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Catabolism and Interconversion of Cortisol and Cortisone in Human Synovial Tissue in Vitro by D

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Catabolism and Interconversion of Cortisol and Cortisone in Human Synovial Tissue in Vitro by D Ann Rheum Dis: first published as 10.1136/ard.28.6.637 on 1 November 1969. Downloaded from Ann. rheum. Dis. (1969), 28, 637 CATABOLISM AND INTERCONVERSION OF CORTISOL AND CORTISONE IN HUMAN SYNOVIAL TISSUE IN VITRO BY D. MURPHY AND H. F. WEST Rheumatism Research Unit, Nether Edge Hospital, Sheffield The object of this study has been to find out whet- Db (1) and Db (2) were women aged 73 with well- her cortisol and cortisone are interconverted and controlled diabetes who had gangrene ofthe toes. Gritti- catabolized in human rheumatoid synovial tissue and Stokes' amputations were performed and the synovial to identify the catabolites. No formal comparison tissue dissected from the lower part of the joint excluding of rheumatoid and non-rheumatoid synovial tissue the suprapatellar pouch. has been made, but sufficient evidence has been The rheumatoid tissue included the suprapatellar obtained to justify such a study. That extra-hepatic pouch and contained much fat. It was histologically tissues are able to metabolize cortisol in vitro has typical of RA. That from the diabetic subjects contained little fat, was much less in quantity, and was not studied been demonstrated by very many authors, but the histologically. relevance of this to events in vivo has been in doubt as it has been generally assumed that cortisol is Radioactive Steroids almost entirely metabolized in the liver. From in- Cortisol-4-14C (14C-cortisol), specific activity 156 tkCi./ copyright. direct evidence Murphy and West (1964) deduced mg., cortisone-1 ,2-T (3H-cortisone), specific activity that this assumption was incorrect, and now Bailey 94 pCi./ ug., and cortisol-1,2-T, specific activity 60pCi./,tg. and West (1969) have confirmed this and have were obtained from the Radiochemical Centre, Amersham shown that under normal conditions it is the extra- and were re-purified before use in the Bush B5 chromato- hepatic tissues that are mainly responsible for the graphy system (Bush, 1961). The quantities used for interconversion and catabolism of cortisol and each incubation from RA (2), RA (3), Db (1), and Db (2) cortisone. Hence the past studies in vitro and those were approximately 0 1 ,tg. 3H-cortisone (10 uCi.); this and 6 pg. 14C-cortisol (1 uCi.). Only 3H-cortisol (0 075 ,tg.- of paper are very relevant to physiological 4- 5 pCi.) was added to the incubates from RA (1). pathological processes. It is possible that a local- http://ard.bmj.com/ ized tissue could have a subnormal effective con- Incubation centration of cortisol that would, among other The excised tissue was immediately cut into small frag- things, reduce the stability of lysosomes. Such a ments and placed in 100 ml. Krebs-Henseleit medium. state of affairs might be advantageous in some The medium, previously gassed with 95 per cent. oxygen circumstances and the reverse in others. and 5 per cent. CO2, was gassed again, the radioactive steroids were added, and incubation was carried out at Material and Methods 37°C. for 2 hrs. At the end of this time the medium Synovial Tissue was poured off and 100 ml. physiological saline were on October 1, 2021 by guest. Protected The entire synovial tissue removed at operation from a added to the tissue which was then left over-night at knee was used in the case of three patients with rheuma- 370C. toid arthritis (RA). Extraction RA (1) A man aged 44 with very active RA who was One-tenth of the medium and of the saline (into which receiving a nigh level of adrenocortical stimulation with the tissue steroids had diffused) was made up to 50 ml. ACTH. with water and extracted with 3 x 1 vol. freshly distilled RA (2) A woman aged 33 who had no general rheuma- ethyl acetate. The extracts were washed with 0- 1 vol. toid activity. The tissue came from a knee that had a N.Na2CO3, 1/20th vol. saturated NaCI and 1/20th vol. thickened synovial membrane and had been the site of 2 per cent. acetic acid. The tissue was shaken for 1 hr recurrent effusions over many years. at 37°C. with 100 ml. ethanol. The ethanol was then replaced with a second 100 ml. and reshaken. The RA (3) A man aged 44 who had moderately active combined ethanol extracts were evaporated to dryness RA and in whom the synovial membrane was chronically and transferred to a separating funnel with 100 ml. thickened. freshly distilled ethyl acetate and 100 ml. water. The 637 Ann Rheum Dis: first published as 10.1136/ard.28.6.637 on 1 November 1969. Downloaded from 638 ANNALS OF THE RHEUMATIC DISEASES ethyl acetate extract was further purified as for the were also extracted and