The rat gut micronucleus assay: a good choice for alternative in vivo genetic toxicology testing strategies.
The in vivo bone marrow (BM) micronucleus assay is one of the three tests in the standard test battery to assess the genotoxic potential of a pharmaceutical candidate. In some cases, depending on results of in vitro studies, the route of administration or the degree of systemic exposure, in vivo assessment of genotoxicity in the BM alone may not be sufficient. Based on the potential for high gut exposures to orally administered compounds with low systemic exposures as well as the potential susceptibility of rapidly dividing cells of the intestinal tissues, we have developed a modified technique for evaluating micronuclei formation in both the duodenum and colon of rats based on earlier publications. Adult male Sprague Dawley rats were treated once daily for 2 days with either vehicle control or with the test articles acetyl salicylic acid (ASA), carbendazim (CAR), cyclophosphamide (CP), dimethylhydrazine (DMH), mitomycin C (MMC) or vinblastine sulfate (VIN). The duodenum, colon, and BM were harvested, processed, and analyzed for micronucleus induction. Results from these studies demonstrated differences in the susceptibility for different test compounds in the three tissues tested. When MMC and VIN were dosed by different routes at the same dose levels both compounds produced positive results in all three tissues by intraperitoneal injection but not oral administration. These studies suggest that overall the GI micronucleus assay might be a useful tool for clastogenic and aneugenic compounds that are expected to produce high sustained concentrations in the gastrointestinal tract with little systemic exposure.
Coffing
Stephanie
S
Pfizer Global Research and Development, Eastern Point Road, Groton, CT.
Engel
Maria
M
Dickinson
Donna
D
Thiffeault
Catherine
C
Spellman
Richard
R
Shutsky
Thomas
T
Schuler
Maik
M
D000818:Animals; D001241:Aspirin / Q000009:adverse effects / Q000494:pharmacology; D001562:Benzimidazoles / Q000009:adverse effects / Q000494:pharmacology; D002219:Carbamates / Q000009:adverse effects / Q000494:pharmacology; D003106:Colon / Q000187:drug effects*; D003520:Cyclophosphamide / Q000009:adverse effects / Q000494:pharmacology; D004249:DNA Damage / Q000187:drug effects; D004127:Dimethylhydrazines / Q000009:adverse effects / Q000494:pharmacology; D004386:Duodenum / Q000187:drug effects*; D008297:Male; D015162:Micronucleus Tests / Q000379:methods*; D016685:Mitomycin / Q000009:adverse effects / Q000494:pharmacology; D009152:Mutagenicity Tests / Q000379:methods; D009153:Mutagens / Q000009:adverse effects / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014747:Vinblastine / Q000009:adverse effects / Q000494:pharmacology
D001562:Benzimidazoles; D002219:Carbamates; D004127:Dimethylhydrazines; D009153:Mutagens; D016685:Mitomycin; D014747:Vinblastine; D003520:Cyclophosphamide; C006698:carbendazim; D001241:Aspirin