17-Hydroxycorticosteroid Metabolism in Liver Disease1

Brown, Harold; Willardson, Donald G.; Samuels, Leo T.; Tyler, Frank H.

doi:10.1172/jci103031

Cited by 128 publications

(38 citation statements)

References 13 publications

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“…In patients with liver disease, cortisone disappeared from the plasma at the normal rate, whereas hydrocortisone has been shown to be metabolized at a much slower rate (1,7). In patients with liver disease, cortisone was metabolized at the same rapid rate as the biologically inactive dihydro and tetrahydro metabolites of cortisone and hydrocortisone.…”

Section: Discussionmentioning

confidence: 99%

“…Tetrahydrocortisone made up the major portion of the metabolites reacting with phenylhydrazine, and tetrahydrocortisone and tetrahydrohydrocortisone accounted for 93 per cent of all the phenylhydrazine-reactive glucuronide conjugates. 7 After prior hydrolysis of the conjugated prod- 7 The following unpublished data may be pertinent to the findings that following intravenous administration of cortisone, the urinary concentration of tetrahydrocortisone glucuronide greatly exceeds the concentration of tetrahydrohydrocortisone glucuronide: Following intravenous infusion of tetrahydrocortisone, seven per cent was recovered in the urine as tetrahydrohydrocortisone, and 40 per cent as tetrahydrocortisone after glucuronidase hydrolysis. Twenty per cent of infused tetrahydrohydrocortisone was recovered in the urine as tetrahydrocortisone, and 30 per cent as tetrahydrohydrocortisone after glucuronidase hydrolysis Thus, the presence of the a, fI unsaturated 3-keto group in ring A seems to direct the enzymatic reduction of cortisone --hydrocortisone, whereas the saturated ring A seems to favor oxidation of the lipgroup (tethydrohydrocortisone -) tetrahydrocortisone).…”

Section: Discussionmentioning

confidence: 99%

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The Physiological Disposition and Metabolic Fate of Cortisone in Man

Peterson¹,

Pierce²,

Wyngaarden³

et al. 1957

J. Clin. Invest.

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In an earlier paper we described studies on the physiological disposition and metabolic fate of hydrocortisone in man (1). This paper describes similar studies on cortisone. Although contributing very little to the body pool of adrenal cortical steroids, cortisone has been used extensively as a therapeutic agent, and it was therefore of interest to compare its metabolism with that of hydrocortisone. Large doses of cortisone and hydrocortisone were administered intravenously and rates of disappearance from the plasma determined in normal subjects and in patients with liver disease, myxedema, thyrotoxicosis, and rheumatoid arthritis. Trace quantities of cortisone-4-C" and hydrocortisone-4-C" were employed in certain studies. From these studies, information was obtained regarding rate of metabolic transformation, rate of absorption, rates and routes of excretion of cortisone and its metabolites, and, to some extent, the identity and amount of these metabolites. Information was also obtained on the in vivo conversion of cortisone to hydrocortisone. MATERIALS AND METHODSAdministration of steroid. The steroids were dissolved in 25 ml. ethanol and added to 500 ml. of sterile five per cent dextrose in water. This solution was administered intravenously over a period of 10 to 20 minutes. For oral or intramuscular administration the steroids were suspended in saline. Cortisone-4-C" was administered intravenously in trace quantities in a small volume of five per cent ethanol in water over a period of 3 to 5 minutes, or mixed with carrier cortisone and given in 500 ml. of three per cent ethanol in five per cent dextrose in sterile distilled water. Following the administration of the steroids, blood samples were drawn in heparinized syringes every 20 or 30 minutes for 2 hours-or more.Urine samples were collected and preserved by freezing.Methods of assay. The extraction procedures for the steroids in plasma and urine were the same as those de-

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The Physiological Disposition and Metabolic Fate of Cortisone in Man

Peterson¹,

Pierce²,

Wyngaarden³

et al. 1957

J. Clin. Invest.

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“…Prolonged stress A quantitative study of the urinary metabolites from a patient severely ill for several months is shown in Table IV 14 . t The absence of detectable quantities of allo-THF is not an artifact of the paper chromatography.…”

