Inhibition of mammalian DNA polymerase-associated 3' to 5' exonuclease activity by 5'-monophosphates of 3'-azido-3'-deoxythymidine and 3'-amino-3'-deoxythymidine.
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.
Bridges
E G
EG
Department of Pharmacology, University of Alabama, Birmingham 35294.
Faraj
A
A
Sommadossi
J P
JP
D000818:Animals; D002417:Cattle; D004261:DNA Replication; D054306:Dideoxynucleotides; D005092:Exonucleases / Q000037:antagonists & inhibitors*; D019384:Nucleic Acid Synthesis Inhibitors; D013938:Thymidine Monophosphate / Q000031:analogs & derivatives* / Q000494:pharmacology; D013942:Thymine Nucleotides / Q000494:pharmacology*; D013950:Thymus Gland / Q000201:enzymology; D015215:Zidovudine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity
D054306:Dideoxynucleotides; D019384:Nucleic Acid Synthesis Inhibitors; D013942:Thymine Nucleotides; C057287:3'-azido-3'-deoxythymidine 5'phosphate; D013938:Thymidine Monophosphate; C080992:3'-amino-3'-deoxythymidine 5'-monophosphate; D015215:Zidovudine; D005092:Exonucleases