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In Vivo Administration of MKT-077 Causes Partial yet Reversible Impairment of Mitochondrial Function

Dana-Farber Cancer Institute, Division of Cellular and Molecular Biology, Harvard Medical School, Boston, Massachusetts 02115 [E. L. W., K. K., Y. L., L. B. C.], and Tufts University, Department of Biology, Medford, Massachusetts 02155 [J. M-N.]

The effects of in vivo administration of a pharmacologically toxic dose of the lipophilic cationic compound, MKT-077, were investigated in selected vital organs of the rat. MKT-077 (15 mg/kg body weight), administered by bolus i.v. injection every day for 5 days, did not detectably influence rat heart and kidney mitochondrial respiration. Although the same dosage of MKT-077 significantly decreased respiratory rates in rat liver mitochondria relative to untreated controls, complete recovery was evident within 3 days following drug withdrawal. Whereas the mitochondrial DNA of rat kidney and liver appeared to be unaffected by MKT-077 treatment, levels of heart mtDNA were noticeably less than control levels in the immediate interval following drug administration. However, this latter effect was partially reversed as early as 10 days following treatment and completely reversed within a 30-day posttreatment period. These results strongly suggest that a pharmacologically toxic dose of MKT-077 minimally affects the overall functional integrity of mitochondria in such critical, although highly vulnerable, tissues as the heart, liver, and kidney.

¹ To whom requests for reprints should be addressed, at Dana-Farber Cancer Institute, Division of Cellular and Molecular Biology, Harvard Medical School, 44 Binney Street, Boston, MA 02115.

Received 6/ 7/95. Accepted 11/17/95.

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