heavy metal detox

Emeramide

BL

Dr Haley and OSR

OSR is eneramide, a compound developed to treat Hg poisoning. N,N’bis-(2pmercaptoethyl)isophthalamide is the official IUPAC chemical name. Emeramide is called NBMI in one of Haley’s publications reviewed on this site. :This compound is made from two dietary agents containing sulfur, Cysteimine is a breakdown product of cyst 24 hour half life in blood of rats. Gets into the plasma and penetrates every tissue of the body and gets into the blood. binds Hg, Cd, Pb… also binds unbound Fe. Binds to Hg and does not let go. Also called NBMI and NMBI. [1] These are just some notes taken while listening to the video. Dr Haley was not interested in showing diagrams, pictures, or what not. A PubMed search on Haley B and mercury revealed many papers on the association of mercury with autism. NBMI/eneramide is shown in the feature image as is Hg complex between the sulfur groups of two glutathione molecules. Note that Hg is in the same periodic group as cadmium and zinc, a structural ligand in many proteins. We will visit Cd and Zn in this post.

Biological half life of mercury

PubChem has a lot of interesting information on this topic. We will look at the half life in rats in one of Haley’s publications.

Metallic and inorganic in whole body: 1-2 months; blood: 2 days to 1 month; methyl mercury in blood: 1 month; methylmercury in whole body: 44-79 days; [TDR, p. 813]

TDR – Ryan RP, Terry CE, Leffingwell SS (eds). Toxicology Desk Reference: The Toxic Exposure and Medical Monitoring Index, 5th Ed. Washington DC: Taylor & Francis, 1999., p. 813

The biological half-life of Hg in fish is approx 2 to 3 yr.

USEPA; Ambient Water Quality Criteria Doc: Mercury p.10 (1984) EPA 440/5-84-026

The whole body half-time of Hg in man is approximately 50 to 70 days. A rapid component in blood has a half-time of about three days, and a slower component has a half-time of about 30 days. A rapid component in the brain has a half-time of about 21 days. There is evidence of a much slower component in brain with a half-time on the order of several years.

USEPA; Mercury Health Effects Update p.2-4 (1984) EPA 600/8-84-019F

For pike, Hg concentrations in muscle after 70-90 days were 1000-1500 times that in water. … The half-life for elimination of Hg from contaminated pike placed in clean water was 65-70 days.

Nat’l Research Council Canada; Effects of Mercury in the Canadian Environment p.89 (1979) NRCC No. 16739

The neurotoxic effect seen after exposure to metallic mercury vapor is attributable to the divalent mercury ion formed through oxidation in the brain tissue. Interference with enzyme function by binding to sulfhydryl groups is one possible mechanism … Transport through the cell membrane via the formation of carrier complexes /sodium and calcium channels/ would also be a possibility, although this has not been demonstrated. Most of the chemical reactions of Hg0 relate to oxidation to Hg2+ by NADP+

What this has to do with autism

What this has to do with autism comes from a 2016 Russian hypothesis paper proposing that mercury is more likely to accumulate in the tissue of obese women than lean ones and that this mercury is transferred to the developing fetus. [2] This Russian Federation group was recommending that NMBI/NBMI/Emeramide be given to pregnant women. [2] This hypothesis paper was cited by a Chinese group who published a heavy metal study in 2023. [3] This study usd 60 children 2.5 to 5.7 years old,[3] Heavy metals in the blood and urine samples were measured by ICP-MS.

The non-significant correlation coefficients have been edited out of Table 4. It is interesting to note that there are differences between cases and control blood heavy metal levels but not in the urine. Table 5 examined the following components of the ABC test: TS Sensory Relating Body/object Use Language Social/self-help. None of the individual test scores correlated with any of the heavy metals. Serbium and Tellurium positively correlated with the total scores. The total scores of the CARS test were presented in Table 6. The only significant correlation was with Mo  − 0.473, p<0.01.

This post is not attempting to summarize the discussion of the Chinese heavy metal in ASD study. [3] Note that Hg does not appear to be a significant player but Zn is.in the language odality..

The NBMI clinical trial

This three armed study involved 36 gold miners with accupational mercury exposure whose urine levels exceeded 15 μg/l . These miners were administered 100 mg NBMI, 300 mg NBMI or placebo for 14 days. [4]. Levels of mercury in urine [μg/l and μg/g creatinine] and plasma l were analyzed. [4]

Therapeutic effect was assessed using the medical intoxication score (MIS) and its single health outcomes (e.g. excessive salivation, sleeping problems), fatigue scores, a neuromotoric test battery (CATSYS) and a neurological outcome (Finger to nose test). The method of mercury analysis in blood and urine was not disclosed.

