Metallothionein Acts as a Cytoprotectant against Doxorubicin Toxicity1
- Tomoki Kimura1,
- Isami Fujita1,
- Norio Itoh1,
- Norio Muto2,
- Tsuyoshi Nakanishi1,
- Kyoko Takahashi1,
- Junichi Azuma1 and
- Keiichi Tanaka1
- 1Graduate School of Pharmaceutical Sciences, Osaka University, Osaka (T.K., I.F., N.I., T.N., Ky.T., J.A., Ke.T.); and 2School of Applied Biosciences, Hiroshima Prefectural University, Hiroshima, Japan (N.M.)
Abstract
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.
Footnotes
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Send reprint requests to: Keiichi Tanaka, Ph.D., Graduate School of Pharmaceutical Sciences, Osaka University, 1–6 Yamada-oka, Suita, Osaka, 565-0871 Japan. E-mail: k-tanaka{at}phs.osaka-u.ac.jp
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↵1 This work was partly supported by a grant from the Houansha Foundation, Osaka, Japan.
- Abbreviations:
- Dox
- doxorubicin
- MT
- metallothionein
- HX
- n-hexane
- CK
- creatine kinase
- GPT
- glutamate pyruvate transaminase
- LDH
- lactate dehydrogenase
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- Received May 20, 1999.
- Accepted September 24, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
