The in vitro recirculation technique was used to study the uptake and transport of uric acid by the jejunum of mouse small intestine. Three components of the serosal secretions appeared to be endogenously derived nucleic acid derivatives; two of these were identified as uric acid and uracil. There was no detectable metabolism of uric acid by the intestine. Uric acid transported from the lumen appeared in the serosal fluid at a concentration higher than that in the lumen. The final serosal/luminal concentration ratio of about 1.18 for exogenous uric acid was found to be constant over the concentration range studied (0.01-0.1 mM). The presence of exogenous uric acid in the lumen did not affect the production of endogenous uric acid by the intestine and its release into the serosal secretions. Mucosal concentration of exogenous uric acid was below, but the total mucosal concentration (exogenous+endogenous) was above, that in the lumen. There was no evidence for the secretion of endogenous uric acid into the lumen. Oxypurinol significantly decreased the rate of serosal appearance of exogenous uric acid. Allopurinol did not affect the transport of exogenous uric acid from the lumen and there was negligible metabolism of allopurinol to oxypurinol by the tissue. Uracil did not affect the transport of exogenous uric acid from the lumen, or the serosal appearance of endogenous uric acid. Likewise uracil transport was unaffected by luminal uric acid.
SUMMARYA simple and specific analytical method incorporating high performance (anion-exchange) liquid chromatography has been used to study the absorption and metabolism of some purine derivatives in an in vitro preparation of adult rat jejunum. When present in the lumen the purine bases guanine (4 x IO--M), hypoxanthine or xanthine (10-4-3 x l0-4 M) do not appear in the serosal secretions but the uric acid (UA) content of these secretions is increased. With UA in the intestinal lumen (10-4-3 x 10-4 M) the serosal UA is increased, in some cases to a higher concentration than that in the lumen. With adenine in the lumen (10-4-10-3 M) there is an increased appearance of UA and adenine also appears in the serosal secretions, but the concentration of adenine never exceeds that in the lumen.It is concluded that purines absorbed from the lumen are significantly metabolized to UA during translocation across rat jejunum. Negligible amounts of metabolites are found in the luminal solutions except for guanine which appears to be degraded in the lumen.
The transport and metabolism of allopurinol and oxypurinol have been examined in a preparation of adult rat jejunum in vitro. When present in the lumen (50-500 mumol/l) allopurinol appeared in the serosal secretions at lower concentrations, together with its metabolite oxypurinol and an unidentified substance. Oxypurinol in the lumen (1.4-430 mumol/l) was transported into the serosal secretions and at luminal concentrations below approximately 150 mumol/l was concentrated in the secretions. The transport of oxypurinol into serosal secretions was greater than that of allopurinol. Allopurinol and oxypurinol decreased the appearance of urate, in the serosal secretions and the luminal fluid, by an amount which was greater than the concomitant increase in oxypurines; they increased the rate constant of the mono-exponential washout of endogenous urate and induced purine secretion into the lumen. The transport of uric acid from the lumen into the serosal secretions was inhibited by allopurinol and oxypurinol. With allopurinol the specific radioactivity (14C) of urate in the serosal secretions approached that in the lumen; with oxypurinol the specific radioactivity was approximately 70% that in the lumen. There was no evidence for the uphill movement of urate from the lumen.
Quarterly Journal of Experimental Physiology 68–1 (1983) On page 40 paragraph 7 should read Enzymes were purine nucleoside phosphorylase (PNP) (E.C. 2.4.2.1.), uricase (E.C. 1.7.3.3.), hexokinase (E.C. 2.7.1.1.), glucose‐6‐phosphate dehydrogenase (E.C.1.1.1.49.), alanine dehydrogenase (E.C.1.4.1.1.), glutamate dehydrogenase (E.C.1.4.1.3.) all from Boehringer, and xanthine oxidase (XOD) (E.C.1.3.2.) from Sigma.
1. The transport of 6-thioguanine and 6-mercaptopurine has been studied with isolated jejunal loops of mouse small intestine. H.p.l.c. was used to identify and quantify the thiopurines and their metabolites in the serosal secretions. 2. When the lumen of the intestinal loops contained either 6-thioguanine or 6-mercaptopurine at a concentration of 1 mmol/l, the concentration of unmetabolized drug in the serosal secretions reached a maximum of 0.13 +/- 0.02 mmol/l (mean +/- SEM). 3. Analysis of the serosal secretions from the perfusions with either of the drugs revealed the appearance of an unknown compound which had the characteristics of a thiopurine and the same time course of appearance as the unmetabolized drug. Thus 6-thioguanine and 6-mercaptopurine are significantly metabolized during absorption in mouse intestine. 4. The unknown compound was identified as 6-thiouric acid, and with 1 mmol/l 6-thioguanine or 6-mercaptopurine in the lumen the concentration of this metabolite in the serosal secretions rose to a maximum of 0.13 +/- 0.01 and 0.18 +/- 0.03 mmol/l, respectively. At luminal drug concentrations of 0.1 mmol/l, the metabolite accounted for approximately 90% of the serosal thiopurine. 5. After an initial lag period of 20 min, linear rates of appearance in the serosal secretions were obtained for both the unmetabolized drugs and 6-thiouric acid. 6. Addition of the xanthine oxidase inhibitor oxypurinol at a luminal concentration of 0.3 mmol/l prevented the formation of 6-thiouric acid from 6-thioguanine. However, the inhibitor reduced the rate of 6-thioguanine appearance in the serosal secretions by 50%. 7. The conversion of 6-mercaptopurine to 6-thiouric acid was prevented when allopurinol or oxypurinol were added to the lumen. At a luminal drug concentration of 1 mmol/l, allopurinol increased the rate at which 6-mercaptopurine appeared in the serosal secretions by 90% compared with an increase of only 50% with oxypurinol. 8. The transport of water and glucose by the mouse intestinal loops was unaffected by 6-thioguanine or the xanthine oxidase inhibitors. However, 6-mercaptopurine caused significant reductions in the rate of water transport (30%) and glucose transport (39%). These effects were observed at a luminal drug concentration of 0.1 mmol/l and there was no further increase at a drug concentration of 1 mmol/l.
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