title: Preclinical toxicology studies with acyclovir: genetic toxicity tests.
abstract: Acyclovir (ACV), an antiviral drug active in the treatment of oral and genital Herpes infections, has been evaluated for mutagenic and carcinogenic potential in a battery of in vitro and in vivo short-term assays. Negative results were obtained in the following in vitro tests: Ames Salmonella, plate incorporation and preincubation modification assays; E. coli polA+/polA- DNA repair; yeast (S. cerevisiae D4) gene conversion; Chinese hamster ovary cells (HGPRT, APRT loci and ouabain-resistance marker); L5178Y mouse lymphoma cells (HGPRT locus and ouabain-resistance marker); and C3H/10T1/2 mouse fibroblast neoplastic transformation assay. All except the last assay were performed in the presence and absence of an exogenous metabolic activation system. ACV was positive at high concentrations X exposure times in the absence of exogenous metabolic activation in the following in vitro systems and at the indicated concentrations: BALB/c-3T3 neoplastic transformation (50 micrograms/mL, 72 h exposure); human lymphocyte cytogenetics (250-500 micrograms/mL, 48 h exposure); and L5178Y mouse lymphoma cells (TK locus, 400-2400 micrograms/mL, 4 h exposure; predominantly small colony mutants of chromosomal origin produced). No effects were seen in vivo (mouse dominant lethal assay; rat and Chinese hamster bone marrow cytogenetics) at up to maximum tolerated doses (MTD). An unusual clastogenic effect was seen in Chinese hamsters at 5 times the MTD. Overall, positive effects were seen only at either high concentrations (greater than or equal to 250 micrograms/mL in vitro or plasma levels) or prolonged exposure (72 hr in the BALB/c-3T3 neoplastic transformation assay). These studies support the view that ACV is a chromosomal mutagen, i.e., one which causes multi-locus damage but not single gene effects. The significance of these results for the genetic risk of ACV to man is discussed.
mesh_terms: D000212:Acyclovir / Q000633:toxicity*; D000818:Animals; D001419:Bacteria / Q000187:drug effects; D002471:Cell Transformation, Neoplastic; D002869:Chromosome Aberrations; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D006561:Herpes Simplex / Q000188:drug therapy; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009152:Mutagenicity Tests; D009153:Mutagens; D051381:Rats; D011919:Rats, Inbred Strains; D012306:Risk; D013937:Thymidine Kinase / Q000235:genetics
chemical_list: D009153:Mutagens; D007041:Hypoxanthine Phosphoribosyltransferase; D013937:Thymidine Kinase; D000212:Acyclovir