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Conversion of Xanthine Dehydrogenase to Oxidase in Ischemic Rat Tissues

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Conversion of Xanthine Dehydrogenase to Oxidase in Ischemic Rat Tissues Conversion of xanthine dehydrogenase to oxidase in ischemic rat tissues. T D Engerson, … , S J Snyder, H P Jones J Clin Invest. 1987;79(6):1564-1570. https://doi.org/10.1172/JCI112990. Research Article In response to global ischemia, tissue xanthine dehydrogenase was converted to xanthine oxidase in all tissues with half- times of conversion at 37 degrees C of approximately 3.6, 6, 7, and 14 h for the liver, kidney, heart, and lung, respectively. The time course of enzyme conversion at 4 degrees C was greatly extended with half-conversion times of 6, 5, 5, and 6 d for the respective tissues. Increases in xanthine oxidase activity were accompanied by the appearance of a distinct new protein species with greater electrophoretic mobility. The oxidase from ischemic rat liver was purified 781-fold and found to migrate with a higher mobility on native gels than the purified native dehydrogenase. Sodium dodecyl sulfate profiles revealed the presence of a single major band of 137 kD for the native dehydrogenase, whereas the oxidase had been partially cleaved generating polypeptides of 127, 91, and 57 kD. Polypeptide patterns for the oxidase resemble those seen following limited in vitro proteolysis of the native dehydrogenase supporting a proteolytic mechanism for the conversion of xanthine dehydrogenase to oxidase in ischemic rat liver. Find the latest version: https://jci.me/112990/pdf Conversion of Xanthine Dehydrogenase to Oxidase in Ischemic Rat Tissues Todd D. Engerson, T. Greg McKelvey, Darryl B. Rhyne, Elizabeth B. Boggio, Stephanie J. Snyder, and Harold P. Jones Departments ofBiomedical Sciences and Biochemistry, University ofSouth Alabama, Mobile, Alabama 36688 Abstract xanthine, would provide substrate for xanthine oxidase. The second event, the intracellular conversion of xanthine dehy- In response to global ischemia, tissue xanthine dehydrogenase drogenase to xanthine oxidase, would cause the enzyme to use was converted to xanthine oxidase in all tissues with half-times oxygen, rather than NAD, as an oxidant. As a result of the con- of conversion at 370C of - 3.6, 6, 7, and 14 h for the liver, version, the active enzyme would produce superoxide, rather kidney, heart, and lung, respectively. The time course of enzyme than NADH, as hypoxanthine was oxidized. Thus when oxygen conversion at 40C was greatly extended with half-conversion was reintroduced into the tissue the action of the oxidase would times of 6, 5, 5, and 6 d for the respective tissues. Increases in provide a burst of superoxide and subsequently derived active xanthine oxidase activity were accompanied by the appearance oxgen species that would inflict damage on the organ. of a distinct new protein species with greater electrophoretic In support ofthis model, Roy and McCord (14) demonstrated mobility. The oxidase from ischemic rat liver was purified 781- that a dramatic conversion of xanthine dehydrogenase to xan- fold and found to migrate with a higher mobility on native gels thine oxidase activity occurred in rat intestinal segments that than the purified native dehydrogenase. Sodium dodecyl sulfate had been subjected to global ischemia with almost total con- profiles revealed the presence of a single major band of 137 kD version of dehydrogenase to oxidase occurring within 1 min. for the native dehydrogenase, whereas the oxidase had been par- However similar studies with rat liver, lung, and kidney showed tially cleaved generating polypeptides of 127, 91, and 57 kD. little conversion (only 10%) during a 1-h period of global isch- Polypeptide patterns for the oxidase resemble those seen fol- emia. lowing limited in vitro proteolysis of the native dehydrogenase In their original paper, Granger et al. (5) proposed that this supporting a proteolytic mechanism for the conversion of xan- conversion might be due to proteolytic processing of the native thine dehydrogenase to oxidase in ischemic rat liver. dehydrogenase. This was suggested by the irreversibility of the conversion with dithiothreitol and by previous reports by other Introduction investigators showing that conversion of xanthine dehydrogenase to oxidase can be accomplished in vitro by limited proteolysis Superoxide has been implicated as playing a major role in post- (15-17). However, dehydrogenase-to-oxidase (D-to-O)' conver- ischemic or reperfusion injury in a wide variety of tissues in- sion can be promoted in vitro by a variety of other treatments cluding intestine, heart, kidney, liver, and brain. Superoxide dis- including heating at 370, anaerobiosis, perturbation with organic mutase, an enzymatic scavenger of superoxide, provides exten- solvents, and sulfhydryl oxidation (17). sive