Genetic toxicity studies of 1,2,3,4-tetrahydro-9-acridinamine (tacrine).
The mutagenicity and clastogenicity of 1,2,3,4-tetrahydro-9-acridinamine (tacrine) were studied in vitro using the Salmonella mutagenicity test and the induction of chromosome aberrations in Chinese hamster ovary (CHO) cells, and in the mouse bone marrow micronucleus test in vivo. This chemical is currently being used to treat dementia arising from Alzheimer's Disease. Tacrine was mutagenic in Salmonella but did not produce chromosome damage in CHO cells or in mouse bone marrow cells. A clear mutagenic response was seen in strain TA97 with rat and hamster liver S9; inconsistent results were obtained without S9. No mutagenicity was seen in strains TA98 and TA100 without S9, and inconsistent results were seen with S9. There was no induction of chromosome aberrations in cultured CHO cells with or without S9. Oral administration to mice of tacrine daily for three days did not result in the induction of micronuclei in their bone marrow cells. The mutagenic response in Salmonella, and the structure of the molecule, suggests that tacrine may be carcinogenic when tested in rodents. This information must be considered when preparing benefit-risk determinations for medical uses of this substance.
Zeiger
E
E
Environmental Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA. zeiger@niehs.nih.gov
Erexson
G
G
Mortelmans
K
K
Thilagar
A
A
D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects; D016466:CHO Cells / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000633:toxicity*; D002869:Chromosome Aberrations; D006224:Cricetinae; D005260:Female; D051379:Mice; D048629:Micronuclei, Chromosome-Defective / Q000187:drug effects*; D009152:Mutagenicity Tests; D051381:Rats; D011916:Rats, Inbred F344; D012486:Salmonella typhimurium / Q000187:drug effects* / Q000235:genetics; D013619:Tacrine / Q000737:chemistry / Q000633:toxicity*
D002800:Cholinesterase Inhibitors; D013619:Tacrine