Histadelia and Sulfur: Part V-b: Oxidative stress

Transsulfuration pathway malfunctions occur in some histadelic bipolars (and most autistics). And if such problems involve underproduction of glutathione or other sulfur antioxidants, they can be an important cause of the undermethylation.

Overactivity of CBS causes low glutathione,  high ammonia and overproduction of sulfur compounds. This is very common, especially in autistics. CBS*  is the critical enzyme in converting  homocysteine to cystathionine (see Methionine cycle, step 4, lower half of diagram). 
 * Cystathionine beta synthase.

Thus, with upregulation of CBS: 
Homocysteine  + B6  (as P5P) + Mg   + CBS  yields overabundant Cystine (instead of cysteine) + excess Ammonia + AKG

Accumulating sulfur metabolites promote formation of cystine rather than cysteine (and then, hydrogen sulfide and thiosulfates.) Lacking cysteine, glutathione cannot be formed. Oxidative stress becomes profound. Methyl cannot attach to B12, impeding the transformation of homocysteine to methionine. Formation of homocysteine from SAH is also suppressed.

The ammonia creates brain fog. In part, because ammonia inhibits axonal electrical potentials, decreases brain ATP, causes astrocyte inflammation. And also because it depletes BH4, which is used in forming tyrosine, dopamine, norepinephrine and serotonin.
 
In summary, CBS upregulation leads to:  Severe oxidative stress. Failure to form methionine and glutathione. Low SAM. SAH  and perhaps some HCY accumulation. Toxic sulfur compounds. Ammonia overload. Brain fog.

Considerations (Roberts)

Brain fog.

Reacts to intake of sulfur foods, meds, or supplements.

High-normal to elevated urinary ammonia
Elevated urinary sulfurs.  (Check ammonia and sulfur periodically. The individual can do this themselves with urinary test strips.)
Homocysteine on the low side.

Treatment Approaches (Walsh, Pietryka, Roberts)

Sulfur issues.

Excess B6 can worsen symptoms. P5P may be a better choice (Roberts). Rosemary Waring suggests  increasing magnesium (to at least 1:1, magnesium:B6; or 2:1 magnesium:P5P).
Diets high in sulfur foods worsen the accumulation of detrimental sulfurs. Animal proteins, and sulfur in foods, nutrients and meds often need to be restricted (perhaps even NAC and glutathione), at least until sulfurs start to normalize. 
GABA may be indicated, if anxiety or overstimulation is developing. (Roberts)
Toxic metal accumulation and metal metabolism dysfunction may have some association with CBS overactivity. (Roberts, See section on CBS.)

Ammonia issues (Yasko, Roberts)

Yucca to help detox ammonia.
RNA support to help neutralize ammonia.
Activated charcoal to neutralize ammonia (at night, with magnesium citrate to insure removal).
Carnitine / CoQ10/ and or NADH if needed to support energy levels.

Countering oxidative stress.
NAC and selenium foster creation of glutathione. Reduced glutathione can be taken. Relatively absorbable forms include sublinguals, creams, sprays (as liposomal preparations), IVs, or suppositories.
Reduce factors worsening oxidative stress, such as, toxicity, illness, poor diet, stress, overexertion and metal metabolism dysfunction. Also, avoid excitotoxins.
Mercury levels may need attention, as mercury will readily bind to the abundant sulfhydryl (thiol) groups and, via the bloodstream, gain greater access to body tissues (Cutler).
 
Methylation cycle issues.
The sulfur pathway may need to be dealt with first to prevent draining out of precursors, as well to encourage enough glutathione to methylate B12. (Roberts)
To support methylation, glutathione and methyl-B12 may need to be provided directly. (Walsh)
Betaine may help create some methionine, if the betaine pathway is working effectively. But usually, methionine and/or SAM is needed. (Walsh)

Reminder: This information is presented for educational purposes only, and is not intended as diagnosis or treatment recommendations for the individual. Even within the histadelic subgroup, each person's biochemical requirements tend to be unique. So if you need treatment for depression, mania, bipolar, or any other medical condition, please consult a knowledgeable physician. 


Next posts: Sulfites, sulfates. Salicylates and phenols.

For info on the role of histadelia in bipolar disorder, see my book, Natural Healing for Bipolar Disorder

Histadelia and Methylation. Part V-a: TransSulfuration Pathway

Homocysteine

Despite the notorious dangers of excess homocysteine,* normal levels are necessary to body chemistry, particularly the methylation cycle and the transsulfuration pathway. Homocysteine lies at the intersection of the two, serving as a precursor to methionine (which forms SAM), and also as the antecedent to cysteine, taurine, glutathione and sulfate.
* Chronically elevated homocysteine is infamous for its association with heart disease and may also play a role in memory impairment. It degrades collagen and elastin and damages the lining of blood and lymphatic vessels, via oxidative stress, inflammation, fibrin deposits, etc.  Similarly, it compromises the blood brain barrier.

The Transsulfuration Pathway (under the Methionine cycle (4) on the bottom right of this diagram)

During the methylation cycle, insufficient glutathione at the homocysteine-to-methionine step prevents methyl from linking to B12, and thereby impedes methionine formation.
Homocysteine  is instead diverted down the transsulfuration pathway to form glutathione.
This pathway transforms homocysteine into sulfur antioxidants and detox agents. And typically removes half the homocysteine from the methylation cycle.  But when it goes wrong, it produces toxic sulfur compounds. 
Here is an introduction to the chemistry:

Essentially:

 Homocysteine with the help of:
        vitamin B6 (as P5P), vitamin B3 (as NAD),

         magnesium, serine, selenium, molybdenum and oxygen

                       produces cysteine, glutathione, taurine and sulfate.
 Or, lacking required nutrients or energy, or with sulfur accumulation or dietary sulfur overload:
      Homocysteine forms cystine (instead of cysteine), excessive ammonia,  hydrogen sulfide and other toxic sulfur compounds.

Specifically (enzymes are in parenthesis):
1 Homocysteine  + B6  (as P5P*) + Mg   (via CBS)  yields Cysteine (+ AKG** + Ammonia).
2 Cysteine + serine + selenium + glutamate   yields  Glutathione.
3 Cysteine  + vitamin B3  (as NAD)   yields  Taurine.
4a Sulfite (from cysteine or food)  + molybdenum + B6 (P5P) + oxygen  (via SUOX***)   yields  Sulfate.
4b Without these nutrients, Sulfite produces toxic sulfur compounds.

* B6 metabolism to P5P is supported by AKG, B6, and magnesium. If there is difficulty forming P5P, it is often supplemented directly. 
** AKG (alpha-ketoglutaric acid) is a Kreb's energy cycle component. AKG also helps remove ammonia, and form P5P.

*** SUOX also influences the creation of glutathione.

Importance of Glutathione, Cysteine and Taurine

Glutathione is the body's premiere counter to oxidative stress, and is critical in encouraging homocysteine metabolism to methionine and SAM.
Cysteine is the precursor of glutathione, taurine and sulfate.

Taurine is a major inhibitory neurotransmitter, which often seems to stabilize both mood and neural activity (and also is critical in heart, eye, liver, and gall bladder function).

Next post: Sulfates, sulfites, and sulfur and phenol sensitivity.
For information on effects of histadelia on bipolar symptoms, see my book, Natural Healing for Bipolar Disorder.