of aldehyde dehydrogenase in the protection of hematopoietic progenitor cells from 4-hydroperoxycyclophosphamide by interleukin 1 beta and tumor necrosis factor.
Preincubation of human bone marrow cells with interleukin 1 beta (IL-1) and tumor necrosis factor alpha (TNF-alpha) for 20 h can protect early progenitor cells from 4-hydroperoxycyclophosphamide (4-HC) toxicity. In this report, we have studied the mechanism for such protection. We examined the effect of the length of incubation time and found that preincubation for at least 20 h with IL-1 and TNF-alpha is needed for significant protection. The addition of 2 micrograms/ml cycloheximide, a protein synthesis inhibitor, during the 20-h preincubation completely abolished the protection observed for all colony-forming cells. In order to study the role of aldehyde dehydrogenase (ALDH), an enzyme which inactivates 4-HC, we used diethylaminobenzaldehyde, an inhibitor of ALDH. Diethylaminobenzaldehyde was added during the last 10 min of the 20-h preincubation with IL-1 and TNF-alpha. Diethylaminobenzaldehyde prevented the protection of colony-forming cells from 4-HC. Finally, using the same protection assay system, we showed that a 20-h preincubation with IL-1 and TNF-alpha can also protect early progenitor cells from phenylketophosphamide, an analogue of 4-HC which is resistant to inactivation by ALDH. From these studies, we conclude that preincubation with IL-1 and TNF-alpha for at lest 20 h is required for the protection of early progenitor cells from 4-HC. During that time period, protein synthesis, specifically aldehyde dehydrogenase synthesis, is critical for the protection from 4-HC. Preincubation with IL-1 and TNF-alpha also protects early progenitors from phenylketophosphamide. Because phenylketophosphamide cannot be metabolized by ALDH, the reason for this protection must be due to other, as yet unidentified, mechanisms.
Moreb
J
J
Department of Medicine, University of Florida, Gainesville 32610.
Zucali
J R
JR
Zhang
Y
Y
Colvin
M O
MO
Gross
M A
MA
D000328:Adult; D000444:Aldehyde Dehydrogenase / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001547:Benzaldehydes / Q000494:pharmacology; D001854:Bone Marrow Cells; D002470:Cell Survival / Q000187:drug effects*; D003520:Cyclophosphamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D007700:Kinetics; D011994:Recombinant Proteins / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D000970:Antineoplastic Agents; D001547:Benzaldehydes; D007375:Interleukin-1; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D003520:Cyclophosphamide; D000444:Aldehyde Dehydrogenase; C011272:perfosfamide