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Inhibition of mammalian DNA polymerase-associated 3' to 5' exonuclease activity by 5'-monophosphates of 3'-azido-3'-deoxythymidine and 3'-amino-3'-deoxythymidine. 1993

E G Bridges, and A Faraj, and J P Sommadossi
Department of Pharmacology, University of Alabama, Birmingham 35294.

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.

UI MeSH Term Description Entries
D002417 Cattle Domesticated bovine animals of the genus Bos, usually kept on a farm or ranch and used for the production of meat or dairy products or for heavy labor. Beef Cow,Bos grunniens,Bos indicus,Bos indicus Cattle,Bos taurus,Cow,Cow, Domestic,Dairy Cow,Holstein Cow,Indicine Cattle,Taurine Cattle,Taurus Cattle,Yak,Zebu,Beef Cows,Bos indicus Cattles,Cattle, Bos indicus,Cattle, Indicine,Cattle, Taurine,Cattle, Taurus,Cattles, Bos indicus,Cattles, Indicine,Cattles, Taurine,Cattles, Taurus,Cow, Beef,Cow, Dairy,Cow, Holstein,Cows,Dairy Cows,Domestic Cow,Domestic Cows,Indicine Cattles,Taurine Cattles,Taurus Cattles,Yaks,Zebus
D004261 DNA Replication The process by which a DNA molecule is duplicated. Autonomous Replication,Replication, Autonomous,Autonomous Replications,DNA Replications,Replication, DNA,Replications, Autonomous,Replications, DNA
D005092 Exonucleases Enzymes that catalyze the release of mononucleotides by the hydrolysis of the terminal bond of deoxyribonucleotide or ribonucleotide chains. Exonuclease,3'-5'-Exonuclease,3'-5'-Exonucleases,5'-3'-Exonuclease,5'-3'-Exonucleases,3' 5' Exonuclease,3' 5' Exonucleases,5' 3' Exonuclease,5' 3' Exonucleases
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D013938 Thymidine Monophosphate 5-Thymidylic acid. A thymine nucleotide containing one phosphate group esterified to the deoxyribose moiety. DTMP,TMP,Thymidylic Acid,Deoxythymidylate,Thymidylic Acids,Acid, Thymidylic,Acids, Thymidylic,Monophosphate, Thymidine
D013942 Thymine Nucleotides Phosphate esters of THYMIDINE in N-glycosidic linkage with ribose or deoxyribose, as occurs in nucleic acids. (From Dorland, 28th ed, p1154) Thymidine Phosphates,Nucleotides, Thymine,Phosphates, Thymidine
D013950 Thymus Gland A single, unpaired primary lymphoid organ situated in the MEDIASTINUM, extending superiorly into the neck to the lower edge of the THYROID GLAND and inferiorly to the fourth costal cartilage. It is necessary for normal development of immunologic function early in life. By puberty, it begins to involute and much of the tissue is replaced by fat. Thymus,Gland, Thymus,Glands, Thymus,Thymus Glands
D015215 Zidovudine A dideoxynucleoside compound in which the 3'-hydroxy group on the sugar moiety has been replaced by an azido group. This modification prevents the formation of phosphodiester linkages which are needed for the completion of nucleic acid chains. The compound is a potent inhibitor of HIV replication, acting as a chain-terminator of viral DNA during reverse transcription. It improves immunologic function, partially reverses the HIV-induced neurological dysfunction, and improves certain other clinical abnormalities associated with AIDS. Its principal toxic effect is dose-dependent suppression of bone marrow, resulting in anemia and leukopenia. AZT (Antiviral),Azidothymidine,3'-Azido-2',3'-Dideoxythymidine,3'-Azido-3'-deoxythymidine,AZT Antiviral,AZT, Antiviral,BW A509U,BWA-509U,Retrovir,3' Azido 2',3' Dideoxythymidine,3' Azido 3' deoxythymidine,Antiviral AZT,BWA 509U,BWA509U
D054306 Dideoxynucleotides The phosphate esters of DIDEOXYNUCLEOSIDES. Dideoxynucleotide Triphosphates,ddNTPs,Triphosphates, Dideoxynucleotide
D019384 Nucleic Acid Synthesis Inhibitors Compounds that inhibit cell production of DNA or RNA. DNA Polymerase Inhibitor,DNA Synthesis Inhibitor,DNA Synthesis Inhibitors,Nucleic Acid Synthesis Inhibitor,RNA Synthesis Inhibitor,RNA Synthesis Inhibitors,DNA Polymerase Inhibitors,Inhibitors, DNA Synthesis,Inhibitors, Nucleic Acid Synthesis,Inhibitors, RNA Synthesis,Inhibitor, DNA Polymerase,Inhibitor, DNA Synthesis,Inhibitor, RNA Synthesis,Inhibitors, DNA Polymerase,Polymerase Inhibitor, DNA,Polymerase Inhibitors, DNA,Synthesis Inhibitor, DNA,Synthesis Inhibitor, RNA,Synthesis Inhibitors, DNA,Synthesis Inhibitors, RNA

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