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Endogenous Benzodiazepine-Like Compounds and Diazepam Binding Inhibitor in Serum of Patients Gut: First Published As 10.1136/Gut.42.6.861 on 1 June 1998

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Endogenous Benzodiazepine-Like Compounds and Diazepam Binding Inhibitor in Serum of Patients Gut: First Published As 10.1136/Gut.42.6.861 on 1 June 1998 Gut 1998;42:861–867 861 Endogenous benzodiazepine-like compounds and diazepam binding inhibitor in serum of patients Gut: first published as 10.1136/gut.42.6.861 on 1 June 1998. Downloaded from with liver cirrhosis with and without overt encephalopathy R Avallone, M L Zeneroli, I Venturini, L Corsi, P Schreier, M Kleinschnitz, C Ferrarese, F Farina, C Baraldi, N Pecora, M Frigo, M Baraldi Abstract The involvement of this receptor system in Background/Aim—Despite some contro- overt hepatic encephalopathy (OHE), discov- versy, it has been suggested that endog- ered in the 1980s during studies on GABAA enous benzodiazepine plays a role in the receptors in the brain of animals with OHE, pathogenesis of hepatic encephalopathy. was considered likely when specific benzodi- The aim of the present study was to evalu- azepine receptor antagonists were shown to ate the concentrations of endogenous ben- revert the symptoms of encephalopathy in ani- zodiazepines and the peptide, diazepam mal models4 and in patients.56 Later, the binding inhibitor, in the blood of patients observation of an increased presence of endog- with liver cirrhosis with and without overt enous benzodiazepine receptor ligands (BZDs) encephalopathy, and to compare these in animals and patients with OHE7–13 suggested levels with those of consumers of com- that this phenomenon may contribute to the mercial benzodiazepines. enhancement of GABAergic neurotrans- 14 Subjects—Normal subjects (90), benzodi- mission. We cannot exclude, however, the azepine consumers (14), and cirrhotic possibility that compounds such as 1315 16 patients (113) were studied. ammonia or neurosteroids contribute to Methods—Endogenous benzodiazepines the above mentioned increased functional were measured by the radioligand binding activity of the GABAA receptor system. BZD- technique after high performance liquid like compounds and ammonia may potentiate chromatography (HPLC) purification. inhibitory GABAergic neurotransmission by Cattedra di Semeiotica 17 The presence of diazepam and acting synergistically. http://gut.bmj.com/ e Metodologia Medica, The endogenous receptor ligands found in Università di Modena, N-desmethyldiazepam was assayed by 79 Modena, Italy HPLC-electrospray tandem mass spec- blood and brain during OHE were called M L Zeneroli trometry. Diazepam binding inhibitor was BZD-like substances since they are a mixture I Venturini studied in serum by radioimmunoassay. of the halogenated 1,4-benzodiazepines (such F Farina as diazepam) and non-halogenated BZDs Results—Endogenous benzodiazepines C Baraldi (called “endozepines”). Although the chemical were below the limit of detection in 7% of structure of the endozepines is not yet fully patients with encephalopathy. When de- on September 27, 2021 by guest. Protected copyright. Lehrstuhl für characterised, it is fair to surmise that they Lebensmittelchemie, tectable, their levels were at least compa- contribute to OHE. Universität Würzburg, rable with those of benzodiazepine Halogenated BZDs are naturally present in Würzburg, Germany consumers and correlated with the liver P Schreier several plants and vegetables,18 in brain tissues dysfunction but not the stage of encepha- M Kleinschnitz of diVerent animal species and in man.19 Their lopathy. Serum levels of diazepam binding sources have not yet been clarified, but the Clinica Neurologica, inhibitor tended to decrease when endog- observation that they are present in human Università di Milano enous benzodiazepines levels increased. brain samples stored since 194020 indicates that (Monza), Italy —Endogenous benzodiaze- C Ferrarese Conclusions they do not derive from environmental pollu- pines may accumulate in patients with N Pecora tion with synthetic BZDs, which have been M Frigo liver cirrhosis during the course of the produced commercially since 1959. These disease, and the phenomenon appears to compounds and their precursors are compo- Dipartimento di be independent of the presence or absence 18 Scienze nents of our diet. An exogenous biosynthetic of encephalopathy. pathway for the production of such compounds Farmaceutiche, (Gut 1998;42:861–867) Università di Modena cannot, however, be excluded since we recently M Baraldi Keywords: benzodiazepine consumers; diazepam showed that a reduction in the intestinal bacte- R Avallone binding inhibitor; endogenous benzodiazepines; liver rial flora caused by a non-absorbable antibiotic L Corsi cirrhosis; overt hepatic encephalopathy partially decreases the levels of these com- 21 Correspondence to: pounds in the blood. Professor Maria Luisa Other endogenous BZDs such as the neuro- Zeneroli, Cattedra di Hepatic encephalopathy is one of the major peptide called diazepam binding inhibitor Semeiotica e Metodologia complications of liver cirrhosis, and it is a com- Medica, Dipartimento di (DBI) and its metabolite, the octadecaneuro- Medicina Interna, Università ponent of fulminant hepatic failure character- peptide, which decreases GABAA neuro- di Modena, Via del pozzo ised by impairment of the central nervous sys- transmission,22 have been found to be increased 71–41100, Modena, Italy. tem, which is believed to develop from in the cerebrospinal fluid of patients with 23 Accepted for publication increased tone of the inhibitory ã-aminobutyric OHE and in brain regions of rats with porta- 1–3 24 18 December 1997 acid (GABAA) receptor system (for reviews, ). caval anastomosis. 