N&PD Moderators: Skorpio | thegreenhand
Detection of desmethyldiazepam and diazepam in brain of different species and plants
by
Unseld E, Krishna DR, Fischer C, Klotz U.
Dr. Margarete Fischer-Bosch-Institut für Klinische Pharmakologie,
Stuttgart, Federal Republic of Germany.
Biochem Pharmacol. 1989 Aug 1;3815):2473-8.
ABSTRACT
Recent data suggest that desmethyldiazepam (DD), a major metabolite of several benzodiazepines (BZD), might be of natural origin. Therefore we tried to quantify DD and diazepam (D) in animals during maturation (e.g. hen, chicken, eggs), in brain of species at different evolutionary stages e.g. salmon, frog, monitor/reptile, rat, cat, dog, deer, bovine) including newborn and adult humans. Since low concentrations of DD (range 0.01-0.04 ng/g wet wt) and D (range 0.005-0.02 ng/g) could be measured in different species by sensitive and specific mass spectrometry (GC-MS), we analysed also several plants (e.g. maize corn, lentils, potatoes, soybeans, rice, mushrooms). Again, DD and D could be detected in low amounts (0.005-0.05 ng/g) in some plant products. This would suggest that DD and D might be of natural origin and incorporated via the foodchain into the animal and human body. The biological role or clinical relevance of these intriguing findings need still to be elucidated.
Occurrence of “natural” benzodiazepines
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Ulrich Klotza
aDr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart/Germany
Received 5 November 1990. Available online 16 November 2002.
Abstract
There is accumulating evidence that benzodiazepines (BZD) — agents widely used as anxiolytics and hypnotics-could be regarded as “natural” drugs since they have been found in trace amounts also in plants, various tissues of different animal species and even humans. The biosynthesis of such BZD is still unknown and the hypothesis is favoured that they may be of plant origin. Besides diazepam (D) and its major metabolite desmethyldiazepam (DD) several other BZD (e.g. delorazepam, deschloro-diazepam, delormetazepam, isodiazepam, lormetazepam, oxazepam) could be detected. In some cases identification of these compounds was accomplished by specific mass spectrometry (GC-MS) and for quantification various methods have been applied resulting in different concentrations which range for D from about 0.005 to 1 ng/g and for DD from 0.01 to 0.5 ng/g. It is very unlikely that these trace amounts exert any direct pharmacological effects and at the moment only speculations upon their physiological/biological role are possible. Recently BZD-receptor binding activity equivalent to surprisingly high levels of more than 900 ng/ml was found in cerebrospinal fluid of patients with advanced hepatic encephalopathy. As long as the structure of this binding activity has not been elucidated no firm conclusions can be drawn from these findings. If pertinent analytical problems (e.g. drugfree biological material; exact quantification by internal standard techniques) are solved and if the source(s) of BZD are established it might be possible to answer also the critical question whether “endogenous” or “natural” BZD play any (in-) direct role in the regulation of CNS activity. Many drugs are of a natural plant origin (e.g. alkaloids). More recently it has been elucidated that morphine and codeine are present in different mammalian tissues (1) and the skeleton of morphine can be synthesized by the rat liver (2). Similarly, benzodiazepines (BZD) represent widely used drugs with a complex chemical structure. Their pharmacological effects are mediated by specific BZD-GABAA-chloride channel receptors (3) whose molecular structures have recently been described (4, 5). Since the discovery of these receptors in 1977 there is an ongoing discussion whether endogenous ligands exist and various putative candidates have been hypothesized (6, 7). The latest contributors to this long list are surprisingly BZD. Therefore it is the aim of this minireview to discuss the natural occurence of these “endogenous” BZD.
