This article is not intended to medical or healthcare advice. You should seek the care and guidance from your M.D. or primary care physician before embarking on any healthcare regimen.
There are many small corners in the world of chronic illness, and those who are super sensitive to sulfur is one of these corners. They break out even when the word is mentioned. I try and encourage folks to get curious rather than stay stuck in a position, belief or paradigm. Its the fixedness of ones beliefs and positions that usually overlaps with those stuck. Curiosity always dispells fear, installs hope, and has the chance to bring people together rather than escond them to corners of this universe.
Heme is a necessary piece to make Hemoglobin. Hmm. Hemoglobin is a protein in the red cells that helps carry oxygen. Hmm. Sounds somewhat important. "Heme is an iron-containing molecule that is important for many biological processes. Heme combines with globin proteins to form hemoglobin, which carries oxygen in red blood cells from the lungs to the rest of the body". [1]
The creation of Heme has 8 primary genes that are involved [11], and two that are well known rate limiting genes for creation of Heme, ALAS, and CPOX [9]. ALAS can be inhibited by lead, and CPOX can be inhibited by mercury - even small amounts for some, and IL-10 {from gut inflammation}. CPOX4 research shows that even low levels of mercury exposure can severely limit this step in heme production. [2] Those with a very specific genetic mutation on COPX4 have significnt impairement with even very modest mercury exposure, and it has been linked to behaviorial modification in children. [3]. Um, Houston, we have a problem.
There is cleary an Andy Cutler camp in the world of mercury toxicity, and there is clearly a Chris Shade camp in this world. Others like Bio Ray, and Econugenics, and various mouth sprays are the latest rage. And all can be "right". It just depends on the person. Andy, and Chris have added great value to helping many get better, and some didn't get better. Both sufferred from extreme mercury exposure, like myself, having a mercury thermometer break in my mouth that was full of mercury based cavity fillings:), both Andy and Chris, took a long time to incrementally get better. I wont get into all the details here, but this specific genetic condition will give you clues on CPOX4.
Why am i writing about Heme ? Why is it so important aside from being important in making hemoglobin and delivering oxygen to the body ? Well its also the last step before HMOX1, which puts the heme with iron into ferritin. Oh, thats important too. And thats not even the smoking gun:).
HEME IS A COFACTOR FOR THE SUOX ENZYME. YES, THE SAME ENZYME THATS OFTEN THE RATE LIMITING FACTOR IN PROCESSING SULFUR!!! YOU CANNOT PROCESS SULFUR WITHOUT HEME.
There you have it, you need heme to process sulfur. And some people make hardly any heme with just a little bit of mercury exposure. A prisoners dilemna... you need sulfur compounds like ALA to make heme, and you need heme to enable SUOX to process sulfur, and you cannot tolerate sulfur. Ugh.
Unfortunately other things can disrupt the heme pathway too, a small sampling below:
HMOX1 and NrF2 are both downregulated by Ochratoxin A [10]
Several mycotoxins inhibit the formation of heme at various steps, T-2, fusasrium, etc.
Lead inhibits both ALAS the rate limiting factor in Heme synthesis, and FECH another gene in the Heme pathway
Mercury inhibits CPOX, and especially CPOX4
IL-10 inhibits CPOX!!!! What ? Yes! IL-10 gets upregulated during GI tract inflammation. [6] Um. uh oh. Better yet, on what gene was the single most statistically significant genettic mutation that differentiated a database of 4,000 clinically diagnosed CFS folks from controls. I dont even have to say it:). And we wonder why gut issues make us feel "icky":). Technically speaking.
Recent research links the ALAS gene to guess what - the IDO genes [7] - the same genes Robert Phaire (CFS researcher) studies for his metabolic trap. Hmmm. Guess what stimulates ALAS:). I dont even have to say it:).
On the flip side, over active ALAS, appears to be linked to colorectal cancer. Caution. [8]
There are variety of steps in the heme pathway that take in compounds from the mitochondria - so one can imagine - mitochondrial dysfunction can also impair the formation of heme. [11]
CYP 450 Phase 1 Detox enzymes are Heme dependent!
Mitochondrial Complexes 2,3,4,5 are all heme dependent!
With all the above said around sulfur, there are other reasons that sulfur can be difficult for some to process, namely genes like SUOX, PAPSS, CTH, CBS, and SULT1a1, SULT2a1. One of the key inhibitors for one of the most important genes in this pathway ? Oxidized glutathione. So mutations in genes like Keap1, Bach1, NrF2, NQO1, GSR and having sufficiency around B2, Molybdenum, Iodine, Selenium are all critical cofactors to start, while NAD, and ubiquination (NQO1) are also needed. Just for fun, what is the cofactor for Bach1? Heme:). Bach1 controls NrF2. Dang. Even better, what is the most important cofactor in the Heme pathway? Lipoic Acid. Hello sulfur. As you can see here, it can be more than just a bit tricky, what one needs to make heme, they cant process well (namely sulfur compounds, like Lipoic Acid).
