Involvement of caspase 3 mediated apoptosis in hematopoietic cytotoxicity of metabolites of ethylene glycol monomethyl ether.
The hematopoietic toxicity of ethylene glycol monomethyl ether (EGME) and its metabolites, methoxy acetaldehyde (MALD) and methoxyacetic acid (MAA), was analyzed using human bone marrow cells from a lymphoma patient without bone marrow involvement and a human leukemia cell line, HL60. After 24-hour incubation, the concentrations of 50 percent inhibition (IC50) of human hematopoietic progenitor cells with MALD or MAA were 3 mM and 3.9 mM, respectively, and EGME (10 mM or more) did not show any cytotoxicity. IC50 (after 48-hour exposure) of MALD and MAA on HL60 cells were 2.45 mM and 5.6 mM, respectively, suggesting that both hematopoietic progenitor cells and HL60 have a similar sensitivity. DNA ladder formation, a characteristics of apoptosis, was observed in MALD- or MAA-treated HL60 cells, but not in EGME-treated samples. Caspase-3 enzyme activity, the effector of the apoptotic process, was greatly enhanced with MALD treatment. The inhibitor of caspase-3 repressed cell death induced with MALD as well as MAA.
Takagi
Akira
A
Department of Medical Technology, Nagoya University School of Health Sciences, Daiko Minami 1-1-20, Higashi-ku, Nagoya 461-8673, Japan.
Yamada
Takayuki
T
Hayashi
Koji
K
Nakade
Yuusuke
Y
Kojima
Tetsuhito
T
Takamatsu
Junki
J
Shibata
Eiji
E
Ichihara
Gaku
G
Takeuchi
Yasuhiro
Y
Murate
Takashi
T
D000079:Acetaldehyde / Q000633:toxicity* / Q000031:analogs & derivatives; D000085:Acetates / Q000633:toxicity*; D017209:Apoptosis / Q000502:physiology*; D053148:Caspase 3; D020169:Caspases / Q000502:physiology*; D005026:Ethylene Glycols / Q000378:metabolism / Q000633:toxicity*; D018922:HL-60 Cells; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D066298:In Vitro Techniques; D007564:Japan; D008297:Male
D000085:Acetates; D005026:Ethylene Glycols; C049826:2-methoxyacetaldehyde; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; C005219:methyl cellosolve; C013598:methoxyacetic acid; D000079:Acetaldehyde