K. Sekihashi et al., A comparison of intraperitoneal and oral gavage administration in comet assay in mouse eight organs, MUT RES-GTE, 493(1-2), 2001, pp. 39-54
Citations number
31
Categorie Soggetti
Molecular Biology & Genetics
Journal title
MUTATION RESEARCH-GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS
One of the important advantages of the comet assay is its ability to detect
genotoxicity in many different organs. Since the exposure route of the tes
t compounds is likely to influence the genotoxicity detected in a given org
an, it is an important factor to consider when conducting the assay. In thi
s study, we compared the effects of numerous model compounds on eight organ
s when administered to mice by intraperitoneal (i.p.) injection and oral (p
.o.) gavage.
Groups of four mice were treated once i.p. or p.o. at the identical proport
ion of LD50 for each route, and the stomach, colon, liver, kidney, bladder,
lung, brain, and bone marrow were sampled 3, 8, and 24h after treatment. F
or 19 of the 20 tested mutagens with various modes of action, genotoxicity
in some organs varied with treatment route; only the genotoxicity of methyl
methane sulfonate was not affected. Treatment route, however, did not prod
uce a qualitative difference in the genotoxicity of promutagens at the site
s of conversion to ultimate mutagens, with aromatic hydrocarbons as the exc
eption. When chemicals with positive responses in at least one organ were c
onsidered to be comet assay-positive, the administration route made no diff
erence. Since azo reduction is mediated by azo reductase synthesized in the
gastrointestinal wall and by gut microflora and i,p.-administered azo dyes
bypass their activation site (colon), the administration route is expected
to make a difference in their in vivo genotoxicity. Direct-acting mutagens
are expected to affect the mucosa of the gastrointestinal tract when given
p.o. For those mutagens, however, the administration route did not make a
qualitative difference in gastrointestinal tract genotoxicity. Moreover, al
though the gastrointestinal mucosa is the first site to be exposed to p.o.
administered agents, the peak times in the stomach tended to be the same as
in most other organs. Based on those results, we concluded that the genoto
xicity at high exposures was due to a systemic effect, and that both routes
are acceptable for the comet assay when the liver and gastrointestinal org
ans are sampled, so long as appropriate dose levels for systemic exposure a
re selected for each route. (C) 2001 Elsevier Science B.V. All rights reser
ved.