1. Biodistribution and metabolism of the Maillard reaction products Frederic J Tessier Frederic.tessier@isab.fr

2. The Maillard reaction products (MRPs) bio- distribution and metabolism are not completely understood but advances have been made. MRPs are usually classified as early MRPs, advanced MRPs and Melanoidins. These different groups of MRPs have been tested in animal experiments. However, only the early MRPs (Amadori product) has been investigated in human studies. Dietary ingestion of food-derived Maillard reaction products

3. R-NH 2 Reducing Sugar + Amadori product (ketoamine) Advanced Glycation End-products (AGEs) and other Advanced Maillard reaction products Pre-melanoidins Melanoidins Brown nitrogenous polymers, Insoluble high molecular weight species Polymerization of the high reactive intermediates rearrangement Maillard Reaction products (MRPs) Chemical structures represented by triangles as followed: Partially identified Well-known Schiff Base Mainly unidentified MRP classification according to Finot and Furniss [1]

4. Example of foods which may contain MRP Raw foods have almost no MRP Bread, biscuit, chocolate, breakfast cereals may contain high level of Amadori product. Heated milk, infant milk formula are two example of beverage which contains lactulosyllysine (Amadori product) French fries, potato chips, coffee contains acrylamide Grilled meat contains heterocyclic amines According to an ELISA test, many foods contain carboxymethyllysine Bread crust, cookies, coffee, chocolate contain melanoidins

5. Bio-distribution and Metabolism of the Amadori product Several experiments were performed mainly with fructoselysine (FL) [2]  FL was the only MRP administered in human trials [3]  FL is not available as a source of lysine  FL is transported out of the intestine by passive diffusion  In rats, at least 60% of orally ingested free FL are excreted in the urine [4]  In humans, urinary excretion of ingested casein-bound FL is 3% [3]  Lactuloselysine (Amadori product form milk) is poorly digested [5]  There is an uptake of FL into the cells of the liver and muscles by passive diffusion  Microorganisms destroy the Amadori product in the large intestine  High excretion rate for human infants: 16% in urine – 55% in faeces [6]

6. Bio-distribution and Metabolism of the Amadori product Liver Urine Feces Passive diffusion 60% of free FL, and 10% of protein-bound FL (Rats) Dietary Ingestion Intestinal digestion of protein- bound FL 3% of protein-bound FL (Humans) Microbial degradation of FL in the hind gut Very low level of FL 1% in adults Elimination of FL within 12h after ingestion Systemic circulation Kidneys

7. Bio-distribution and Metabolism of the advanced MRPs  Dietary ingested Acrylamide is easily absorbed through the intestine tract, rapidely metabolized and excreted. However acrylamide and its metabolites can accumulate in the body when bound to protein in nervous system tissues or hemoglobin in blood.  Heterocyclic amines are also easily absorbed and metabolized through phase-I enzyme systems [7]  HMF has been shown to accumulate in kidneys, bladder and liver of rats [8]  CML, a well-known AGE or advanced MRP, has been quantified in many foods. CML can be also formed endogenously. However Liardon et al. assumed that the dietary CML is the main source of the urinary CML [9] The structural diversity and the wide range of molecular weights of the advanced MRPs make difficult to summarized their biodistribution and metabolism N  -carboxymetyllysine (CML), acrylamide, 5-hydroxymethyl-furfuraldehyde (HMF), dicarbonyls, heterocyclic amines are some example of advanced MRPs which have been studied individually.

8. Tissues Liver Based on a human study, Koshinsky et al. calculated that “the total amount of orally absorbed AGEs * found in blood was equal to 10% of that estimated to be present in the ingested meal. Of that, only 30% was excreted in the urine of persons with normal renal function” [10] Systemic circulation Kidneys Urine Bio-distribution and Metabolism of food-derived AGEs * 10% absorbed 30% excreted (of the 10% absorbed) Some dietary AGE derivatives react with endogenous proteins in the blood & tissues * AGE content measured by ELISA [11] Dietary ingestion of food-derived AGEs *

9. Liver Systemic circulation Kidneys Urine Bio-distribution and Metabolism of food-derived AGEs Some dietary AGE analogs react with circulating proteins such as LDL LDL Cell Some dietary AGE analogs bind to the cellular receptors for AGEs (i.e. RAGE) at the surface of cells AGE-receptor And may induce -Intracellular oxidative stress -Endocytosis and removal of AGEs Some dietary AGE analogs react with tissue proteins such as collagen

10. Bio-distribution and Metabolism of the melanoidins Experiments were performed mainly on rats and reviewed recently by Faist and Erbersdobler [12]  The difficulty to study the biodistribution and metabolism of melanoidins is that their chemical structure remains almost unknown  The absorption of the melanoidins is dependent of their molecular weight and solubility. The absorption of the low molecular weight and water soluble melanoidins seems to be favored [13]  In rats 70 to 90% of orally ingested melanoidins are excreted in the feces, and only 1 to 5% in urine [14,15,16]

11. Liver Systemic circulation Kidneys Urine Feces Bio-distribution and Metabolism of the melanoidins 1 to 5% (Rats)70 to 90% (Rats) Limited absorption by the intestines Apparently not utilized by the organism, and excreted Suspected digestive or microbial degradation of melanoidins

12. Melanoidins and other MRPs affect the microflora composition in the gut Feces Colon Bio-distribution and Metabolism of the melanoidins Bifidobacteria (beneficial on host health) Clostridia (detrimental on host health) Using an in vitro gut model Tuohy et al. found that glycated bovine serum albumin reduces numbers of bifidobacteria and increases number of clostridia [17]

13. 1.Finot & Furniss, 1989 2.Erbersdobler & Faist, 2001 3.Lee & Erbersdobler, 1994 4.Finot & Magnenat, 1978 5.Finot, 1973 6.Niederweiser et al., 1975 7.Shina et al., 1994 8.Germond et al., 1987 9.Liardon et al., 1987 10.Koschinsky et al., 1997 11.Makita et al., 1992 12.Faist & Erbersdobler, 2001 13.Nair et al., 1981 14.Valle-Riestra & Barnes, 1969 15.Finot & Magnenat, 1981 16.Homma & Fujimaki, 1981 17.Tuohy et al., 2005 References