Hepatobiliary circulation and dominant urinary excretion of homogentisic acid in a mouse model of alkaptonuria.

Publisher: Wiley Country of Publication: United States NLM ID: 7910918 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1573-2665 (Electronic) Linking ISSN: 01418955 NLM ISO Abbreviation: J Inherit Metab Dis Subsets: MEDLINE

Publication: 2019- : [Hoboken, NJ] : Wiley
Original Publication: [Lancaster, Eng.] MTP Press.

Alkaptonuria*/urine ; Alkaptonuria*/metabolism ; Homogentisic Acid*/urine ; Homogentisic Acid*/metabolism ; Disease Models, Animal* ; Nitrobenzoates* ; Cyclohexanones*/urine; Animals ; Mice ; Male ; Tyrosine/metabolism ; Tyrosine/urine ; Liver/metabolism ; Phenylalanine/metabolism

Altered activity of specific enzymes in phenylalanine-tyrosine (phe-tyr) metabolism results in incomplete breakdown of various metabolite substrates in this pathway. Increased biofluid concentration and tissue accumulation of the phe-tyr pathway metabolite homogentisic acid (HGA) is central to pathophysiology in the inherited disorder alkaptonuria (AKU). Accumulation of metabolites upstream of HGA, including tyrosine, occurs in patients on nitisinone, a licenced drug for AKU and hereditary tyrosinaemia type 1, which inhibits the enzyme responsible for HGA production. The aim of this study was to investigate the phe-tyr metabolite content of key biofluids and tissues in AKU mice on and off nitisinone to gain new insights into the biodistribution of metabolites in these altered metabolic states. The data show for the first time that HGA is present in bile in AKU (mean [±SD] = 1003[±410] μmol/L; nitisinone-treated AKU mean [±SD] = 45[±23] μmol/L). Biliary tyrosine, 3(4-hydroxyphenyl)pyruvic acid (HPPA) and 3(4-hydroxyphenyl)lactic acid (HPLA) are also increased on nitisinone. Urine was confirmed as the dominant elimination route of HGA in untreated AKU, but with indication of biliary excretion. These data provide new insights into pathways of phe-tyr metabolite biodistribution and metabolism, showing for the first time that hepatobiliary excretion contributes to the total pool of metabolites in this pathway. Our data suggest that biliary elimination of organic acids and other metabolites may play an underappreciated role in disorders of metabolism. We propose that our finding of approximately 3.8 times greater urinary HGA excretion in AKU mice compared with patients is one reason for the lack of extensive tissue ochronosis in the AKU mouse model.
(© 2024 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)

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1101052 Alkaptonuria Society

Keywords: hepatobiliary circulation; homogentisic acid; organic acids; tyrosine disorders; tyrosine metabolites

NP8UE6VF08 (Homogentisic Acid)
K5BN214699 (nitisinone)
0 (Nitrobenzoates)
0 (Cyclohexanones)
42HK56048U (Tyrosine)
47E5O17Y3R (Phenylalanine)

Date Created: 20240315 Date Completed: 20240717 Latest Revision: 20240717

20240717

10.1002/jimd.12728

38487984