Endogenous BZDs

[Ham-milton]

I was reading this book at google today. It says that it's been pretty well established that there are endogenous BZDs (the first peice has diazepam and n-desmethyldiazepam as present in the mammalian brain- which I never knew) and talks various fungi (I think) that produce benzodiazepines.

That's pretty cool.

What else is known about these though?

 

[Jamshyd]

^ I only remember hearing about Potato and Wheat producing minute amounts of Diazepam, Bromazepam, and Nordiazepam (and one other, I believe). I find it very surprising that Diazepam is not only natural, but endogenous as well!

 

[Reminisant B]

Haven't read the study in full (admittedly) however always wondered isn't it a whole field of potatoes produces 10mg diazepam or something equally minute/trace?

If so, how do they know it wasn't from an un-natural source? (water treatment, contamination of samples or the farmer dropped a pill in the fertilizer! ??)

Anyway would be interested in study if anyone has link.

 

[LuxEtVeritas]

uh i'm thinking, no

if so there would be benzodiazepine structures likely of some nature found with some prevalence in natural sources and to my knowledge such does not exist

not talking compounds that effect BZD, but classical BZD structures, of some nature,,,,

 

[swilow]

^Hmm, I guess prozacs in british drinking water, so who knows....

uh i'm thinking, no

if so there would be benzodiazepine structures likely of some nature found with some prevalence in natural sources and to my knowledge such does not exist

not talking compounds that effect BZD, but classical BZD structures, of some nature,,,,

Well, it is known that potatoes do contain diazepam and other benzodiazepines.

 

[Ham-milton]

if so there would be benzodiazepine structures likely of some nature found with some prevalence in natural sources and to my knowledge such does not exist

not talking compounds that effect BZD, but classical BZD structures, of some nature,,,,

They absolutely do exist; Cyclopeptine ought to be the classical example (were it not for those damn potatoes)

 

[UnfortunateSquid]

Does anyone know anything of the biosynthetic pathway to these endogenous benzos?

 

[LuxEtVeritas]

cyclopeptine in Penicillium OK, given, but the potato sounds like contamination...and endogenous in mammals...how the hell and why...not like it would even be in an amount in any degree to have any true effect ...

 

[Jamshyd]

Hmm, the fact that Bromazepam was found in Potatos is probably the biggest pointer for contamination, since I imagine it is extremely unlikely for a biosynthesis of Bromazepam...

 

[swilow]

^Bromazepam from diazepam possibly, somehow, maybe? If diazepam is present, could that not form bromazepam?

 

[Reminisant B]

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;38(15):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.

So even taking the high value 0.05ng,

=> 0.000000000005g desmethyldiazepam / g potato

or alternatively to produce 10mg (0.01g) of desmethyldiazepam it would require 200000000g of potatoes or 200 metric tonnes!!

Someone please tell me how at that concentration it can be concluded it is 100% a natural product and not contamination.

Occurrence of "natural" benzodiazepines
by
Klotz U.
Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology,
Stuttgart/Germany.
Life Sci. 1991;48(3):209-15.

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. drug-free 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.

 

[mad_scientist]

There does seem to be some evidence for natural and even endogenous benzodiazepines, but I'd like to see better evidence that its not just from bioaccumulation of groundwater contaminants, considering the amount of synthetic pharmaceuticals that they are finding in aquifers now days. I guess its hard to prove where its coming from when the amounts they are detecting are so tiny though.

 

[Jamshyd]

So even taking the high value 0.05ng,

=> 0.000000000005g desmethyldiazepam / g potato

or alternatively to produce 10mg (0.01g) of desmethyldiazepam it would require 200000000g of potatoes or 200 metric tonnes!!

Someone please tell me how at that concentration it can be concluded it is 100% a natural product and not contamination.

Haha, good job! You make a very good case, sir .

So err, what solvent do I use for extraction?

 

[vecktor]

seems likely this is an artifact or contamination, chloro compounds are rather rare in nature, but chloro compounds are very persistent and resistant to degradation.
have any further studies been carried out? one way to eliminate the contamination possibility is high resolution MS, which would show where the carbons came from, that and the oxygen isotope ratio which would indicate whether this was biosynthesised in temperate regions. I wonder whether the carbon 14 ratio can reveal whether something came from recent biological sources or from crude oil, obviously crude oil has a very depleted amount of carbon 14, this is helped by atmospheric testing of nuclear weapons in the 50's and 60's which spike the carbon 14 in the atmosphere. so recent biological sources would have much higher 14 than pre 1940's sources which will have higher levels than fossil sources.

