Β-Glucuronidase HYDROLYSIS OF URINARY CORTICOSTEROID CONJUGATES: THE EFFECT OF SALICYLATE GLUCURONOSIDE AS a COMPETING SUBSTRATE AND THE EFFECT OF ENZYME INACTIVATION*

Stempfel, Robert S.; Sidbury, James; Migeon, Claude J.

doi:10.1210/jcem-20-6-814

Cited by 26 publications

(8 citation statements)

References 13 publications

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“…This indicates an inhibition of ,B-glucuronidase by DPH or its major metabolite, 5-(p-hydroxyphenyl) -5-phenylhydantoin (24), which is conjugated with glucuronic acid (25). Although the mechanism of inhibition was not studied, it is conceivable that it might be a competitive one as noted with the glucuronide of acetylsalicylic acid (26 (11,12,16,23,27) and by Ulstrom, Colle, Burley, and Gunville (13). The latter group noted that 6-OHF was a major metabolite of cortisol in newborn infants.…”

Section: Discussionmentioning

confidence: 99%

Effect of Diphenylhydantoin on Cortisol Metabolism in Man *

Werk¹,

MacGee²,

Sholiton³

1964

J. Clin. Invest.

166

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During a study of cortisol metabolism in advanced cancer and other disease states (1), we observed in patients receiving DPH 1 therapy for convulsive seizures an abnormal pattern of excretion of cortisol metabolites in urine. This abnormal pattern was characterized by increased urinary output of the polar unconjugated metabolite 6-OHF, suggesting an interference with extraadrenal metabolism of cortisol by DPH. We =5,5'-diphenylhydantoin; 6-hydroxycortisol (6 -OHF) = 6a (/3), 11,/, 17a, 21 -tetrahydroxy -4 -pregnene-3,20 -dione; 17-OHCS = 17-hydroxycorticosteroids; ACTH = adrenocorticotrophic hormone; methopyrapone (Metopirone, Ciba Pharmaceutical Co., Summit, N. J.) =2-methyl-1,2-di-(3-pyridyl)-1-propanone. Tetrahydro derivatives: THF (tetrahydrocortisol) = 3a,11,, 17a,21-tetrahydroxy-5/8-pregnan-20-one; allo-THF (allotetrahydrocortisol) = 3a,11/3,17a,21-tetrahydroxy-5a-?pregnan-20-one; THE (tetrahydrocortisone) = 3a,17a,21-trihydroxy-5p-pregnan-11,20-dione. Cortol = 3a,11,8,17a,20a (/3),21-pentahydroxy-5/3-pregnane; cortolone = 3a,17a,20a (/3) ,21-tetrahydroxy-5/8-pregnan-11-one; 17-KS = 17-ketosteroids; 1 1-hydroxyetiocholanolone = 3a,1j1/-dihydroxy-5,B-androstan-17-one; dehydroisoandrosterone = 3/3-hydroxy-5-androstene-17-one; TPNH = reduced triphosphopyridine nucleotide; o,p'DDD = 2,2-bis (2-chlorophenyl,4-chlorophenyl) 1,1-dichloroethane. since a) adrenal hypertrophy was observed in intact rats and b) in adrenalectomized rats treated with DPH a more profound decrease in brain excitability was demonstrated than in intact rats. Goncharov has observed that acute administration of DPH to dogs and guinea pigs increases adrenocortical output of cortisol (3). Reports by Staple (4) and Bonnycastle and Bradley (5) have, however, indicated an inhibition of pituitary-adrenal secretion after chronic DPH treatment of mice and rats.In humans also cortisol has been shown to enhance brain excitability (6). After chronic DPH therapy to patients, excretion of corticosteroids in urine is reported to decrease (7, 8) after an initial increase (7). These findings have led to the suggestion that the decrease in brain excitability induced by DPH might be mediated partially through adrenocortical suppression. However, levels of 17-OHCS in plasma from patients treated with DPH are usually normal (8, 9), as are responses to ACTH (8, 9) and rates of disappearance from plasma of infused cortisol (8). These observations detract from the possibility that direct adrenocortical suppression plays a significant role in therapeutic effectiveness of DPH. Recently, however, Krieger has demonstrated that control subjects treated with DPH manifest a reduced response in the methopyrapone test, which suggests an interference with ACTH release (10).2) The increased excretion of 6-OHF produced by DPH appears to be similar to that we have observed in patients with advanced cancer and certain terminal illnesses (1) as well as to that reported after estrogen therapy (11), during pregnancy (12), and in newborn infants (13).Thus we hoped that furthe...