And what is the amino acid that enters the heme pathway first ? Glycine. I often see mutations in PON1, SHMT1 (makes glycine from serine), SHMT2 (makes glycine from serine), and GCAT (makes glycine from threonine) in these folks - and or high levels of glyphosate which blocks glycine (PON1's job is to detox glyphosate) or salycilate toxicity - where glycine is needed to bind it up [12, 13]. All this impedes the avalability of glycine to get the heme cycle started:). See my other article on PON1, and its backup job, neutralizing Super Oxide.
There is a simple urine test that can be done, called a porphyrin's test that helps assess the functioning of the heme pathway. It is available at mymedlabs.com and is by Doctors Data, and i believe Mosaic (formerly Great Plains lab) has one too. $200ish. Given heme is needed for hemoglobin, checking hemoglobin levels pay be a worthwhile practice as well:).
Mercury Toxicity also correlated to APO-E4 genotype:
"In a group of 465 patients diagnosed as having chronic mercury toxicity (CMT), 32.3% had severe fatigue, 88.8% had memory loss, and 27.5% had depression. A significant correlation was found between CMT and the Apo-lipoprotein E4 genotype (p=0.001). An investigation into an additional 864 consecutively seen general practice patients, resulted in 30.3% having evidence consistent with CMT, and once again a significant correlation was found with the APO-E4 genotype (p=0.001). Removal of amalgam mercury fillings when combined with appropriate treatment resulted in a significant symptom reduction (p<0.001) to levels reported by healthy subjects."[14]
More CPOX4 Details:
"We also compared the catalytic activities of CPOX and CPOX4 in human liver samples. The specific activities of CPOX in mutant livers were significantly lower (40-50%) than those of either wild-type or heterozygous. Additionally, enzymes from mutant, heterozygous and wild-type livers were comparably inhibited by Hg(2+) (10 microM), decreasing CPOX4 activity to 25% that of the wild-type enzyme. These findings suggest that CPOX4 may predispose to impaired heme biosynthesis, which is limited further by Hg exposure. These effects may underlie increased susceptibility to neurological deficits previously observed in Hg-exposed humans with CPOX4."[15]
CPOX4 Variants Also Effects UROD - Another Gene In the Heme Pathway
"This study focused on the genetic etiology of an atypical porphyrinogenic response (APR) seen among the remaining 15% of Hg-exposed subjects, characterized by excess excretion of 4- and 5-carboxyl porphyrins and also of the atypical ketoisocoproporphyrin (KICP). Automated DNA-sequencing-based assays were developed to examine the 7 exons and flanking intron-exon boundaries of the CPOX gene. Among several polymorphisms identified, an A814C variant in exon 4 encoding a N272H substitution was found to be predominant among subjects with the APR. Studies suggest that this variant CPOX preferentially converts the upstream 5-carboxylporphyrin (5-CP) to KICP. By partially inhibiting the 5- to 4-decarboxylation step of UROD, Hg promotes 5-CP accumulation, accounting for e xcess KICP excretion and the APR in Hg-exposed subjects carrying the variant CPOX gene. This finding represents the first report of a polymorphism in a human gene that modifies the effect of Hg on a biological process. The APR might serve as a biomarker of both Hg exposure and susceptibility to Hg toxicity."[16]
A Study On The Impact of Mercury Exposure On Dentists/Assistants With CPOX4 variants
"Here, we examined potential consequences of this polymorphism ("CPOX4") on performance within neurobehavioral domains, symptoms, and mood that are known to be affected by elemental mercury (Hg degrees ) exposure in human subjects. A behavioral test battery was administered on the day of urine and buccal cell collections for 194 male dentists (DDs) and 233 female dental assistants (DAs) occupationally exposed to Hg degrees for an average of 19 and 10 years, respectively. Subjects had no history of health disorders and were employed for a minimum of 5 years in the dental profession. Respective mean urinary mercury (HgU) levels in DDs and DAs were 3.32 (4.87) microg/l and 1.98 (2.29) microg/l. Corresponding indices of chronic occupational Hg degrees exposure, weighted for historical exposure, were 27.1 (20.6) and 15.2 (12.3). The frequencies of the homogygous common (A/A), heterozygous (A/C), and homozygous polymorphic (C/C) genotypes were 75%, 23% and 2% for DDs and 73%, 25%, and 2% for DAs, respectively. DDs and DAs were evaluated separately. Regression analyses controlled for age, premorbid intelligence, alcohol consumption, and education. Statistically significant associations with HgU (p<0.05) were found for nine measures among DDs (BEES Digit SpanForward and Backward, WMS-R Visual ReproductionN Correct, BEES Symbol DigitRate, BEES Finger TappingDom/Non-dom, and Alternate Partialed, Hand SteadinessFactor1, and BEES Tracking), and eight measures among DAs (BEES Digit SpanForward, BEES Symbol DigitRate, BEES Pattern Discrimination Rate, BEES Trailmaking B, BEES Finger TappingDom/Non-dom, and Alternate Partialed, Hand SteadinessFactor1, and Vibration SensitivityHits). CPOX4 status was associated with four measures in DDs (BEES Spatial SpanForward, BEES Pattern MemoryN Correct, BEES Symbol DigitRate, and BEES VigilanceHit) and five measures in DAs (BEES Digit SpanForward, WMS-R Visual ReproductionsN Correct, BEES Symbol DigitRate, BEES Simple and Choice Reaction TimeMove. Both groups experienced an additive effect (no interaction term) for HgU and the CPOX4 polymorphisms on the DigitRate whereas DAs also had additive effects for BEES Digit SpanForward and for Beck's Depression factor 'Worthlessness'. These exploratory findings suggest that the CPOX4 polymorphism may affect susceptibility for specific neurobehavioral functions associated with mercury exposure in human subjects."[17]
If you would like to discuss your genetics, or examine the pathways for Heme in detail, we can review published research that may point to specific things of interest to you. Please send an email requesting an appointment, or schedule an appointment on line.
