Norman, BP 
ORCID: 0000-0001-9293-4852, Sutherland, H, Wilson, PJM, Rutland, DA, Milan, AM, Hughes, AT, Davison, AS, Khedr, M, Jarvis, JC, Gallagher, JA et al (show 2 more authors)
(2024)
Hepatobiliary circulation and dominant urinary excretion of homogentisic acid in a mouse model of alkaptonuria.
Journal of inherited metabolic disease.
![[img]](https://livrepository.liverpool.ac.uk/style/images/fileicons/other.png) |
XML Word Processing Document (DOCX)
Bile HGA paper main body final JIMD_AcceptedVersion.docx - Author Accepted Manuscript Download (396kB) |
Abstract
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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | hepatobiliary circulation, homogentisic acid, organic acids, tyrosine disorders, tyrosine metabolites |
| Divisions: | Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Life Courses and Medical Sciences |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 20 Mar 2024 16:19 |
| Last Modified: | 20 Mar 2024 16:19 |
| DOI: | 10.1002/jimd.12728 |
| Open Access URL: | https://onlinelibrary.wiley.com/doi/10.1002/jimd.1... |
| Related URLs: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3179756 |
Dimensions
Dimensions
