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6‐THIOPURINES AS SUBSTRATES AND INHIBITORS OF PURINE OXIDASES: A PATHWAY FOR CONVERSION OF AZATHIOPRINE INTO 6‐THIOURIC ACID WITHOUT RELEASE OF 6‐MERCAPTOPURINE
Author(s) -
Chalmers AH,
Knight PR,
Atkinson MR
Publication year - 1969
Publication title -
australian journal of experimental biology and medical science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.999
H-Index - 104
eISSN - 1440-1711
pISSN - 0004-945X
DOI - 10.1038/icb.1969.27
Subject(s) - azathioprine , chemistry , xanthine oxidase , allopurinol , oxidase test , uric acid , mercaptopurine , aldehyde oxidase , metabolite , glutathione , stereochemistry , enzyme , biochemistry , pharmacology , medicine , biology , disease
Summary Previous studies have shown that azathioprinc (6‐(1‐methyl‐4‐nitroimidazol‐5‐yl)‐thiopuruie) is converted into 6‐mercaptopurine by a nonenzymic reaction with glutathione, and that 6‐thiouric acid is the major urinary metabolite of azathioprine in man and other mammals; formation of 6‐thiouric acid has been attributed to oxidation of 6‐mercaptopurine by xanthinc oxidase. This paper describes an alternative pathway for conversion of azathioprine into 6‐thiouric acid that does not involve 6‐mercaptopurine as an intermediate. Aldehyde oxidase from human and rabbit liver oxidises azathioprine to 8‐hydroxy‐azathioprinc. which reacts spontaneously with glutathione. forming 8‐hydroxy‐6‐ mercaptopurine, which is converted into 6‐thiouric acid on oxidation by xanthinc oxidase. The maximal velocity of oxidation of azathioprine with aldehyde oxidase from rabbit liver is 75% of the maximal velocity with N 1 ‐methylnicotinomide. the usual assay substrate, and the Michaclis constant (0·08 mM azathioprine) is lower than the constant for N 1 ‐methylnicotinamidc (2·4 mM). Menadione is a competitive inhibitor of oxidation of azathioprine (inhibitor constant K 1 , 1·2 μM) and the reaction is not inhibited by allopurinol, which inhibits xanthinc oxidase. 6‐Thiouric acid and uric acid are competitive inhibitors of oxidation of 6‐mercaptopurine by xanthinc oxidase from calf liver. The possibility that this inhibition contributes to the increased toxicity of azathioprine used as an immunosuppressive agent during impaired function of a renal transplant in discussed. Preparation of 9‐butylazathioprine is described. This compound is not a substrate for aldehyde oxidase, but is converted by glutathione into the 9‐butyl‐6‐mercaptopurine, a known antimetabolite.