Hippurate
| Metabolite Information | Value |
|---|---|
| HMDB ID | HMDB0000714 |
| KEGG ID | C01586 |
| IUPAC name | 2-(phenylformamido)acetic acid |
| Structure |  |
| SMILES | OC(=O)CNC(=O)C1=CC=CC=C1 |
| Average molecular weight | 179.1727 |
Hippurate (hippuric acid) is an acyl glycine formed by the conjugation of benzoic acid and glycine. Glycine acyltransferase catalyses the transfer of benzoate from benzoyl-CoA to glycine. The resulting hippurate is excreted via urine.
Human diet contains benzoate in variable amounts. Sodium benzoate is a common preservative that is particularly effective in acidic foods, so can be found in soft drinks, fruit juices, salad dressings, pickled foods etc. Benzoate can also be derived from dietary sources of polyphenolic compounds, including some fruits, vegetables, tea, and coffee (Lees 2013).
It has been estimated that 83-100% of ingested benzoate is excreted as hippurate, and that this varies by species. The observed differences have been attributed to variations in glycine and glucuronic acid conjugation capacity of the liver and kidneys, and the rate of glycine mobilisation (Bridges 1970).
Animal studies have shown hippurate increases with age during the early stages of life. In male Wistar-derived rats, urine samples showed low and variable hippurate levels at four weeks of age, then an increase and eventual stabilisation beginning at approximately 8 weeks of age (Guthrie 2022). Maturation of the gut microbiome and adaptation to an adult diet are believed to contribute to this change.
Benzoate, and subsequent hippurate, can be derived from a number of dietary metabolites including phenylalanine (Rowe 1975), quinate (Pero 2009), shikimate (Pero 2009)(Brewster 1978)(Booth 1960), and polyphenolic compounds such as chlorogenate and (+)-catechin (Olthof 2003).
Production of hippurate following ingestion of tea for example is the result of metabolism of catechins (and related polymers, e.g. theaflavins and thearubigens) (Balentine 1997). In addition, tea-derived phenolic compounds are poorly absorbed in the small intestine, and are available for metabolism by colonic microbiota (Olthof 2001), which cleave the catechin ring into valerolactones that can be further metabolised to phenylpropionates. Phenylpropionates are asborbed and metabolised in the liver via β-oxidation to produce benzoate, and subsequent glycine conjugation and excretion as hippurate (Das 1971)(Phipps 1998).
Hippurate has been identified as decreased, and a highly discriminatory metabolite, in urine samples from obese individuals (Calvani 2010). Decreased excretion has also been observed in Zucker (fa/fa) obese rats compared to lean (fa/-) control rats (Salek 2007). These rats also exhibited lower Bifidobacteria counts (Waldram 2009).
Changes to hippurate levels are often attributed to gut microbial changes; germ-free animals do not produce hippurate, however after 2-3 weeks post-exposure to conventional environments, hippurate becomes a dominant aromatic metabolite. If the germ-free animals are maintained in a sterile environment, they are unable to excrete hippurate or related metabolites (Scheline 1970)(Peppercorn 1972)(Claus 2008)(Nicholls 2003).
Hippurate excretion has been found signficantly decreased in urine from both ulcerative colitis and Crohn's disease (Williams 2009)(Schicho 2012). Detailed dietary records were used to minimise confounding effects of diet-derived sources of precursors for benzoate and hippurate; statistical analysis of the diet factors revealed no significant differences. Instead, pertubation of the gut microbiome may be responsible for different levels of hippurate excretion. This is supported by a study showing no underlying deficiency in the capacity for glycine conjugation of benzoate; differences in levels of excreted hippurate between Crohn's patients and healthy controls were absent at sampling 1 hour after an exogenous dose of benzoate (Williams 2010).
Interestingly, in ulcerative colitis and Crohn's patients, urinary p-cresol sulfate levels decreased alongside hippurate, while formate levels were increased (Manichanh 2006).
Comparisons of age- and sex-matched children and adolescents have revealed significantly elevated hippurate secretion in individuals with type 1 diabetes (Zuppi 2002). One theory is that the glomerular filtration rate is increased (a characteristic of type 1 diabetes)(Thomson 2004), or that there are other differences in renal function. Increased availability of hepatic acetyl-CoA in diabetic individuals, and thus an increased capacity for glycine conjugation of benzoate is another suggestion.