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Section: Discussionmentioning

confidence: 99%

Effect of Diphenylhydantoin on Cortisol Metabolism in Man *

Werk¹,

MacGee²,

Sholiton³

1964

J. Clin. Invest.

166

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“…These two patients re¬ ceived aspirin; it is probable that the low values reported were due to the inhibitory effect of the competing salicylate conjugate present in the urines. 19 Urinary 17 OHCS were elevated in three of four patients under hypothermia and in the survivor of varicella encephalopathy, but were relatively less elevated than were the CPRs. In the patients under hypo¬ thermia, this may have resulted from the inhibitory effect of hypothermia on glucuronidation.15 Summary Cortisol production rates (CPRs) were increased in encephalopathy due to rubella and varicella in five of six patients.…”

Section: Use Of Steroids In Encephalopathy Andmentioning

confidence: 87%

Cortisol Production

Preeyasombat¹

1965

Am J Dis Child

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“…It is curious that in many of the studies on the activity of ß-glucuronidase in a variety of biological fluids including urine relatively little effort has been made to eliminate or minimize the effect of endogenous inhibitors, considering that the presence of inhibitors has been known for almost two decades [1,8], Similarly, in the analysis of steroid hormones in biological fluids where enzymatic hydrolysis has been used to cleave glucuronic acid from the steroid, the most common approach has been to use prolonged incubations with a large excess of enzyme rather than to remove the inhibitors [11,13,26]. The prolonged incubations are less than satisfactory because in some applications prompt results are requisite and because of the potential lability of some steroids under these conditions [25].…”

Section: Discussionmentioning

confidence: 99%

Urinary Inhibitors of ß-Glucuronidase

Kushinsky¹,

Chen²

1967

Enzymol Biol Clin

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A study has been made of some of the properties of the inhibitors of ß-glucuronidase in human urine. The inhibitory properties were determined by comparing the effect on the activity of ß-glucuronidase of urine pre-treated in many ways with that of a control containing no urine. A significant though variable fraction of the inhibition is caused by rapidly hydrolyzing competitive substrates of normal dietary or therapeutic origin. Other inhibitors such as 1,4-saccharolactone probably account for a substantially greater fraction of the inhibition than do the competitive substrates. The inhibition by 1,4-saccharolactone is a function of the pH, temperature and time of equilibration of the medium. Saccharolactone can he separated from the conjugated estrogens in urine by gel-filtration on Sephadex. The extent which non-substrate, competitive inhibitors or competitive substrates reduce the activity of ß-glucuronidase is a function of the inhibitor constant (K(I)) or the Michaelis constant (Km) respectively and the concentrations of these substances. On prolonged standing the activity of ß-glucuronidase is reduced more in the presence of urine than in the absence of urine. This phenomenon probably is due at least partially to the slow formation of saccharolactone from endogenous saccharic acid in urine.

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Β-Glucuronidase HYDROLYSIS OF URINARY CORTICOSTEROID CONJUGATES: THE EFFECT OF SALICYLATE GLUCURONOSIDE AS a COMPETING SUBSTRATE AND THE EFFECT OF ENZYME INACTIVATION*

Cited by 26 publications

References 13 publications

Effect of Diphenylhydantoin on Cortisol Metabolism in Man *

Effect of Diphenylhydantoin on Cortisol Metabolism in Man *

Cortisol Production

Urinary Inhibitors of ß-Glucuronidase

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