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Originally published In Press as doi:10.1074/jbc.M101156200 on April 27, 2001

J. Biol. Chem., Vol. 276, Issue 26, 23832-23837, June 29, 2001
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Insights into the Molecular Mechanism of Mitochondrial Toxicity by AIDS Drugs*

Joy Y. FengDagger §, Allison A. Johnson||, Kenneth A. Johnson||, and Karen S. AndersonDagger **

From the Dagger  Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06510 and || Institute for Cellular and Molecular Biology, University of Texas, Austin, Texas 78712

Several of the nucleoside analogs used in the treatment of AIDS exhibit a delayed clinical toxicity limiting their usefulness. The toxicity of nucleoside analogs may be related to their effects on the human mitochondrial DNA polymerase (Pol gamma ), the polymerase responsible for mitochondrial DNA replication. Among the AIDS drugs approved by the FDA for clinical use, two are modified cytosine analogs, Zalcitabine (2',3'-dideoxycytidine (ddC)) and Lamivudine (beta -D-(+)-2',3'-dideoxy-3'-thiacytidine ((-)3TC])). (-)3TC is the only analog containing an unnatural L(-) nucleoside configuration and is well tolerated by patients even after long term administration. In cell culture (-)3TC is less toxic than its D(+) isomer, (+)3TC, containing the natural nucleoside configuration, and both are considerably less toxic than ddC. We have investigated the mechanistic basis for the differential toxicity of these three cytosine analogs by comparing the effects of dideoxy-CTP), (+)3TC-triphosphate (TP), and (-)3TC-TP on the polymerase and exonuclease activities of recombinant human Pol gamma . This analysis reveals that Pol gamma  incorporates (-)3TC-triphosphate 16-fold less efficiently than the corresponding (+)isomer and 1140-fold less efficiently than dideoxy-CTP, showing a good correlation between incorporation rate and toxicity. The rates of excision of the incorporated analogs from the chain-terminated 3'-end of the DNA primer by the 3'-5'-exonuclease activity of Pol gamma  were similar (0.01 s-1) for both 3TC analogs. In marked contrast, the rate of exonuclease removal of a ddC chain-terminated DNA occurs at least 2 orders of magnitude slower, suggesting that the failure of the exonuclease to remove ddC may play a major role in its greater toxicity. This study demonstrates that direct analysis of the mitochondrial DNA polymerase structure/function relationships may provide valuable insights leading to the design of less toxic inhibitors.

* This work was supported by National Institutes of Health Grants GM44613 (to K. A. J.) and GM49551 (to K. S. A.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ Current address: Triangle Pharmaceuticals, 4 University Place, 4611 University Dr., Durham, NC 27707.

∥ These authors contributed equally to this work.

** To whom correspondence should be addressed: Dept. of Pharmacology, Yale University School of Medicine, 333 Cedar St., New Haven, CT 06510. Tel.: 203-785-4526; Fax: 203-785-7670; E-mail: karen. anderson{at}yale.edu.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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