Effects of human intestinal flora on mutagenicity of and DNA adduct formation from food and environmental mutagens.
Although the intestinal flora is believed to have a critical role in carcinogenesis, little is known about the role of the human intestinal flora on the effects of mutagens in vivo. The aim of the present study was to address a possible role of the human intestinal flora in carcinogenesis, by exploiting human-flora-associated (HFA) mice. The capacity of human faeces to activate or inactivate 2-amino-3-methyl-3H:-imidazo[4,5-f]quinoline (IQ) and 2-nitrofluorene was determined using the Ames assay. Human faecal suspensions that were active in this regard were then selected and orally inoculated into germfree NMRI mice to generate HFA mice. HFA, germfree, conventionalized and conventional mice were administered IQ, 2-amino-9H:-pyrido[2,3-b]indole (2-amino-alpha-carboline; AAC) and 2-nitrofluorene. The activity of human intestinal flora against mutagens could be transferred into the mice. In comparing germfree mice and mice harbouring an intestinal flora, the presence of a flora was essential for the activities of faeces against mutagens. After administration of IQ and 2-nitrofluorene, DNA adducts were observed in the mice with a flora, while adducts were extremely low or absent in germfree animals. DNA adducts after AAC treatment were higher in germfree mice in some tissues including colon than in mice with bacteria. Differences in DNA adduct formation were also observed between HFA mice and mice with mouse flora in many tissues. These results clearly indicate that the intestinal flora have an active role in DNA adduct formation and that the role is different for the different chemicals to which the animals are exposed. The results also demonstrate that the human intestinal flora have different effects from the mouse flora on DNA adduct formation as well as in vitro metabolic activities against mutagens. Studies using HFA mice could thus provide much-needed information on the role of the human intestinal flora on carcinogenesis in vivo.
Hirayama
K
K
Departments of Medical Nutrition and Biosciences, Karolinska Institutet, NOVUM, S-141 86 Huddinge, Sweden. akazu@mail.ecc.u-tokyo.ac.jp
Baranczewski
P
P
Akerlund
J E
JE
Midtvedt
T
T
Möller
L
L
Rafter
J
J
D000328:Adult; D000818:Animals; D001711:Biotransformation; D002243:Carbolines / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity; D002273:Carcinogens / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity*; D002274:Carcinogens, Environmental / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D018736:DNA Adducts / Q000096:biosynthesis*; D005243:Feces / Q000382:microbiology; D005260:Female; D005449:Fluorenes / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity; D005502:Food; D005615:Freezing; D005856:Germ-Free Life; D006801:Humans; D008658:Inactivation, Metabolic; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000382:microbiology*; D008297:Male; D051379:Mice; D009153:Mutagens / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity*; D011804:Quinolines / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity
D002243:Carbolines; D002273:Carcinogens; D002274:Carcinogens, Environmental; D018736:DNA Adducts; D005449:Fluorenes; D009153:Mutagens; D011804:Quinolines; C019499:2-nitrofluorene; C029216:2-amino-3-methylimidazo(4,5-f)quinoline; D004247:DNA; C017822:2-amino-9H-pyrido(2,3-b)indole