Occurrence of pharmacologically active benzodiazepines in trace amounts in wheat and potato

Wildmann, Johannes; Vetter, Walter; Ranalder, Urs B.; Schmidt, Klaus Werner; Maurer, R.; Möhler, Hanns

doi:10.1016/0006-2952(88)90384-x

Cited by 61 publications

(25 citation statements)

References 11 publications

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“…However, dietary sources may be important, since BZs have been reported in a number of plant and animal foodstuffs (26). We have isolated active fractions that exhibit retention times identical with known BZs in extracts of the chow fed to the rats used in the present experiments (data not shown).…”

Section: Discussionmentioning

confidence: 75%

Brain concentrations of benzodiazepines are elevated in an animal model of hepatic encephalopathy.

Basile

Pannell

Jaouni

et al. 1990

Proc. Natl. Acad. Sci. U.S.A.

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Brain extracts from rats with hepatic encephalopathy due to thioacetamide-induced fulminant hepatic failure contained 4-to 6-fold higher concentrations of substances that inhibit radioligand binding to benzodiazepine receptors than corresponding control rat extracts. Both isocratic and gradient-elution HPLC indicated that this inhibitory activity was localized in 3-8 peaks with retention times corresponding to deschlorodiazepam, deschlorolorazepam, lorazepam, oxazepam, diazepam, and N-desmethyldiazepam. The presence of diazepam and N-desmethyldiazepam was confirmed by mass spectroscopy. Both mass spectroscopic and radiometric techniques indicated that the concentrations of N-desmethyldiazepam and diazepam in brain extracts from encephalopathic rats were 2-9 and 5-7 times higher, respectively, than in control brain extracts. While benzodiazepines have been identified previously in mammalian and plant tissues, this report demonstrates that concentrations of these substances are increased in a pathophysiological condition. These findings provide a rational basis for the use of benzodiazepine receptor antagonists in the management of hepatic encephalopathy in humans.Hepatic encephalopathy (HE) is a complex neuropsychiatric disorder arising from the metabolic abnormalities associated with acute or chronic liver failure (1). It has been proposed that an increase in the activity of y-aminobutyric acid (GABA)-containing pathways contributes to the manifestations of this disorder (2). Studies of visual evoked responses in the galactosamine-treated rabbit model of HE due to fulminant hepatic failure (FHF) (3) and in rats with HE due to thioacetamide (TAA)-induced FHF (4) indicate that central nervous system (CNS) GABAergic tone is increased in these models of HE. Electrophysiologic studies of single cerebellar Purkinje neurons in the rabbit model of HE further support this hypothesis. These neurons are hypersensitive to depression by the GABA receptor agonist muscimol and the benzodiazepine (BZ) receptor agonist flunitrazepam, but not to the a-adrenergic receptor agonist phenylephrine (5). In contrast, BZ receptor antagonists increase the spontaneous firing rate of these neurons and reverse their hypersensitivity to muscimol at concentrations that do not affect the firing rates of control neurons (5). Furthermore, BZ receptor antagonists correct the abnormalities in visual evoked responses associated with HE while transiently reversing the behavioral manifestations of this syndrome in both the rabbit and rat models of this disorder (3, 4).These observations indicate that the increase in "GABAergic tone" found in HE may be mediated by the BZ receptor, possibly as a consequence of an increase in the concentration or availability of a BZ receptor ligand with agonist (BZ-like) properties (6, 7). Elevated concentrations of substances that competitively and reversibly inhibit radioligand binding to BZ receptors have recently been found in extracts of brain and peripheral tissues from the TAA-treated rat model of HE (8)....

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Section: Discussionmentioning

confidence: 75%

Brain concentrations of benzodiazepines are elevated in an animal model of hepatic encephalopathy.

Basile

Pannell

Jaouni

et al. 1990

Proc. Natl. Acad. Sci. U.S.A.

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“…Malabsorption could interfere with the regulation of mood, bearing in mind that a high number of food factors are involved in monoaminergic synthesis [27] . Previous studies also showed that some foods, in particular those containing carbohydrates as wheat, contain a series benzodiazepine-like molecules, such as 5-phenyl-l-4-benzodiazepines [28,29] , used in 'folkloric' medicines as tranquilizers and/or sedative hypnotics. Although a trace of these molecules are present in foods, it has been suggested that chronic intake of trace amounts could increase the levels of these drugs in the brain and have an influence on brain function and behavior [29] .…”

Section: Possible Factors Involved In the Associationmentioning

confidence: 99%

Affective and Psychiatric Disorders in Celiac Disease

Addolorato

Leggio

D’Angelo

et al. 2008

Dig Dis

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Several extraintestinal clinical manifestations have been reported in celiac disease (CD). Among them, growing evidence suggests the association between CD and affective and psychiatric disorders. In this review the most frequent affective and psychiatric disorders associated with CD and the possible mechanisms involved in these associations were analyzed. The available data suggest that screening for CD in patients with affective and/or psychiatric symptoms may be useful since these disorders could be the expression of an organic disease rather than primary psychiatric illnesses.

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“…Moreover, evidence has been provided that some gut bacteria, such as Acinetobacter lwoffi, can produce precursors of benzodiazepine receptor ligands [36]. Since NBZDs have been found in food [25][26][27][28]37], it could be speculated that at least part of these compounds found in the human body could be of alimentary source.…”

Section: Natural Benzodiazepinesmentioning

confidence: 99%

“…NBZDs such as diazepam and nordiazepam and other unknown benzodiazepine-like compounds are naturally present in several plants and vegetables [25][26][27][28], in different animal species and in humans [29][30][31]. Moreover, both plasma and brain contain other compounds with benzodiazepine-like activity called 'endozepines' apparently produced in mammalian cells [32,33].…”

Section: Natural Benzodiazepinesmentioning

confidence: 99%

Management of Hepatic Encephalopathy: Role of Rifaximin

Zeneroli

Avallone²,

Corsi³

et al. 2005

Chemotherapy

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Hepatic encephalopathy (HE) is a neuropsychiatric syndrome, which develops in patients with acute or chronic liver failure. It is widely accepted to be due to impairment of hepatic clearance of toxic products from the gut such as ammonia. Accumulation of ammonia induces a glutamate neurotoxicity leading to an increased tone of the γ-aminobutyric acid A (GABA-A) receptor system in the brain which results in HE. Factors either increasing the ammonia levels (protein load, constipation, sepsis, or gastrointestinal bleeding) or potentiating the functional activity of the GABAergic system [natural benzodiazepine-like compounds (NBZDs) or exogenous benzodiazepines] may act as precipitating factors of HE. NBZDs are present in trace amounts in the blood of normal subjects and have been found to be increased in the blood of patients with liver cirrhosis, with or without HE. These compounds may derive either from the diet since they have been found in plants, vegetables and animals or from gut bacteria. The observation that intestinal bacterial flora is involved in the production of both primary agent of HE (ammonia) and precipitating factors (NBZDs) suggests that the use of nonabsorbable antibiotics such as rifaximin may be useful in preventing episodes of HE in patients with liver cirrhosis.

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Occurrence of pharmacologically active benzodiazepines in trace amounts in wheat and potato

Cited by 61 publications

References 11 publications

Brain concentrations of benzodiazepines are elevated in an animal model of hepatic encephalopathy.

Brain concentrations of benzodiazepines are elevated in an animal model of hepatic encephalopathy.

Affective and Psychiatric Disorders in Celiac Disease

Management of Hepatic Encephalopathy: Role of Rifaximin

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