chromatographed as for medium and saline above. The water in each extract the incubates. In both cases some impurities were was frozen out and the subsequently evaporated extracts found that were the same in the standards as in the partitioned between I ml. petroleum ether (100 120°) and heated cultures. Fig. 1 shows the saline diffusate 4 ml. 70 per cent. methanol. The petroleum ether extract and control saline diffusate extract of RA (2) layer was removed and the aqueous methanol extract evaporated to dryness. on B5 chromatograms. It will be seen that there was a little radioactivity of highly polar nature in the Chromatography control. When the most polar region of the B5 Extracts were run in duplicate in the Bush B5 chroma- chromatograms were eluted and acetylated and run tography system (Bush, 1961) at 280 in a constant temp. in the Smith VI system, some unidentified radio- room until the solvent front had progressed 38-39 cm. activity stayed near the origin-this may have been One of each pair was cut into 38 to 40 1-cm. strips for the contaminating material. Fig. 1 also shows that elution and radioactivity measurement. On the basis of there was some radioactivity near the solvent front these measurements four regions were cut from the where 11-desoxy-17-oxosteroids would run. This duplicate chromatograms for further analysis of the more area of the incubate chromatograms was not further polar metabolites (mainly 20-dihydrocortisols), the less polar metabolites (mainly 20-dihydrocortisones), cortisol, studied. and cortisone (see Fig. 1). An aliquot of each eluate was acetylated and run in the Bush 3b system (Bush, 1961). Identification of the Steroids In the case of RA (1), another aliquot of each eluate was Fraction 1 (Fig. 1).-In each case this fraction was oxidized with sodium bismuthate and run in the Smith VI system (Smith, Foell, De Maio, and Halwer, 1959), eluted from the duplicate B5 chromatogram, acety- and aliquots of the most polar region from RA (1), RA (3) lated, and run in the Smith VI system. Fig. 2 shows and Db (2) were run in the Smith II system (Smith and a representative Smith VI chromatogram(from Db2). others, 1959). For further identification of cortisol, The peak at the origin, the identity of which was cortisone, 20a-dihydrocortisol, 2013-dihydrocortisol, 20a- unknown, was always most prominent in the medium dihydrocortisone, and 20P-dihydrocortisone, larger ali- extract. The 2nd and 3rd peaks have the Rfs of quots of the extracts were chromatographed and the 20fi-dihydrocortisol and 20a-dihydrocortisol di-copyright. named steroids isolated as their acetates. The combined acetates respectively. The diffuse double peaknearthe peaks of 20a and 20,B-dihydrocortisone were eluted and solvent front corresponded in Rf to the diacetates separated by thin layer chromatography using 5 per cent. the cortols and cortolones. In RA fraction ethanol in ether. To each isolate was added 5 mg. of the of (1), relevant standard steroid acetate and the specific activity I run in the Smith II system gave a small peak with measured. The steroids were then crystallized from the Rf of 6,B-hydroxycortisol, but in RA (3) and acetone/hexane or acetone/methanol/hexane four times. Db (2) there was no such peak. In the Smith VI Each time the specific activities of the mother liquor and chromatograms of the acetates, 6,B-hydroxycortisol the crystals were measured. diacetate, if present, would have run with 20f,- dihydrocortisol diacetate. 20a and 2O0-dihydro-http://ard.bmj.com/ Radioactivity Measurements cortisol were further identified in the tissue and A "Tricarb" Model 3003 liquid scintillation spectro- saline extracts of RA (1) and RA (2) by crystalliza- meter was used. To specimens in 1 ml. ethanol, 10 ml. tion of their diacetates to constant specific activity Butyl-PBD was added (Ciba 6g./1). For chromatogram with standards. Table I gives the findings in eluates and clean extracts the efficiencies were in the RA which confirmed that the eluted steroids tritium channel for tritium 16-5 per cent. and for 14C (2), 4 per cent.; in the 14C channel, 14C 58 per cent. contained little contaminating material. on October 1, 2021 by guest. Protected Results TABLE I CRYSTALLIZATION TO CONSTANT SPECIFIC ACTIVITY More than 90 per cent. of the radioactivity added OF 20a and 2013-DIHYDROCORTISOL ACETATES ELUTFD FROM CHROMATOGRAMS was recovered in the ethyl acetate extracts, thus (miLCi./mg.) showing that if conjugates were present at all the Acetates 20a-dihydrocortisol 200-dihydrocortiso1 amount was very small. 3H 14C 'H 1UC Controls Eluate 2-9 04 4-7 0o9 Crystals 1st 3-2 0 S 4-8 1.0 In RA (1) and RA (2) the tissues were divided into 2nd 3-0 0.4 4-9 1-0 3rd 3-3 0 5 5 2 1-1 two and placed in separate flasks with incubation 4th 3-3 05 5 2 1-1 media.
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