Role of the intestinal microbiota in the activation of the promutagen 2,6-dinitrotoluene to mutagenic urine metabolites and comparison of GI enzyme activities in germ-free and conventionalized male Fischer 344 rats.
After male germ-free and conventionalized Fischer 344 rats were administered per os (p.o.) 75 mg/kg 2,6-DNT, intestinal nitroreductase, beta-glucuronidase, and azo reductase activities were lower in the cecum and large intestine of germ-free animals. However, there was no significant difference in the small intestinal nitroreductase and azo reductase compared to the conventionalized counterparts. This indicated a potential mucosal source for the enzymes. Urines from germ-free rats (1144 +/- 64 revertants/ml) were less mutagenic than those from conventionalized animals (1467 +/- 171 revertants/ml) in Salmonella typhimurium strain TA98 without S9. In the presence of S9, urine from conventionalized animals (894 +/- 56 revertants/ml) was more mutagenic than that from germ-free rats (686 +/- 60 revertants/ml). The presence of the intestinal flora plays an important role in the activation of 2,6-DNT but other metabolic pathways, such as the small intestinal mucosal and/or hepatic enzymes, are present that can generate excreted genotoxicants.
Genetic Toxicology Division (MD 68A), U.S. Environmental Protection Agency, Research Triangle Park, NC 27711.
S E
SE
George
R W
RW
Chadwick
M J
MJ
Kohan
J C
JC
Allison
R W
RW
Williams
J
J
Chang
D000818:Animals; D001711:Biotransformation; D004136:Dinitrobenzenes / Q000493:pharmacokinetics / Q000652:urine*; D005856:Germ-Free Life; D005966:Glucuronidase / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D007420:Intestine, Large / Q000378:metabolism / Q000382:microbiology; D007421:Intestine, Small / Q000378:metabolism / Q000382:microbiology; D007422:Intestines / Q000382:microbiology*; D008297:Male; D009152:Mutagenicity Tests; D009601:Nitroreductases / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344
D004136:Dinitrobenzenes; D009601:Nitroreductases; D005966:Glucuronidase; C023514:2,6-dinitrotoluene