Metallothionein acts as a cytoprotectant against doxorubicin toxicity.
The protective role of metallothionein (MT) against the myocardiotoxicity and hepatotoxicity of doxorubicin (Dox) was investigated in mice. Dox-induced elevations of plasma creatine kinase activity, a measure of myocardiac damage, and plasma glutamate pyruvate transaminase activity, reflecting hepatic damage, were prevented by pretreatment with an MT inducer. Pretreatment with zinc induced MT in the liver and heart, thereby reducing Dox toxicity in these two organs. Pretratment with n-hexane also induced MT and reduced Dox toxicity, but only in the liver. In primary hepatocyte cultures, the leakage of lactate dehydrogenase induced by Dox was prevented by zinc pretreatment. These results suggest that MT induction prevents Dox toxicity in vivo and in vitro. Furthermore, we determined that MT-null mice were more sensitive to the myocardiotoxic and hepatotoxic effects of Dox. These findings indicate that both basal and induced MT protect against Dox toxicity.
Kimura
T
T
Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.
Fujita
I
I
Itoh
N
N
Muto
N
N
Nakanishi
T
T
Takahashi
K
K
Azuma
J
J
Tanaka
K
K
D000410:Alanine Transaminase / Q000097:blood*; D000818:Animals; D002478:Cells, Cultured; D003402:Creatine Kinase / Q000097:blood*; D019610:Cytoprotection / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000633:toxicity*; D004347:Drug Interactions; D006321:Heart / Q000187:drug effects; D007770:L-Lactate Dehydrogenase / Q000032:analysis; D008099:Liver / Q000187:drug effects; D008297:Male; D008668:Metallothionein / Q000494:pharmacology*; D051379:Mice; D008813:Mice, Inbred ICR; D013997:Time Factors; D015032:Zinc / Q000494:pharmacology*
D004317:Doxorubicin; D008668:Metallothionein; D007770:L-Lactate Dehydrogenase; D000410:Alanine Transaminase; D003402:Creatine Kinase; D015032:Zinc