Section: -18 Altered Ratio Op Urinary Cortisol Metabolitesmentioning

confidence: 99%

“…Together with urinary procedures (5,6) these techniques have been employed to determine the secretion of cortisol by the adrenal in normal and pathological conditions (7)(8)(9) and to evaluate the factors involved in the "removal" of cortisol from the plasma in surgery (10)(11)(12)(13) and liver disease (14)(15)(16).…”

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confidence: 99%

Quantitative Determination of the Urinary Cortisolc Metabolites, “Tetrahydro F,” “Allo-Tetrahydro F” and “Tetrahydro E”: Effects of Adrenocorticotropin and Complex Trauma in the Human1

Gold¹,

Singleton²,

Macfarlane³

et al. 1958

J. Clin. Invest.

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Methods for the quantitative estimation of plasma cortisol concentration have been devised by Nelson and Samuels (1), Silber and Porter (2), and Peterson and Wyngaarden (3) who used the sulfuric acid-induced fluorescence developed by Sweat (4). Together with urinary procedures (5, 6) these techniques have been employed to determine the secretion of cortisol by the adrenal in normal and pathological conditions (7-9) and to evaluate the factors involved in the "removal" of cortisol from the plasma in surgery (10-13) and liver disease (14-16).Although a considerable amount of work has been done in isolating and identifying such urinary metabolites of cortisol as THF8 and THE (17-22) and their interconversions (23-25), much less has been done to relate the quantitative transformations of these urinary metabolites from cortisol under normal and pathological conditions. In 1953, deCourcy, Bush, Gray, and Lunnon (26) reported daily excretion values for two chromatographically separated urinary steroids corresponding in migration rates to THF and THE, in 10 1 This work was suported in part by a grant from the Atomic Energy Commission. It was sponsored and supported in part by the Subcommittee on Metabolism in Trauma, Advisory Committee on Metabolism, Office of the Surgeon General, Department of the Army, through a contract (DA-49-MD472) with Harvard University.The assistance of Winthrop Laboratories, Inc., and The Upjohn Co. is gratefully acknowledged.2 Present address: The Medical College of St. Bartholomew's Hospital, London. 3 Compounds referred to are the following: THF, tetrahydrocortisol (3a,11p,17a,21-tetrahydroxypregnan-20-one ); allo-THF (3a,1 1,l17a,21-tetrahydroxyallopregnan-20-one); THE, tetrahydrocortisone (3a,17a,21-trihydroxypregnan-11,20-dione); F, cortisol (llfi,17a,21-trihydroxypregnan-3,20-dione); E, cortisone (17a,21-dihydroxypregnan-3,11,20-trione).normal men. The mean values were 212 tg. per 24 hours for THF and 1.5 mg. per 24 hours for THE, giving a ratio for THF: THE of 0.14. Romanoff, Seelye, Rodriquez, and Pincus (27) have recently published quantitative data on the excretion of THF and THE combined with allo-THF (28, 29) in one group of normal men and in a group of schizophrenic men. There was no essential difference in the ratio of THF:(THE plus allo-THF) between the two groups of men, and the ratio was reported as approximately 1: 2. Cope and Hurlock (30) published data on the excretion of urinary THF and THE in several normal and surgical cases. Their results indicated increased excretion of these metabolites after surgery but did not show any other definite pattern of alteration of the metabolism of cortisol, although they state that "a tendency can be observed for tetrahydro-compound F excretion to rise more than does tetrahydrocortisone." In a preliminary report, Gold, Macfarlane, and Moore (31) showed that the relative proportions of the two urinary cortisol metabolites, THF and THE, were related to situations of "stress" and adrenocorticotropin (ACTH) administration. It is the purpo...

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“…6 The same authors believe that the defect in degradation of corticoids manifested by all these types of patients lies not in failure of conjugation but is due to a block in the normal mechanism which transforms free hydrocortisone to the tetrahydroderivatives. In a few instances, hypothyroid CHART II.…”

Section: Discussionmentioning

confidence: 99%