Evaluation of the mutagenic and genotoxic activities of anti-hepatitis B analogs of beta-L-adenosine by the Ames test and the Comet assay.
beta-L-2'-deoxyadenosine (beta-L-dA), beta-L-2',3'-dideoxyadenosine (beta-L-ddA) and its two bis (S-acyl-2-thioethyl; SATE) phosphotriester derivatives, beta-L-2',3'-dideoxyadenosine-5'-monophosphate-bis(MeSATE) and beta-L-2',3'-dideoxyadenosine-5'-monophosphate-bis(tButylSATE) have been previously shown to exhibit potent and selective anti-hepatitis B activity in vitro. None of the four compounds was mutagenic up to 100 microg in the Ames test (microtechnique) using Salmonella typhimurium strains TA 97a, TA 98, TA 100 and TA 102, with and without metabolic activation. In addition, the genotoxicity of beta-LdA and the three other compounds was evaluated in human lymphocytes using the Comet assay, at doses up to 5 microg with or without the addition of a microsomal S9 fraction. None of the four compounds induced DNA strand breakage with and without metabolic activation. In summary, the data clearly demonstrate that the purine nucleoside beta-L-dA, beta-L-ddA and the two prodrugs, beta-L-ddAMP-bis(MeSATE) and beta-L-ddAMP-bis(tButylSATE) are not mutagenic in the Ames test and do not induce DNA damage in human lymphocytes, as assessed by the Comet assay.
Placidi
L
L
Department of Pharmacology, University of Alabama at Birmingham, 1670 University Boulevard, Volker Hall G019, Birmingham, AL 35294, USA.
De Meo
M
M
Gosselin
G
G
Imbach
J L
JL
Bryant
M L
ML
Dumenil
G
G
Sommadossi
J P
JP
D000998:Antiviral Agents / Q000633:toxicity; D020552:Comet Assay / Q000379:methods; D003839:Deoxyadenosines / Q000633:toxicity*; D016048:Dideoxyadenosine / Q000633:toxicity; D006509:Hepatitis B / Q000188:drug therapy; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects; D009152:Mutagenicity Tests; D009153:Mutagens / Q000633:toxicity*; D012486:Salmonella typhimurium / Q000187:drug effects* / Q000235:genetics
D000998:Antiviral Agents; D003839:Deoxyadenosines; D009153:Mutagens; D016048:Dideoxyadenosine; C058118:2'-deoxyadenosine