I would guess that rather than a diazepine, the endogenous ligand for the BZP site is probably a carboline or an amino acid.

 

[LuxEtVeritas]

yes, a peptide methinks also may be a possibility...

 

[Reminisant B]

So err, what solvent do I use for extraction?

Nothing less than 200 litres of the finest Wine available in such quantities 8)

 

[negrogesic]

I was reading something about this a few weeks ago:

The possible occurrence of benzodiazepine-like substances in human breast milk was investigated in 35 healthy, newly delivered women who were known not to be taking benzodiazepines. Maternal blood samples and a sample of breast milk were obtained on the fifth post partum day. A radioreceptor technique (lower limit of detection 1.5 ng/ml; difference between duplicates at various concentrations <7%) was used for measuring benzodiazepine-like substances in blood and breast milk (with and without prior extraction). No benzodiazepine-like substances could be demonstrated in any of the blood samples taken from the 35 women. Measurable concentrations of benzodiazepine-like substances were demonstrated in all but 1 of the 35 breast milk samples. The mean concentration of benzodiazepine-like substances for all 35 women was 4.3±2.3 ng/ml (range 0–9.3 ng/ml) expressed as lorazepam. The corresponding value for extracted breast milk was 2.6±1.5 ng/ml (range 0–7.0 ng/ml). There was no association between concentrations of benzodiazepine-like substances in breast milk and maternal age, weight, height and body mass or parity, or the sex of the infant and infant birth weight. We suggest that non-detectable amounts of benzodiazepine-like substances in serum are concentrated in the mammillary glands and excreted in a higher concentration in breast milk. It is less likely that the relevant benzodiazepines are produced in the mammillary glands. http://www.springerlink.com/content/f5022019t7v58268/

 

[Putingrad]

^ Very interesting! I agree that it seems very unlikely benzos coulder be biologically synthesized... there is however an abundance of evidence pointing to the accumulation of pharmaceuticals and other chemicals in water, etc. - sources we come into contact with everyday!

 

[Reminisant B]

Human health risk assessments for three neuropharmaceutical compounds in surface waters.

Enhanced sensitivity of analytical chemistry methods has enabled the detection of low-levels of pharmaceuticals in the environment, resulting in questions about the safety of surface waters used for drinking supplies. Human health risk assessments were performed to evaluate the risks from residues of atomoxetine, duloxetine, and olanzapine, which might be found in surface waters. Preclinical safety studies and human clinical data were used to determine an acceptable daily intake (ADI) for each compound: atomoxetine, 1.4 microg/kg/day; duloxetine, 1.8 microg/kg/day; and olanzapine, 1.4 microg/kg/day. The calculated predicted no-effect concentrations (PNECs) for children were 25.7, 19.1, and 35.9 microg/L for atomoxetine, duloxetine, and olanzapine, respectively. Estimated exposure concentrations determined using United States Food and Drug Administration guidelines and predicted exposure concentrations from the PhATE model were compared with each PNEC to determine margins of safety, which ranged from 147 to 642. Based on currently available data used in this assessment, no appreciable human health risks exist from exposure to the highest 99th percentile of predicted residue levels of atomoxetine, duloxetine or olanzapine in surface waters under low-flow conditions.

PMID: 18331773

Environmental risk assessment of human pharmaceuticals in Denmark after normal therapeutic use.

An environmental risk assessment is presented for the 25 most used pharmaceuticals in the primary health sector in Denmark. Predicted environmental concentrations (PECs) for the aquatic environment were calculated using conservative assumptions and all PECs exceeded 1 ng/l. Measured concentrations were in general within a factor of 2-5 of PECs and ranged from approximately 0.5 ng/l to 3 micrograms/l for nine of the pharmaceuticals reported in literature. The calculation of predicted no-effect concentration (PNEC) based on aquatic ecotoxicity data was possible for six of the pharmaceuticals. PEC/PNEC ratio exceeded one for ibuprofen, acetylsalicylic acid, and paracetamol. For estrogens the PEC/PNEC ratio approached one when non-standard test was used. The ratio was below one for estrogens (standard test), diazepam and digoxin. For the terrestrial compartment, toxicity data were not available, and no assessment was carried out. Comparisons of predicted concentrations of furosemide, ibuprofen, oxytetracycline and ciprofloxacin in sludge based on either preliminary experimental sludge-water partition coefficients (Kd), octanol-water coefficients (Kow) or acid-base constants (pKa) revealed large variations.

PMID: 10705557

Can't find the exact data for diazepam although should be in the second article above. Would guess concentrations present in water or vegetables are still lower than PNEC (Predicted No effect concentration) in humans (well at the moment anyway )