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Antiviral nucleoside analogues have been developed toinhibit theenzymatic activities of the hepatitis B virus (HBV) polymerase, therebypreventing the replication and production of HBV. However, the usageof these analogues can be limited by drug toxicity because the 5′-triphosphatesof these nucleoside analogues (nucleotide analogues) are potentialsubstrates for human DNA polymerases to incorporate into host DNA.Although they are poor substrates for human replicative DNA polymerases,it remains to be established whether these nucleotide analogues aresubstrates for the recently discovered human X- and Y-family DNA polymerases.Using presteady state kinetic techniques, we have measured the substratespecificity values for human DNA polymerases β, λ, η,ι, κ, and Rev1 incorporating the active forms of the followinganti-HBV nucleoside analogues approved for clinical use: adefovir,tenofovir, lamivudine, telbivudine, and entecavir. Compared to theincorporation of a natural nucleotide, most of the nucleotide analogueswere incorporated less efficiently (2 to >122,000) by the six humanDNA polymerases. In addition, the potential for entecavir and telbivudine,two drugs which possess a 3′-hydroxyl, to become embedded intohuman DNA was examined by primer extension and DNA ligation assays.These results suggested that telbivudine functions as a chain terminator,while entecavir was efficiently extended by the six enzymes and wasa substrate for human DNA ligase I. Our findings suggested that incorporationof anti-HBV nucleotide analogues catalyzed by human X- and Y-familypolymerases may contribute to clinical toxicity. [ABSTRACT FROM AUTHOR]