NBMI and Hg PKPD in rats

This 2012 study has some incredible detail

  • The average plasma half-life (t1/2) for NBMI was determined to be 6.18 ± 0.98 hours with and an average plasma clearance rate of 1.01 ± 0.22 L hr−1 kg−1.after intravenous dosing of 1 mg kg−1
  • IV injection of NBMI had approximately 30% of the liver blood flow of a typical rat (3.3 L hr−1 kg−1). The average volume of distribution of NBMI was determined to be 6.7 ± 1.0 L kg−1, which is greater than the total body water of a typical rat (0.7 L kg−1), suggesting extensive distribution throughout the body tissues.[5]
  • For the oral route, average half-lives (5.47 ± 1.75 hours and 5.60 ± 1.02 hours) and average tmax values (2.3 ± 1.2 hours for both doses) The absorbance of NBMI was also consistent between the two oral doses with average values of 13 ± 5.9% and 15 ± 3.6% for the 7 and 35 mg kg−1 doses, respectively. [5]
  • NBMI oral gavage revealed highest levels at 2 hours: mall intestines > subcutaneous fat > liver > kidney > spleen = bone marrow > brain 2 hours after administration. 24 hrs: : small intestines > kidney > liver > spleen> subcutaneous fat > bone marrow > brain. After 24 hours 13.4% of that retained after 2 hours was left.
The rather curious thing is that NMNI remains in the small intestine even after 24 hours.It does not appear to be cleared from the spleen.

Table 5 contained whole body brain, kidney, and liver weight over a five day Hg dosing regimen with no statistically significant changes..

Mean mercury concentration measured in urine and feces collected during the 5 day exposure period. Values are expressed as mean (in parts per billion) ± SEM.

*Indicate [Hg] is statistically different from that measured in other groups, but are indistinguishable from each other.

Clearly Pb is coming out more in the feces.

Hg levels 5 days after HgCl2 injection and/or treatment with NBMI. “Unexposed” = saline only. Statistical details online [4]. # Mean Hg levels in these organs were significantly higher in “Hg Only” or “Hg and NBMI” groups than in that organ other groups (p<0.0001). * Mean Hg level in the “Hg only” group was not significantly different from the Hg levels in the “Hg + NBMI” group. It was significantly higher than mean Hg levels in other groups (p<0.001). Mean Hg level in the “Hg + NBMI” group was greater than in the “Unexposed” and “NBMI Only” groups.

Somehow the numbers in figure 2 do not seem to be all of that impressive. The real utility of NMBU/NBMI is in preventing Hg induced death.

Each group consisted of 6 rats that were first injected subcutaneously with the indicated amount of mercury chloride dissolve in PBS under the right side of the stomach area. After twenty to twenty-five minutes an injection of NBMI dissolved in isotonic DMSO/PBS (25/75 ratio), was injected subcutaneously under the left side of the stomach area. 1, 2 and 14 mg of HgCl2 are equivalent to 3.5, 7.3 and 51.4 micromoles of Hg2+/kg body weight, respectively.
*NBMI treatment subjects received 528 micromoles or 150 mg NBMI/(kg body weight).
#NBMI treatment subjects received 880 micromoles or 250 mg NBMI/(kg body weight). The NBMI/HgCl2 molar ratios were 150, 72, and 17.1 for the 1 mg, 2mg and 14 mg HgCl2 groups, respectively.

Other mechanisms to be aware of

Boyd Haley is middle author of many more emeramide studies that have a more mechanistic focus. One paper declares Haley’s association with CTI Science as a potential but not credible conflict of interest. Infact, emeramide does not seem to be part of CTI Science’s portfolio.

