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Application of a dynamic in vitro gastrointestinal tract model to study the availability of food mutagens, using heterocyclic aromatic amines as model compounds

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Author: Krul, C.A.M. · Luiten-Schuite, A. · Baan, R. · Verhagen, H. · Mohn, G. · Feron, V. · Havenaar, R.
Source:Food and Chemical Toxicology, 9, 38, 783-792
Identifier: 56829
doi: doi:10.1016/S0278-6915(00)00071-5
Keywords: Biology · Medicine · Geneeskunde · Health · Gezondheid · Dietetics · Voedingsleer · Availability · Dynamic in vitro gastrointestinal model · Heterocyclic aromatic amines · Meat mutagens · Transit time · Aromatic amine · Heterocyclic amine · Mutagenic agent · Animal experiment · Animal tissue · Bile secretion · Bioavailability · Computer model · Controlled study · Digestion · Gastrointestinal tract function · In vitro study · Intestine absorption · Intestine transit time · Male · Nonhuman · Pancreas secretion · Peristalsis · PH · Rat · Salmonella typhimurium · Stomach secretion · Temperature · Validation process · Biological Availability · Chromatography, High Pressure Liquid · Digestive System · Heterocyclic Compounds · Models, Biological · Mutagenicity Tests · Mutagens · Animalia · Mammalia · Salmonella typhimurium · Typhimurium


The TNO gastro-Intestinal tract Model (TIM) is a dynamic computer-controlled in vitro system that mimics the human physiological conditions in the stomach and small intestine. In the current TIM physiological parameters such as pH, temperature, peristaltic movements, secretion of digestion enzymes, bile and pancreatic juices, and absorption of digested products - by removal through dialysis - was simulated. Heterocyclic aromatic amines (HAA; viz. IQ, MeIQ, MeIQx and PhIP) were used as model compounds for food mutagens, and the passage through TIM was investigated for each of these compounds separately. Subsequently, the influence of a matrix and different rates of passage on the availability for absorption and distribution were studied in experiments with prepared meat, supplemented with MeIQx. Samples taken at various time points from the jejunal and ileal dialysates and from the lumen at the end of the small intestine (ileal delivery) were tested for the presence of mutagenic activity in the Ames test with Salmonella typhimurium strain TA98 as indicator, in the presence of mammalian metabolic activation (rat S9 mix). The results show that, comparable with the human in vivo situation, all four HAA are quickly removed (approx. 50% in 2 hr; approx. 95% in 6 hr) and mainly recovered from the lumen into the jejunal and ileal dialysates (94% of recovery). Only 5 ± 1.5% is recovered in the chyme at the end of the small intestine. When MeIQx was added to meat, its availability for absorption was slower, although the influence of the gastrointestinal passage time on the availability of MeIQx was more pronounced than this matrix effect. More MeIQx was found in the jejunal dialysate (23%; P < 0.01) and less in the ileal delivery (8%; P < 0.01) when simulating the gastrointestinal passage of solid meals was compared to simulating that of liquid meals. The present experiments demonstrate that TIM can be applied to study in vitro the availability of heterocyclic aromatic amines in the gastrointestinal tract. More generally, these studies indicate that TIM shows promise as a useful tool for various research purposes dealing with the availability for absorption of mutagenic as well as antimutagenic components in food. (C) 2000 Elsevier Science Ltd. Chemicals/CAS: Heterocyclic Compounds; Mutagens