protection against reperfusion injury in both in vivo and in If the model as proposed by Granger et al. (5) is to be gen- vitro heart, kidney, intestine, and liver models (1-7). eralized to explain reperfusion injury in tissues other than the One major source of superoxide in these reperfused tissues intestine, it is important to demonstrate that D-to-O conversion is the enzyme xanthine oxidase. Allopurinol and pterinaldehyde, occurs in these tissues in a time frame consistent with the isch- two structurally dissimilar inhibitors of xanthine oxidase, are emia-reperfusion injury process. Also, because the model calls both highly protective against certain types of reperfusion injury. for enzyme modification via proteolysis, it is important to doc- Allopurinol blocks reperfusion injury in the heart, kidney, in- ument that physical changes in the xanthine dehydrogenase/ testine, and liver (3, 4, 7, 8), improves posttransplant renal func- xanthine oxidase enzyme do accompany changes in dehydrog- tion and graft survival (9, 10), and increases survivability in enase and oxidase activities within the tissue and that those response to circulatory shock (1 1), whereas pterinaldehyde po- changes are due to proteolysis. tently decreases postischemic injury in the intestine (12). In the In this paper, we report the kinetic parameters of the con- heart, allopurinol also provides protection against reperfusion- version of xanthine dehydrogenase to xanthine oxidase in isch- induced arrhythmias (13). emic rat liver, lung, heart, and kidney, the temperature depen- The mechanism of xanthine oxidase-mediated reperfusion dence of this conversion, and the appearance of an ischemia- injury was first proposed by Granger et al. (5). According to their induced xanthine oxidase that is structurally distinct from the hypothesis, two important events were required during the isch- xanthine dehydrogenase found in normal tissue. In addition, we emic period to poise the tissue for injury once oxygen returned. report the purification ofthis converted oxidase form from isch- One of these events, the breakdown of ATP to AMP to hypo- emic rat livers and present evidence that the conversion of xan- thine dehydrogenase to oxidase in ischemic tissues is mediated Address correspondence to Dr. Harold P. Jones, Chairman, Department by proteolysis. of Biomedical Sciences, University of South Alabama, Mobile, AL 36688. Receivedfor publication 25 September 1986 and in revisedform 22 January 1987. Methods Materials. DEAE Sephacel and J. Clin. G-25 Sephadex were purchased from Invest. Pharmacia Inc., Piscataway, NJ, and HA-Ultrogel from LKB Instruments, © The American Society for Clinical Investigation, Inc. 0021-9738/87/06/1564/07 $1.00 Volume 79, June 1987, 1564-1570 1. Abbreviation used in this paper: D-to-O, dehydrogenase-to-oxidase. 1564 Engerson, McKelvey, Rhyne, Boggio, Snyder, and Jones Inc., Gaithersburg, MD. Acrylamide and ammonium persulfate were light brown in coloration, was applied to a 35 X 2.5-cm DEAE-Sephacel obtained from Boerhinger Mannheim Biochemicals, Indianapolis, IN, column preequilibrated with buffer A enzyme activity and eluted with and bisacrylamide, sodium dodecyl sulfate, and molecular weight stan- a 500 ml, 0.05-0.25 M NaCl gradient in buffer A. 5-ml fractions were dards from Bio-Rad Laboratories, Richmond, CA. a-chymotrypsin was collected and assayed for activity. obtained from Worthington Diagnostic Systems, Inc., Biochemical Pooled fractions from DEAE-Sephacel were desalted by chromatog- Products Division, Freehold, NJ, and bovine pancreatic trypsin from raphy on G-25-equilibrated with 50 mM potassium phosphate, 1 mM Sigma Chemical Co., St. Louis, MO. Protein was assayed with the Bio- dithiothreitol, 1 mM EDTA, and 0.2 mM phenylmethylsulfQnylfluoride, Rad Laboratories protein assay kit using bovine serum albumin purchased pH 7.0. The enzyme preparation was then applied to an hydroxylapatite from Sigma Chemical Co. as a standard. Leupeptin was obtained from column (HA-Ultrogel) (48 X 1.5 cm). The column was washed with the Boerhinger Mannheim Biochemicals. All other protease inhibitors, an- same buffer until no detectable protein eluted from the column asjudged tibiotics, and chemicals were purchased from Sigma Chemical Co. by absorbance measurements at 280 mM. Enzyme activity was then Tissue preparation and homogenation for measurement ofconversion. eluted from HA-Ultragel with a 500-ml, 0.05-0.40 M potassium phos- Tissues were surgically excised from male Sprague-Dawley rats, 250- phate gradient, pH 7.0, containing 1 mM EDTA, 1 mM dithiothreitol, 275 g, that had been euthanized by decapitation. Tissues were rinsed in and 0.2 mM phenylmethylsulfonylfluoride. 5-ml fractions were collected a phosphate-buffered saline (PBS) solution (0.15 M potassium phosphate, and assayed for xanthine dehydrogenase plus xanthine oxidase activity
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