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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.
Insights
Acyclovir (ACV) showed mutagenic potential in vitro at high concentrations, primarily causing chromosomal damage, but not in vivo. Further research is needed to assess its genetic risk to humans.
Area of Science:
- Toxicology and Pharmacology
- Genetics and Mutagenesis
Background:
- Acyclovir (ACV) is a key antiviral medication for herpes infections.
- Evaluating the mutagenic and carcinogenic potential of ACV is crucial for patient safety.
Purpose of the Study:
- To assess the mutagenic and carcinogenic potential of Acyclovir (ACV).
- To evaluate ACV's effects across a range of in vitro and in vivo assays.
Main Methods:
- Conducted a battery of in vitro assays including Ames Salmonella, E. coli DNA repair, yeast gene conversion, and mammalian cell gene mutation/cytogenetics.
- Performed in vivo assays such as the mouse dominant lethal assay and rodent bone marrow cytogenetics.
- Utilized metabolic activation systems in select in vitro tests.
Main Results:
- Negative results were observed in most in vitro and all in vivo assays at maximum tolerated doses.
- Positive mutagenic effects (chromosomal damage) were noted in vitro at high ACV concentrations or prolonged exposure.
- An unusual clastogenic effect was observed in Chinese hamsters at 5 times the maximum tolerated dose.
Conclusions:
- Acyclovir (ACV) demonstrates potential as a chromosomal mutagen in vitro under specific high-dose or long-exposure conditions.
- The in vivo data and lack of single-gene mutations suggest limited genotoxic risk at therapeutic levels.
- Further investigation into the human genetic risk associated with ACV is warranted.