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Biochem Pharmacol. 1993 Apr 22;45(8):1571-6.

Inhibition of mammalian DNA polymerase-associated 3' to 5' exonuclease activity by 5'-monophosphates of 3'-azido-3'-deoxythymidine and 3'-amino-3'-deoxythymidine.

Author information

1
Department of Pharmacology, University of Alabama, Birmingham 35294.

Abstract

3'-Azido-3'-deoxythymidine 5'-monophosphate (AZT-MP) has been hypothesized by us to possibly affect 3'-azido-3'-deoxythymidine (AZT) excision from host cell DNA. In the present study, AZT-MP inhibited 3' to 5' exonuclease activity of calf thymus DNA polymerase delta at pharmacological relevant intracellular concentrations. Other 2',3'-dideoxynucleoside-5'-monophosphate (ddN-MP) analogs, including 3'-amino-3'-deoxythymidine-5'-monophosphate (AMT-MP), were also assayed as potential inhibitors of 3' to 5' exonuclease activity. The monophosphate derivative of 3'-amino-3'-deoxythymidine (AMT), an in vivo toxic catabolite of AZT, was the most potent of the ddN-MP analogs tested, inhibiting this activity by more than 50% at 100 microM. These results suggest that inhibition of 3' to 5' exonuclease activities by AZT-MP and AMT-MP may increase steady-state levels of AZT in host DNA, accounting in part for the cell toxicity associated with this drug. The present study also raises the question of whether AZT-MP inhibition of this activity may lead to potential mutagenic effects due to inhibition of 3' to 5' exonuclease-mediated proofreading functions involved in DNA replication.

PMID:
8387298
DOI:
10.1016/0006-2952(93)90296-9
[Indexed for MEDLINE]

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