Studies in alkaptonuria reveal new roles beyond drug clearance for phase I and II biotransformations in tyrosine metabolism

Brendan P. Norman, Andrew S. Davison, Juliette H. Hughes, Hazel Sutherland, Peter J. Wilson, Neil G. Berry, Andrew T. Hughes, Anna M. Milan, Jonathan C. Jarvis, Norman B. Roberts, Lakshminarayan R. Ranganath, George Bou-Gharios, James A. Gallagher

Research output: Contribution to journalArticle

Abstract

Background and Purpose: alkaptonuria (AKU) is an inherited disorder of tyrosine metabolism caused by lack of the enzyme homogentisate 1,2-dioxygenase (HGD). The primary biochemical consequence of HGD-deficiency is increased circulating homogentisic acid (HGA), which is central to AKU disease pathology. The aim of this study was to investigate the wider metabolic consequences of targeted Hgd disruption. Experimental Approach: the first metabolomic analysis of the Hgd-/- AKU mouse model was performed. Urinary metabolites altered in Hgd-/- were further validated by showing that the HGA-lowering drug nitisinone reversed their direction of alteration in AKU Key Results: comparison of Hgd-/- (AKU) versus Hgd+/- (heterozygous control) urine revealed increases in HGA and a group of 8 previously unreported HGA-derived transformation products from phase I and II metabolism. HGA biotransformation products HGA-sulfate, HGA-glucuronide, HGA-hydrate and hydroxymethyl-HGA were also decreased in urine from both mice and patients with AKU on the HGA-lowering agent nitisinone. Hgd knockout also revealed a host of previously unrecognised associations between tyrosine, purine and TCA cycle metabolic pathways. Conclusion and Implications: AKU is rare, but our findings further what is currently understood about tyrosine metabolism more generally, and show for the first time that phase I and II detoxification is recruited to prevent accumulation of endogenously-produced metabolites in inborn errors of metabolism. The data highlight the misconception that phase I and II metabolic biotransformations are reserved solely for drug clearance; these are ancient mechanisms, which represent new potential treatment targets in inherited metabolic diseases.
Original languageEnglish
JournalbioRxiv
DOIs
Publication statusPublished - 16 Apr 2020
Externally publishedYes

Keywords

  • Biotransformation
  • Drug metabolism
  • Hepatopharmacology
  • Metabolism
  • Metabolomics
  • Mice
  • Transgenic

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