862 Avallone, Zeneroli, Venturini, et al Table 1 Patient characteristics The serum obtained from all patients was stored at −80°C until used and individually Liver cirrhosis processed for the assay of BZDs and DBI. The Controls A B C BZD comsumers study was carried out with the approval of the Gut: first published as 10.1136/gut.42.6.861 on 1 June 1998. Downloaded from No 90 33 41 39 14 local ethical committee. Men 461828303 Women 44 15 13 9 11 QUANTIFICATION OF ENDOGENOUS BZD-LIKE Age (y) (mean (SD)) 63 (9) 59 (9) 57 (11) 50 (11) 65 (4) Aetiology of cirrhosis COMPOUNDS 9 Viral – 22 27 28 – As previously described, aliquots of all the Alcoholic – 6 11 6 – serum samples (1 ml) were acidified with ace- Viral + alcoholic – 535– Overt encephalopathy (stage) tic acid (1 M), and centrifuged at 3000 g for ten 0 – 33 16 10 – minutes. The supernatant was passed through I––166–previously washed Sep-Pak C cartridges II – – 9 10 – 18 III – – – 8 – (Millipore, Medford, MA, USA). The material IV – ––5– was eluted from Sep-Pak with acetonitrile/ 0.1% trifluoroacetic acid (TFA) and then A–C, functional status of the liver classified according to Child-Pugh. lyophilised. The lyophilised samples were Since few studies have been performed on reconstituted with 1 ml water, and aliquots endogenous circulating BZDs in patients with (200 µl) were chromatographed in duplicate at OHE due to fulminant hepatic failure13 or liver 0.8 ml/min on a LiChrospher 100 RP-18 cirrhosis,7910the aim of the present study was column (250 × 4.0 mm; 5 µm) equilibrated to (a) evaluate the concentrations and nature of with 80% water/0.1% TFA and 20% ac- BZD-like compounds in the plasma of patients etonitrile. Absorbance was monitored at 230 with liver cirrhosis with and without OHE, (b) nm. Samples were chromatographed using a compare the levels found in liver cirrhotic water/0.1% TFA and acetonitrile gradient at patients with those present in the plasma of 0.5% per minute from 20 to 58% acetonitrile. consumers of commercial BZDs in order to Seventy five fractions (one per minute) from estimate their pharmacological relevance, and each sample were collected, lyophilised, and (c) study the levels of DBI in both the patients reconstituted with water before radioreceptor and BZD consumers, bearing in mind that lit- assay. Known concentrations of diazepam, tle is known about the mutual interaction of N-desmethyldiazepam, oxazepam, lorazepam, BZD compounds and DBI at the periphery. delorazepam, and 2’-chlordiazepam were run in parallel with the plasma samples. Methods Unless otherwise indicated, all reagents were SUBJECTS (TABLES 1 AND 2) obtained from Sigma Chemical Co. and were We studied 113 patients with liver cirrhosis and all high performance liquid chromatography http://gut.bmj.com/ 90 normal subjects, who appeared to be free of (HPLC) grade. All the fractions were then commercial BZD medication for at least three tested for their ability to inhibit months as verified by patient, family, and [3H]flunitrazepam (1 nM; specific activity 87 medication records. Moreover 14 normal sub- Ci/mmol; NEN, Boston, MA, USA) binding to jects who were habitual consumers of commer- rat cerebellar membrane preparations, which cial BZDs were included in the study. The are a source of BZD receptors,9 and containing diagnosis of liver cirrhosis was based on 180–200 µg protein/100 µl measured by Brad- biochemical tests and liver biopsy. Fifty nine ford’s method.27 Data were expressed as on September 27, 2021 by guest. Protected copyright. patients showed no evidence of OHE while the diazepam equivalents (DE) based on extrapo- other 54 showed diVerent stages of impaired lation from standard displacement curves gen- mental status. The stage of OHE was evaluated erated using diazepam. The total concentration on the basis of electroencephalographic of BZD-like compounds present in each serum pattern.25 This test allowed the classification of was calculated by determining the DE derived the cirrhotic patients into the following catego- from the displacement activity of any single ries: 59 with stage 0, 22 with stage I, 19 with peak and then summing the values of all peaks. stage II, eight with stage III, and five with stage Since the chemical identities of all the com- IV. The functional status of the liver was clini- ponents of the BZD-like material are not cally classified according to the Child-Pugh known, their extraction eYciencies could not classification.26 Table 1 gives the characteristics be determined. The limit of detection of of the patients included in the study, and table diazepam by [3H]flunitrazepam binding was 2 2 contains laboratory data. nmol DE/l with a coeYcient of variation of The 14 regular consumers of BZDs, who 0.52.
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