This article is not medical or healthcare advice. Seek the care and guidance of a M.D. or healthcare practitioner before starting any health related regimen.
Thats kind of a mouthful for a title eh? This article will dive into heme dysregulation, and attempt to tie several things together across mutliple symptomologies. Before that, i will try and outline some things about the heme pathway, what it does, and the key bottlenecks and cofactors that are involved. This will be a long one, so hang in there. I will add more to this article as the days go on, and will add references as well.
Heme is created in the body to make hemoglobin (which is on any CBC panel). "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". [2] To create heme the entry point uses Glycine, and Succinyl CoA from the Krebs Cycle. So you need Glycine, which can be converted from Serine (SCHMT1,2) or Threoneine, an essential amino acid (GCAT), and you will need B6 and or folate to do the conversion. The heme pathway goes through a dozen key steps (and genes) and each step requires a cofactor to work, and also can be upregulted (made to go faster) or inhibited by certain things (like metals, mycotoxins, etc). At each of these steps, different types of Porphyrins are created - and these end up in our bile, and can create little crystals that interfere with the galbladders exit tubes, the livers exit tubes, and the illeosacral valve between the large and small intestine. And of course, we see SIBO, mal digestion (poor bile delivery) with this crowd when there are too many Porphyrins, which are created when their is a block or buildup along one of a dozen or so steps to make heme. The final step after the last gene (FECH), heme goes on to be used as a cofactor in the body for many functions, some listed below, and to a gene called HMOX1 which then combines the heme with iron and stores it into Ferritin. Aha. Now we see why some people who are really compromised in ferritin levels, can simply be very compromised on HMOX1:). Below I will try and describe the symptomology, the heme pathway, considerations, and co mingling touble makers with heme pathway dysregulation.
Short Version Classic Symptomology (detailed list at end of article):
Fatigue
Mast cell activation
Mysterious intense abdominal pain (gall bladder issues/attacks),
Histamine issues
Neurological issues
Maldigestion (poor bile flow); SIBO (poor illeosacral valve functioning)
High porphyrins from a blocked heme pathway, block the Gaba receptors, anxiety.
Alcohol sensitivity - can cause gallbaldder attacks!NOS3
Reactions to herbs, medications, alcohol that tax CYP 450 Phase I detox pathway
Very reactive to foods, supplements, herbs, and medications.
Systemic/Co-Morbidities: Edema, Fatigue, Fibromyalgia, Autism, Autoimmunity, PMS, Low grade fever, Insomnia, Increased sweating, or inability to sweat, EMF Sensitivity, Immuno deficiency, Mast Cell disorders, Hypoxia; Environmental toxin exposure cormorbidity is very high.
Not Enough Heme - the easiest marker here is low hemoglobin on CBC panel, low red cells, and we would expect ferritin to also be low. Hemoglobin contains six trytpophan residues:).
A block somewhere in the heme pathway - we would would expect high porphyrins - which will cause all sorts of potential symptomology. The block can come from one or more of 6 main factors:
Short on the input substrate to the pathway: Glycine or Succynl Co A
Short on one of the many cofactors in the heme pathway: Cu, Zn, Iron, B6, B2, Tryptophan, Lipoic Acid, Oxygen (Hypoxia!), etc
Inhibition of one of the genes by a toxin: Lead, Mercury, Mycotoxins have specific research related to some of the dozen genes in the heme pathway.
Genetic mutations on one or more of the dozen genes in the pathway that compromise the genes function.
Gut inflammation, IL-10 blocks one of the key genes in this pathway
Inability to process sulfur - compromise in the sulfur pathway (genetically, cofactor deficiency - b2, molybdenum, selenium, iodine primarily, or excess oxidized glutathione): CBS, CTH, PAPSS1, PAPSS2, SUOX, SULT1A1, SULT2A1
Artemesian and wormwood inhibit heme biosynthesis [24]
This study references: Dioxins, DDT, Â polychlorinated phenols, benzylchlorophenol and sodium hypochlorite, vinyl chloride in a polyvinyl chloride, Â polybrominated biphenyls (PBBs) , polychlorinated biphenyls (PCBs) in food oil, and diazinon. [17]. These toxins have less specificity where they inhibit the pathway, than the step by step analysis below.