Abstract
Naturally occurring benzodiazepines have been identified in regular food such as wheat and potato, but there is still no evidence that potato extracts can affect CNS responses in vivo. Here we found that undiluted potato juice and potato juice diluted with saline 1 : 2 administered 10 min intracisternally ( I. C.) and 30 min per os before bicuculline exerted significant anticonvulsant activity in the bicuculline-induced seizure threshold test in mice. In vitro, potato juice from different harvests at dilution series from 10 % to 0.000001 %, diluted 100,000-fold, displaced 50 % of gamma-aminobutyric acid (GABA) receptor ligand [ (3)H]GABA and diluted 40-fold displaced 50 % of [(3)H]flunitrazepam from binding sites in mice forebrain membranes. The low content of diazepam (0.04 +/- 0.01 mg/kg) determined by HPLC and mass spectrometry in the potato extracts could not sustain the anticonvulsant activity of potato juice in vivo; therefore we hypothesized that potato juice might contain GABA (A) receptor GABA-site active compounds. The findings of this study suggest that potato juice as well as potato taken as food may have the capacity of influencing brain GABA-ergic activity.
sourceAbstract
Aqueous acid extracts of wheat grains and potato exhibit after HPLC separation a series of compounds that are able to inhibit the binding of benzodiazepines to benzodiazepine receptors of rat brain membranes. In wheat one of the inhibiting compounds was shown to be identical to diazepam by means of HPLC characterization and gas chromatography combined with mass spectrometry. In potato one of the most prominent components in terms of binding inhibiting activity was identified as lormetazepam. In wheat and potato germination increases total inhibiting activity of the whole plant extracts as well as the content of the benzodiazepines approximately by factor five. Because uptake of benzodiazepines from the surrounding was excluded these findings indicate the biosynthesis of the benzodiazepines diazepam and lormetazepam by the plants investigated.
Because uptake of benzodiazepines from the surrounding was excluded
Abstract
Naturally occurring benzodiazepines have been identified in regular food such as wheat and potato, but there is still no evidence that potato extracts can affect CNS responses in vivo. Here we found that undiluted potato juice and potato juice diluted with saline 1 : 2 administered 10 min intracisternally ( I. C.) and 30 min per os before bicuculline exerted significant anticonvulsant activity in the bicuculline-induced seizure threshold test in mice. In vitro, potato juice from different harvests at dilution series from 10 % to 0.000001 %, diluted 100,000-fold, displaced 50 % of gamma-aminobutyric acid (GABA) receptor ligand [ (3)H]GABA and diluted 40-fold displaced 50 % of [(3)H]flunitrazepam from binding sites in mice forebrain membranes. The low content of diazepam (0.04 +/- 0.01 mg/kg) determined by HPLC and mass spectrometry in the potato extracts could not sustain the anticonvulsant activity of potato juice in vivo; therefore we hypothesized that potato juice might contain GABA (A) receptor GABA-site active compounds. The findings of this study suggest that potato juice as well as potato taken as food may have the capacity of influencing brain GABA-ergic activity.
i doubt its pollution, an easier way would be to grow these in a lab where no pollutants could possible effect them and see the concentrations
So if these are produced in nature(which dont think is farfetched at all)does this mean the patents(for the ones discovrd)are now void. Anyone wanna market some "herbal"benzo "extacts" $$$
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I would predict if an endogenous agonist exists that it is probably a peptide or rather more complicated molecule than a simple known BZD. Think Anandamide, 2-Arachidonoylglycerol (2-AG) (CB receptors agonists), endomorphins (opioid receptor peptides)
if someone had the research grant the question could be answered. The most direct way would be to look for 14C isotope ratios because the phenyl ring in synthetic benzodiazepines will have been made from crude oil whereas plant produced materials will have been produced from photosynthetic products (probably within the last growing season). Thanks to atmospheric nuclear tests there is a nice spike in 14C in all plant matter from the 1950's onwards. If the ratio suggests recent synthesis from a photosynthesis product then that is very strong evidence of it being natural.
Well i wasn't actually suggesting performing an extraction, hence the ""s on "extraction". I was thinkn synthesizing them in a lab and calling it "extract". No one could ever proove otherwise