  • Boyd Haley was involved with preliminary tests of emeramide on development. [6] Is this compound safe to give to pregnant women? The nematode C elegans was the test model. The developmental regulator trnscription factor Daf-16 was compromised. What gets frustrating is that zinc levels were not addressed.
  • Boyd Haley was a middle author in a study of bovine aorta endothelial cells exposed to Hg.[7] For some reason the authors concentrated on phospholipase D. Not to be conflused with PLC, which cleaves off the phospholipid head group at the glycerol backbone, PLD cleaves between the head group and the phosphate leaving the phosphate attached to the glycerol backbone.
Figure 3.
N,N′-bis(2-Mercaptoethyl)isopthalamide (NBMI) attenuates the mercury-induced phospholipase D (PLD) activation in similar fashion to N-acetyl-L-cysteine (NAC) and meso-2,3-dimercaptosuccinic acid (DMSA) in mouse aortic endothelial cells (MAECs). TheMAECs (5 × 105 cells/35 mm dish) were labeled with [32P]orthophosphate in phosphate-free Dulbecco-modified Eagle medium (DMEM) for 12 hours. Following[32P]orthophosphate labeling, cells were pretreated with minimal essential medium (MEM) alone or MEM containing NBMI (50 μmol/L) and MEM containing NAC (50 μmol/L, A and 5 mmol/L, B) or DMSA (50 (C) μmol/L and 5 mmol/L (D)) for 1 hour. After pretreatment, cells were treated with MEM alone or MEM containing methylmercury (10 μmol/L) or thimerosal (25 μmol/L) for 1 hour in the presence of 0.05% (volume/volume[vol/vol]) 1-butanol. At the end of the incubation period, [32P]phosphatidylbutanol ([32P]PBt) formed was determined. Data represent mean ± standard deviation (SD)
calculated from 3 independent experiments. *Significantly different atP < .05 as compared to cells treated with MEM alone. **Significantly different at P < .05 as compared to cells treated with MEM containing mercury alone.

The Haley paper, with Secor as first author, continued along these lines promoting emeramid as an alternative to small molecule Hg chlators. [7] Preventing thiol redox perturbation by Hg was proposed as the mechanism.[7]

References

  1. OSR by Dr Haley
  2. Skalny AV, Skalnaya MG, Bjørklund G, Nikonorov AA, Tinkov AA. Mercury as a possible link between maternal obesity and autism spectrum disorder. Med Hypotheses. 2016 Jun;91:90-94.
  3. Zhao G, Liu SJ, Gan XY, Li JR, Wu XX, Liu SY, Jin YS, Zhang KR, Wu HM. Analysis of Whole Blood and Urine Trace Elements in Children with Autism Spectrum Disorders and Autistic Behaviors. Biol Trace Elem Res. 2023 Feb;201(2):627-635 PMC free paper
  4. Schutzmeier P, Focil Baquerizo A, Castillo-Tandazo W, Focil N, Bose-O’Reilly S. Efficacy of N,N’bis-(2-mercaptoethyl) isophthalamide on mercury intoxication: a randomized controlled trial. Environ Health. 2018 Feb 14;17(1):15. PMC free article
  5. Clarke D, Buchanan R, Gupta N, Haley B. Amelioration of Acute Mercury Toxicity by a Novel, Non-Toxic Lipid Soluble Chelator N,N’bis-(2-mercaptoethyl)isophthalamide: Effect on Animal Survival, Health, Mercury Excretion and Organ Accumulation. Toxicol Environ Chem. 2012;94(3):616-640. PMC free article
  6. Ke T, Antunes Soares FA, Santamaría A, Bowman AB, Skalny AV, Aschner M. N,N’ bis-(2-mercaptoethyl) isophthalamide induces developmental delay in Caenorhabditis elegans by promoting DAF-16 nuclear localization. Toxicol Rep. 2020 Jul 31;7:930-937. PMC free article
  7. Secor JD, Kotha SR, Gurney TO, Patel RB, Kefauver NR, Gupta N, Morris AJ, Haley BE, Parinandi NL. Novel lipid-soluble thiol-redox antioxidant and heavy metal chelator, N,N’-bis(2-mercaptoethyl)isophthalamide (NBMI) and phospholipase D-specific inhibitor, 5-fluoro-2-indolyl des-chlorohalopemide (FIPI) attenuate mercury-induced lipid signaling leading to protection against cytotoxicity in aortic endothelial cells. Int J Toxicol. 2011 Dec;30(6):619-38.PMC free article
  8. Patel RB, Kotha SR, Sauers LA, Malireddy S, Gurney TO, Gupta NN, Elton TS, Magalang UJ, Marsh CB, Haley BE, Parinandi NL. Thiol-redox antioxidants protect against lung vascular endothelial cytoskeletal alterations caused by pulmonary fibrosis inducer, bleomycin: comparison between classical thiol-protectant, N-acetyl-L-cysteine, and novel thiol antioxidant, N,N’-bis-2-mercaptoethyl isophthalamide. Toxicol Mech Methods. 2012 Jun;22(5):383-96. PMC free article

Published by BL

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