References:
NIH: National Institute of Diabetes, Digestive, and Kidney Diseases. Getting Heme into Hemoglobin. Research Update Aug. 26, 2014
Cloning, Expression, and Biochemical Properties of CPOX4, a Genetic Variant of Coproporphyrinogen Oxidase that Affects Susceptibilitly to Mercury Toxicity in Humans. Lee, Woods, et. al. Toxicol Sci. 2009 Jun; 109(2): 228–236. Published online 2009 Apr 1. doi: 10.1093/toxsci/kfp066. PMCID: PMC2683923. PMID: 19339664
Modification of neurobehavioral effects of mercury by a genetic polymorphism of coproporphyrinogen oxidase in children. Woods, Heyer, et al. PMID: 22765978.
NIH: The effects of insulin and glucose on the induction and intracellular translocation of delta-aminolevulinic acid synthase. Arch Biochem Biophys. 1984 Aug 15;233(1):64-71.
Recent Progress in Heme Synthesis and Metabolism . Dr. Shigeru Sassa, The Rockefeller University, 1230 York Avenue, New York, N.Y. 10021, USA. OAlphaMed Press ISBN 1-880854 18-X
 Adherence modifies the regulation of gene expression induced by interleukin-10
Hypothesis: Metabolic targeting of 5-aminolevulinate synthase by tryptophan and inhibitors of heme utilisation by tryptophan 2,3-dioxygenase as potential therapies of acute hepatic porphyrias. Abdulla A-B Badawy. Med Hypotheses. 2019 Oct:131:109314.
Inhibition of ALAS1 activity exerts anti-tumour effects on colorectal cancer in vitro
Multiple regulatory steps in erythroid heme biosynthesis. S I Woodard 1, H A Dailey. Arch Biochem Biophys. . 2000 Dec 15;384(2):375-8. doi: 10.1006/abbi.2000.2069. PMID: 11368326. DOI: 10.1006/abbi.2000.2069
Effect of heme oxygenase-1 on ochratoxin A-induced nephrotoxicity in mice
Regulation of Heme Synthesis by Mitochondrial Homeostasis Proteins
Successful therapy of salicylate poisoning using glycine and activated charcoalSchweiz Med Wochenschr. 1996 Dec 7;126(49):2127-9. S Mühlebach 1, P Steger, D Conen, P A Wyss. PMID: 8999500
Patel D, Ogunbona A, Notarianni L, Bennett P, Depletion of plasma glycine and effect of glycine by mouth on salicylate metabolism during aspirin overdose. Human and Experimental Toxicology 1990; 9:6389 - 95Â Â Â
APO E4 Genotype And Mercury Toxicity: Mercury toxicity presenting as chronic fatigue, memory impairment and depression: diagnosis, treatment, susceptibility, and outcomes in a New Zealand general practice setting (1994-2006). Wojcik DP, Godfrey ME. Neuro Endocrinology Letters, 01 Aug 2006, 27(4):415-423PMID: 16891999Â
Cloning, expression, and biochemical properties of CPOX4, a genetic variant of coproporphyrinogen oxidase that affects susceptibility to mercury toxicity in humans
The association between genetic polymorphisms of coproporphyrinogen oxidase and an atypical porphyrinogenic response to mercury exposure in humans
The association between a genetic polymorphism of coproporphyrinogen oxidase, dental mercury exposure and neurobehavioral response in humans