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

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. MRP classification according to Finot and Furniss [1] + R-NH2 Reducing Sugar Chemical structures represented by triangles as followed: Schiff Base Well-known Amadori product (ketoamine) rearrangement Advanced Glycation End-products (AGEs) and other Advanced Maillard reaction products Partially identified Maillard Reaction products (MRPs) Pre-melanoidins Polymerization of the high reactive intermediates Melanoidins Brown nitrogenous polymers, Insoluble high molecular weight species Mainly unidentified

4. Example of foods which may contain MRP Raw foods have almost no MRP Bread, biscuit, chocolate, breakfast cerealsmay 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 Dietary Ingestion Passive diffusion Systemic circulation Intestinal digestion of protein-bound FL Microbial degradation of FL in the hind gut Kidneys Liver Elimination of FL within 12h after ingestion Urine 3% of protein-bound FL (Humans) Very low level of FL 1% in adults Feces 60% of free FL, and 10% of protein-bound FL (Rats)

7. Bio-distribution and Metabolism of the advanced MRPs The structural diversity and the wide range of molecular weights of the advanced MRPs make difficult to summarized their biodistribution and metabolism Ne-carboxymetyllysine (CML), acrylamide, 5-hydroxymethyl-furfuraldehyde (HMF), dicarbonyls, heterocyclic amines are some example of advanced MRPs which have been studied individually. • 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]

8. Bio-distribution and Metabolism of food-derivedAGEs * Dietary ingestion of food-derived AGEs * 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] Tissues 10% absorbed Some dietary AGE derivatives react with endogenous proteins in the blood & tissues Systemic circulation Liver Kidneys * AGE content measured by ELISA [11] 30% excreted (of the 10% absorbed) Urine

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

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 to90% of orally ingested melanoidins are excreted in the feces, and only 1 to 5% in urine [14,15,16]

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

12. Bio-distribution and Metabolism of the melanoidins Colon Melanoidins and other MRPs affect the microflora composition in the gut 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] Bifidobacteria (beneficial on host health) Clostridia (detrimental on host health) Feces

13. References • Finot & Furniss, 1989 • Erbersdobler & Faist, 2001 • Lee & Erbersdobler, 1994 • Finot & Magnenat, 1978 • Finot, 1973 • Niederweiser et al., 1975 • Shina et al., 1994 • Germond et al., 1987 • Liardon et al., 1987 • Koschinsky et al., 1997 • Makita et al., 1992 • Faist & Erbersdobler, 2001 • Nair et al., 1981 • Valle-Riestra & Barnes, 1969 • Finot & Magnenat, 1981 • Homma & Fujimaki, 1981 • Tuohy et al., 2005