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© 1983 Oxford University Press

research-article

Preclinical Toxicology Studies with Acyclovir: Genetic Toxicity Tests

DONALD CLIVE*, NANCY T. TURNER, JOHN HOZIERA, A. GAIL BATSON and WALTER E. TUCKER, Jr.

Wellcome Research Laboratories 3030 Cornwallis Road, Research Triangle Park, NC 27709 AFlorida Institute of Technology Melbourne, FL 32901

Preclinical Toxicology Studies with Acyclovir: Genetic Toxicity Tests. Clive, D., Turner, N.T., Hozier, J., Batson, A.G. and Tucker, W.E., Jr. (1983). Fundam. Appl. Toxicol 3: 587–602. 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 vivoshort-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); L5178 Y mouse lymphoma cells (HGPRT locus and ouabain-resistance marker); and C3H/10T1/2mouse fibroblast neo-plastic 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 /µg/mL, 72 h exposure); human lymphocyte cytogenetics (250–500 µg/mL, 48 h exposure); and L5178Y mouse lymphoma cells (TK locus, 400–2400 µg/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 (≥250 µg/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.


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