Effects of risk-associated human dietary macrocomponents on processes related to carcinogenesis in human-flora-associated (HFA) rats.
Dietary fat, protein and fibre have been shown to modulate cancer risk in humans and the present study examined the biological effects in human-flora-associated (HFA) rats of altering intake levels within the normal human range. Two control groups, one HFA and the other germfree (GF), consumed a human diet low in fat, fibre and beef for 4 weeks; three other groups consumed human diets similar except for independent 3-fold increases in fat, beef protein or fibre. After 2 weeks on the diets, magnetically recoverable microcapsules were given orally to the rats and subsequently recovered from the faeces to assess endogenous cross-linking agents. After 4 weeks, measurements were made of gut microfloral enzyme activities, hepatic activation of dietary mutagens and hepatic DNA adducts by 32P-postlabelling. Activation in vitro of the dietary mutagens 2-amino-3-methyl-3H-imidazo[4,5-f]quinoline (IQ) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) by hepatic S9, formation of endogenous hepatic DNA adducts in vivo and the beta-glucuronidase activity of caecal contents were all increased in the sequence high fat > high fibre > high beef = control. Of the two DNA adducts found in all HFA rats, only one was present in GF controls, indicating that the human gut microflora (subject to human dietary modulation) either releases a DNA-adducting product able to act outside the gastrointestinal tract, or stimulates the generation of such a product by mammalian processes. Caecal nitrate reductase activity was highest in rats fed the high beef diet, whilst entrapment of cross-linking agents was highest in those fed the high fibre diet. These results show that risk-related components of human diets interact with human gut microflora to modulate the production of endogenous DNA-adducting and cross-linking substances.
BIBRA Toxicology International, Carshalton, Surrey, UK.
C J
CJ
Rumney
I R
IR
Rowland
T M
TM
Coutts
K
K
Randerath
R
R
Reddy
A B
AB
Shah
A
A
Ellul
I K
IK
O'Neill
D000818:Animals; D001711:Biotransformation; D002432:Cecum / Q000201:enzymology; D003043:Cocarcinogenesis; D003432:Cross-Linking Reagents; D004249:DNA Damage; D004041:Dietary Fats / Q000493:pharmacokinetics / Q000633:toxicity*; D004043:Dietary Fiber / Q000493:pharmacokinetics / Q000633:toxicity*; D004044:Dietary Proteins / Q000493:pharmacokinetics / Q000633:toxicity*; D004339:Drug Compounding; D005966:Glucuronidase / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000493:pharmacokinetics / Q000633:toxicity; D007422:Intestines / Q000382:microbiology*; D008297:Male; D009374:Neoplasms, Experimental / Q000209:etiology; D050901:Nitrate Reductase; D009565:Nitrate Reductases / Q000378:metabolism; D011094:Polyethyleneimine; D011804:Quinolines / Q000493:pharmacokinetics / Q000633:toxicity; D051381:Rats; D011916:Rats, Inbred F344
D003432:Cross-Linking Reagents; D004041:Dietary Fats; D004043:Dietary Fiber; D004044:Dietary Proteins; D007093:Imidazoles; D011804:Quinolines; C029216:2-amino-3-methylimidazo(4,5-f)quinoline; D011094:Polyethyleneimine; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine; D009565:Nitrate Reductases; D050901:Nitrate Reductase; D005966:Glucuronidase