Entry (Glycine) / Succinyl Co A From Krebs Cycle - combines with PLP (b6 form) and makes ALA
The krebs cycle is inhibited by Aluminum or a lack of glutathione at Aconitase (ACO2, ACO1). [20] The heme cycle shares these requirements, so i wanted to highlight the interconnected dependency and impact of these two things. On Organic Acids tests , this is the MOST common block i see, at Aconitase. Aconitase also has iron-sulfur clusters, and is also inhibited by Peroxynitrite. And the heme cycle has 3 genes that have iron sulfur clusters below, so also is inihibited by Peroxynitrite.
Step 1: ALAS1/ ALAS2 - ALAS2 is rate limiting factor, and uses tryptophan here; vegans take note, Plant-based sources of tryptophan include leafy greens, sunflower seeds, watercress, soybeans, pumpkin seeds, mushrooms, broccoli, and peas.
Modulated by circadium rythm[9]
Fasting up regulates ALAS1; feeding down regulates ALAS1[9]
Disturbed (down regulated) by Measles V Virus protein [6]
PPAR Gamma1Alpha co-activates (Berberine, Circumin)[9]
ALAS2 has gain of function mutations [7,8]
ALAS1 induced by the anti fungal griseofulvin
Tryptophan dependent (ALAS2)[9]
Blocked by Lead [9]
Inhibited by Cobalt [12,32]
Inhibited by Manganese [13,14]
ALAS2 indirectly relies on iron sulfur clusters and is thus inhibited by perxoynitrite [21,22,23]
Inhibited by Aluminum
Stimulated by excess Selenium [35]
Inhibited by glucose [26]
Step 2: SLC25A38 - Mitochondrial glycine transporter
Step 3: ABCB10 is one of the three ATP-binding cassette (ABC) transporters found in the inner membrane of mitochondria. ABCB10 is essential for erythropoiesis, and for protection of mitochondria against oxidative stress. ABCB10 is a potential therapeutic target for diseases in which increased mitochondrial reactive oxygen species production and oxidative stress play a major role.
If impaired hurts mitochondrial import of iron
Step 4: ALAD (Lead blocks, B3 and Zn Cofactor) - combines two molecules of delta-aminolevulinic acid (the product of the prior step) to form a compound called porphobilinogen. At least 10 mutations in the ALAD gene can cause a rare form of porphyria called ALAD deficiency porphyria. Most of these mutations change single protein building blocks ( amino acids) in delta-aminolevulinate dehydratase. These changes reduce the activity of the enzyme, allowing delta-aminolevulinic acid to build up to toxic levels in the body. This compound is formed during the normal process of heme production, but reduced activity of delta-aminolevulinate dehydratase allows it to accumulate to toxic levels. Very high levels of this compound can cause attacks of abdominal pain, vomiting, and other signs and symptoms of ALAD deficiency porphyria. A common variation (polymorphism) in the ALAD gene may affect the risk of developing lead poisoning in people exposed to environmental lead. Lead is a heavy metal that is toxic when inhaled or ingested. Lead poisoning can cause significant health problems involving the nervous system, blood, kidneys, and reproductive system. This variation may influence the amount of lead in a person's blood and bones. [19]
hereditary tyrosinemia type I, succinylacetone accumulates and potently inhibits ALAD[9]
ALAD can also be inhibited by styrene in animals and humans[9]
Arsenic inhibits ALAD [13]
Inhibited by Manganese [13,14]
Inhibited by VOC's (styrene, benzene, toluene) [16]
Contains iron sulfur clusters, which can be inhibited by peroxynitrite [21,22,23]
Inhibited by Aluminum [25]
Inhibited by high levels of selenium (toxicity - electronics mfg exposure) [33,35]
Inhibited by cadmium, 50% of this inhibition can be rescued with Vit C [34]
"Exposure of HepG2 and Hep3B cells to Cu2+ inhibited the enzymes PBGD and ALAD of the heme synthesis pathway and, in parallel, upregulated heme oxygenase-1 (HO-1)."[37]
Step 5: HMBS - combines four molecules of porphobilinogen (the product of the prior step) to form a compound called hydroxymethylbilane. Acute Intermittent Porphyria results from hydroxymethylbilane synthase (HMBS) mutations that markedly decrease HMBS enzymatic activity. This dominant disease is diagnosed when heterozygotes have life-threatening acute attacks, while most heterozygotes remain asymptomatic and undiagnosed.
