Article

Mutagenicity of aristolochic acid in the lambda/lacZ transgenic mouse (Muta™Mouse)

Division of Genetics and Mutagenesis, National Institute of Health Sciences, 1-18-1, Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan; Faculty of Pharmaceutical Sciences, Nagoya City University, 3-1, Tanabedouri, Mizuho-ku, Nagoya 467-8603, Japan; Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033 Japan
Mutation Research/Genetic Toxicology and Environmental Mutagenesis DOI:10.1016/S1383-5718(01)00350-3 pp.63-72

ABSTRACT Aristolochic acid (AA) is found in a plant that causes urothelial carcinomas in patients with Chinese herb nephropathy (CHN). To evaluate the in vivo mutagenicity of AA, we analysed the mutant frequency (MF) in the lacZ and cII gene of 10 organs of the lambda/lacZ transgenic mouse (Muta™Mouse) after intragastric treatment with AA (15 mg/kg per week × 4). Simultaneously, the clastogenicity of AA was evaluated by the peripheral blood micronucleus assay. The nature of the mutations induced by AA was revealed by the sequence analysis of the cII gene, which is also a phenotypically selectable marker in the lambda transgene. MFs in the target organs-forestomach, kidney, and bladder of AA-treated mice were significantly higher than those of control mice (forestomach 33- and 15-fold; kidney 10- and 9-fold; bladder 16- and 31-fold, for the lacZ and cII, respectively). The MFs in non-target organs, except the colon, showed only slight increases. Sequence analysis of cII mutants in target organs revealed that AA induced mainly A:T to T:A transversions whereas G:C to A:T transitions at CpG sites predominated among spontaneous mutations. These results suggested that AA, which is activated by cytochrome P450 and peroxidase to form cyclic nitrenium ions that bind to deoxyadenine, caused the A to T transversions in the target organs of mice.

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Keywords

10 organs
 
AA induced
 
AA-treated mice
 
causes urothelial carcinomas
 
Chinese herb nephropathy
 
cII gene
 
CpG sites predominated
 
cytochrome P450
 
form cyclic nitrenium ions
 
intragastric treatment
 
lambda/lacZ transgenic mouse
 
mutations induced
 
non-target organs
 
peripheral blood micronucleus assay
 
phenotypically selectable marker
 
Sequence analysis
 
slight increases
 
T transversions
 
target organs-forestomach
 
vivo mutagenicity