[Metallothionein inhibited DOX-induced cardiac apoptosis in mice].
OBJECTIVE
To investigate the inhibitive effect of metallothionein (MT) on DOX-induced cardiac apoptosis and the involved possible mechanisms.


METHODS
Adult male C57BL mice (6-8 weeks old) were randomly assigned into four groups and given the following treatment: Zinc (ZnSO4, 300 micromol/kg, s.c., once a day for 2 days) or equal volume of physiological saline prior to a single dose of DOX (15 mg/kg, i.p.) or equal volume of saline. Animals were sacrificed on the 4th day after DOX administration and hearts were excised for further studies, including cadmium-hemoglobin affinity assay for MT concentration, ELISA detection of DNA fragmentation and Western blot analysis of Bax and Bcl-2.


RESULTS
DOX administration decreased heart weight by 10% and caused remarkable cardiac apoptosis as demonstrated by DNA fragments, while Zinc pretreatment significantly increased the MT levels and therefore inhibited the cardiac apoptotic effect of DOX. Elevated expression of Bax was obviously observed after DOX treatment, while this elevation was prevented by MT induction by Zinc. On the contrary, Bcl-2 protein level was not altered significantly among each group.


CONCLUSIONS
These findings suggest that metallothionein induced by Zinc exhibits protective effects on the cardiac apoptosis of DOX, which might be mediated through the prevention of Bax protein up-regulation by DOX and associated elevation of Bax/Bcl-2 ratio.
Shuai
Yi
Y
Beijing Institute of Pharmacology and Toxicology, National Beijing Center for Drug Safety Evaluation and Research, Beijing 100850, China.
Guo
Jun
J
Peng
Shuang-qing
SQ
Zhang
Li-shi
LS
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001835:Body Weight / Q000187:drug effects; D004317:Doxorubicin / Q000009:adverse effects*; D005786:Gene Expression Regulation / Q000187:drug effects; D006321:Heart / Q000033:anatomy & histology / Q000187:drug effects* / Q000502:physiology; D008297:Male; D008668:Metallothionein / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000166:cytology* / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D015032:Zinc / Q000494:pharmacology; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; C052617:Bcl2 protein, mouse; D004317:Doxorubicin; D008668:Metallothionein; D015032:Zinc