Step 6: UROS (Cofactor, Lipoic Acid) - hydroxymethylbilane (the product of the prior step) is rearranged to form uroporphyrinogen III. Congenital erythropoietic porphyria (CEP) is an inborn error of heme biosynthesis characterized by uroporphyrinogen III synthase (UROS) deficiency resulting in deleterious porphyrin accumulation in blood cells responsible for hemolytic anemia and cutaneous photosensitivity. We analyzed here the molecular basis of UROS impairment associated with twenty nine UROS missense mutations actually described in CEP patients. We show evidence that abnormal protein homeostasis is a prevalent mechanism responsible for UROS deficiency and that modulators of UROS proteolysis such as proteasome inhibitors or chemical chaperones may represent an attractive therapeutic option to reduce porphyrin accumulation and prevent skin photosensitivity in CEP patients when the genotype includes a missense variant.
Step 6B: UROD
Inhibited by : Polychlorinated biphenyls (PCBs) [27]
2,3,7,8-Tetrachorodibenzo-pdioxin (TCDD)[27]
Hexachlorobenzene (HCB)[27]
Step 7: CPOX (iron is cofactor) {IL-10 Regulates CPOX}- removal of carbon and oxygen atoms from coproporphyrinogen III. Hereditary coproporphyria is an acute hepatic porphyria characterized by the occurrence of neurovisceral manifestations. This rare metabolic disorder is due to deficient activity of the mitochondrial enzyme coproporphyrinogen oxidase (CPOX) and it's usually inherited in an autosomal dominant pattern. On one specific location of CPOX4, a single mutation can inhibit the gene significantly even with minor mercury exposure (think fish, fillings, and injections). A single copy of this mutation occurs in about 15-20% of the populations (african decent 40%), while a double copy of this mutation occurs in only 2% of the population. See my article, "The Sulfur People....". Some of the people who i have seen struggle the most, have this mutation. Il-10 (gut inflammation) blocks this gene! I wonder why people with high gut inflammation feel 'tired'.
The discovery that IL-10 can inhibit the production of CPOX, coproporphyrinogen oxidase may shed some lights on the mechanisms of anaemia induced by IL-10". [5]
CPOX inhibited by Arsenic and Lead [13]
Step 8: ABCB6 - This protein is a member of the heavy metal importer subfamily and plays a role in porphyrin transport. This gene is the molecular basis of the Langereis (Lan) blood group antigen and mutations in this gene underlie familial pseudohyperkalemia and dyschromatosis universalis hereditaria. Analysis of mutant yeast mitochondria suggested that ABCB6 may help maintain respiratory function and may also transport Fe/S clusters from mitochondria to the cytosol, thereby helping to prevent iron accumulation and DNA damage in the organelle.
Step 9: PPOX (Oxygen and FAD/B2 dependent)- hydrogen atoms are removed from protoporphyrinogen IX to form protoporphyrin IX. Variegate porphyria (VP) is a low-penetrance, autosomal dominant disorder characterized clinically by skin lesions and acute neurovisceral attacks that occur separately or together. It results from partial deficiency of protoporphyrinogen oxidase encoded by the PPOX gene. VP is relatively common in South Africa, where most patients have inherited the same mutation in the PPOX gene from a common ancestor, but few families from elsewhere have been studied.
Phenoxy acid herbicides are potent PPOX inhibitors[9]
These chemicals are also potent inducers of hepatic ALAS1, which further contributes to PPIX accumulation[9]
Fomesafen[27]
Step 10: FECH (Iron/zn, Copper [11] are cofactors, along with P5P/B6) - an iron atom is inserted into the center of protoporphyrin IX (the product of the prior step) to form heme. Erythropoietic protoporphyria (EPP), an autosomal dominant disease, is caused by partial deficiency of ferrochelatase (FECH), which catalyzes the terminal step of heme biosynthesis because of loss-of-function mutations in the FECH gene. To date, only a few cases have been described in Asia. "..these findings illustrate that FECH is responsible for salicylic acid-induced inhibition of heme synthesis..". [4]
Loss of function mutations (Thaper and Bonkovsky, 2008)[9]
Anti fungal Griseofulvin inhibits FECH[9, 27]
Salicylic acid inhibits FECH[9]
Competitively Inhibited by Manganese [15,27]
Inhibited by VOC's (benzene, toluene, styrene) [16,27]
Has iron sulfur clusters [21]- and can be inhibited by peroxynitrite [22,23]
"Ferrous iron is then inserted by the inner membrane ferrochelatase to form heme."[29,30]
Inhibited by Silver
Lead [27]
DDC/DDT - 3,5-Diethoxycarbonyl-1,4- dihydro-2,4,6-trimethylpyridine (DDC). [27]
Cobalt [27] (high serum b12, from low glutathione and or b2)
3-[2-(2,4,6-Trimethylphenyl)- thioethyl]-4-methylsydnone (TTMS)[27]
Tralkoxydim[27]
Step 11: Output Path 1 - Heme is a Cofactor Used In the following Pathways/Genes/Systems:
a. Tryptophan Pyrrolase: Metabolism of Tryptophan through TDO, IDO1, IDO2 - yes these are the same genes studtied by Robert Phaire under his 'metabolic trap' theory for CFS.
