Comparative in-vivo genotoxicity of antiviral nucleoside analogues; penciclovir, acyclovir, ganciclovir and the xanthine analogue, caffeine, in the mouse bone marrow micronucleus assay.
Three purine nucleoside analogues, penciclovir (PCV), acyclovir (ACV) and ganciclovir (GCV), were assessed for in-vivo genotoxicity in the mouse bone marrow micronucleus assay, together with the xanthine (purine) analogue, caffeine (CAF). All these compounds exhibit anti-viral properties and the first three are marketed anti-viral drugs. All have been shown to be genotoxic in separate in-vitro and in-vivo studies. Because of their widespread use, we considered it important to directly compare their relative in-vivo genotoxic potencies as an aid to assessing their relative genotoxic risk to humans. Accordingly, two-dose (0 and 24 h)/single sample mouse micronucleus assays were performed on all four compounds. PCV and ACV appeared to give essentially arithmetic increases in induction of micronucleated polychromatic erythrocytes (MNPCE) with arithmetic increases in dose with apparent thresholds at approx. 1078 mumols/kg per day and 316 mumols/kg per day, respectively. The dose-response curve for GCV appeared more exponential, without a threshold, but with a no-effect dose of around 150 mumols/kg per day. With CAF, systemic toxicity allowed the assessment of only very weak effects, such that our estimate of a no-effect dose of 388 mumols/kg per day is subject to large errors. Taking into account magnitude of response, slope of dose-response curve and no-effect doses, the order of potency was GCV > ACV > (CAF?) > PCV. The relevance of these findings in terms of risk is uncertain.
Haynes
P
P
SmithKline Beecham Pharmaceuticals, Welwyn, Herts, UK.
Lambert
T R
TR
Mitchell
I D
ID
D000212:Acyclovir / Q000031:analogs & derivatives* / Q000633:toxicity*; D000818:Animals; D000998:Antiviral Agents / Q000633:toxicity*; D001853:Bone Marrow / Q000187:drug effects*; D001854:Bone Marrow Cells; D002110:Caffeine / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D015774:Ganciclovir / Q000633:toxicity*; D006147:Guanine; D008297:Male; D051379:Mice; D015162:Micronucleus Tests
D000998:Antiviral Agents; C053539:penciclovir; D002110:Caffeine; D006147:Guanine; D015774:Ganciclovir; D000212:Acyclovir