b. GPX - Glutathione Peroxidase Enzymes 1-8; yes these are the same enzymes used to detoxify lipid peroxides from cell membrane oxidation. Especially important is GPX4, the only GPX, located inside the mitochondria.
c. Catalase and just like GPX, Cat neutralizes hydrogen peroxide!
d. NADPH - NAD - the single most common cofactor in the body, followed by magnesium, and b6:)
e. Cytochrome p450 (Phase 1 detox enzymes), enzymes are heme dependent! Low heme - inability to detox! These people are VERY sensitive to alcohol!
f. NOS3 mutations and inhibition is tied to NOS Uncoupling (massive oxidative stress), POTS - from poor blood flow, and poor circulation - cold hands and feet; and finally inhibits mast cell activation.
g. Finally SUOX - our sulfur friends. An un deniable link between heavy metal toxocity / exposure and our sulfur friends. For a few, even very minor mercury exposure causes issues:). Hmm. Maybe RFK is onto something:).
h. Electron Transport - Mitochondrial function in complexes 2,3,4 uses heme.
i. Hemoglobin, Myoglobin, Neuroglobin, Cytochrome C
Step 12 - Parallel To Step 11: Output directly to HMOX1 -
HMOX1 stores iron into ferritin, promotes billiverdin (which turns into billirubin) and blocks mast cell activation. Mast cell folks have low ferritin for a reason.
Heme oxygenase (HMOX1) is the primary antioxidant enzyme involved in heme group degradation. A variety of stimuli triggers the expression of the inducible HO-1 isoform, which is modulated by its substrate and cellular stressors. A major anti-inflammatory role has been assigned to the HO-1 activity. Therefore, in recent years HO-1 induction has been employed as an approach to treating several disorders displaying some immune alterations components, such as exacerbated inflammation or self-reactivity. Many natural compounds have shown to be effective inductors of HO-1 without cytotoxic effects; among them, most are chemicals present in plants used as food, flavoring, and medicine. This review opens a new outlook on the investigation of naturally derived HO-1 inducers, mainly concerning autoimmunity. Garlic, Quercetin, Circumin, Caeffeic Acid, ECGC, Capsacin, Hops.
Lee and Chau (2002)Â showed that IL10, but not IL6 (147620), induces expression of Hmox1 in mouse macrophages through the p38 MAP kinase
How to asssess - Where Is The Problem ?
One could imagine the power of a micronutrient panel that can assess the nutritional status for the required cofactors/substrates. The Porphyrins test by Doctors Data or Mosaic (ordered at mymedlab.com), can help us pinpoint where in the heme pathway the block may be occurring, by showing us which Porphyrin is elevated. A heavy metals and mycotoxin panel can assess toxicity from metals and molds. Genetics can help us see reasons for blocks that are not obvious from a lack of cofactors, contaminants, etc. IL-10 can be measured by most hospitals and labs. The order in which this is explored is important, we need heme, but if we stimulate the cycle at the wrong point we will cause more of a back up, and symptoms become worse.
A few words about Glyphosate :
It is well known that glyphosate is molecularly similar to glycine - and is believed to substitute itself in glycine's place in various pathways. Even if we stop here, we see the potential issues with heme formation. But it goes on. We already spoke about the PON1 gene being responsible for deoxifying glyphosate, so we know its at least partially in play there too.
Glyphosate Inhibits CYP450 Enzymes - which - if we are short on heme - is already compromised
"Glyphosate's inhibition of cytochrome P450 (CYP) enzymes is an overlooked component of its toxicity to mammals. CYP enzymes play crucial roles in biology, one of which is to detoxify xenobiotics. Thus, glyphosate enhances the damaging effects of other food borne chemical residues and environmental toxins. Negative impact on the body is insidious and manifests slowly over time as inflammation damages cellular systems throughout the body. Here, we show how interference with CYP enzymes acts synergistically with disruption of the biosynthesis of aromatic amino acids by gut bacteria, as well as impairment in serum sulfate transport." [1]
Glyphosate inhibits ALA (delta aminolevulinic acid)!
"Thus, the site of action of glyphosate may involve two enzyme pathways:one controlling the conversion of α-ketoglutarate to ALA (a key cofactor in heme), and the other controlling the condensation of glycine with succinyl CoA to form ALA and carbon dioxide. Inhibition of ALA synthesis blocks synthesis of chlorophyll, as well as all other porphyrin ring compounds..."[3]
If you would like to explore this topic in detail and see how your labs and genetics may give us clues to what is going, send me a note to schedule an appointment. It shouldn't take long to explore this:).
Overview of  Protoporphyria:
Erythropoietic Protoporphyria (EPP) and X-linked Protoporphyria (XLP) are rare, genetic photodermatoses resulting from defects in enzymes of the heme-biosynthetic pathway. EPP results from the partial deficiency of ferrochelatase, and XLP results from gain-of-function mutations in erythroid specific ALAS2. Both disorders result in the accumulation of erythrocyte protoporphyrin, which is released in the plasma and taken up by the liver and vascular endothelium. The accumulated protoporphyrin is activated by sunlight exposure, generating singlet oxygen radical reactions leading to tissue damage and excruciating pain. About 2–5% of patients develop clinically significant liver dysfunction due to protoporphyrin deposition in bile and/or hepatocytes which can advance to cholestatic liver failure requiring transplantation.[10]
Clinically these patients present with acute, severe, non-blistering phototoxicity within minutes of sun-exposure. Anemia is seen in about 47% of patients and about 27% of patients will develop abnormal serum aminotransferases. The diagnosis of EPP and XLP is made by detection of markedly increased erythrocyte protoporphyrin levels with a predominance of metal-free protoporphyrin. Genetic testing by sequencing the FECH or ALAS2 gene confirms the diagnosis. [10]
Treatment is limited to sun-protection and there are no currently available FDA-approved therapies for these disorders. Afamelanotide, a synthetic analogue of α-melanocyte stimulating hormone was found to increase pain-free sun exposure and improve quality of life in adults with EPP. It has been approved for use in the European Union since 2014 and is not available in the U.S. In addition to the development of effective therapeutics, future studies are needed to establish the role of iron and the risks related to the development of hepatopathy in these patients.[10]
Detailed Symptomology Below[2]
Gastro intestinal
Unexplain abdominal pain, nausea, vomitng, constipation, diarrhea, spastic colon, belching, bloating
Bowel symptoms caused by neurologic disturbance
Difficulty swallowing
Hiatal hernia, gastroparesis, paraltic ileus
Cardiovascular / Hematopoietic:
Rapid heart rate, hypertension, POTS
Blood disorders
Chest pain of inderterminant cause
Nervous System / Neurological
Anxiety, panic, restlessness, irratibility, poor concentration, tremors, OCD, hysteria, depression, paranoia, hallucinations, manic depression, hyper activity, psychosis
Dizziness
Nerve burning, itching, feeling of bugs crawling
Peripherla neurathy, tics, twitches
Pain: epigastric, stomach, generalized abdominal, musculoskeletal (back, head, neck)
Abdomnal, back, extremity pains
Endocrin Systems
Thyroid issues
Adrenal complications
Musculoskeletal and Respiratory
Muscle weakness
Respiratory weakness
Prolonged attacks impair sensory and motor function
Asthma
Foot drop and clumsiness
Metabolic
Frequent Hunger Pains
food addictions and cravings
Alcholism, Drug addiction
Obesity
Multiple Chemical Sensitivities
Sensitivity to chemicals, pesticides, alcohol, caeffeine, anesthetics, foods, supplements
Eating disorders
Organ Involvement
Kidney, bladder problems
Dark urine, red, brown
Dry eyes
Visual disturbances
Triggers:
Genetics
Fasting or rapdi weight loss
Keo diets
Stress
Infections
CYP 450 burdens - toxins, estrogen, medications, pesticides, VOC's, some herbs
Nutrient deficiencies
Hypoxia
UV Light
Alcohol
ROS - oxidative stress
Herbicides
Oxidized iron (too high of iron)
Sulfur foods
References:
Glyphosate’s Suppression of Cytochrome P450 Enzymes and Amino Acid Biosynthesis by the Gut Microbiome: Pathways to Modern Diseases. by Anthony Samsel, Stephanie Seneff. Entropy 2013, 15(4), 1416-1463; https://doi.org/10.3390/e15041416
Porphyria: The Ultimate Cause of Common, Chronic, and Environmental Illnesses - With Breakthroughs in Diet, Supplements, and Energy Balancing Paperback – January 1, 2009 Ph.d Rochlitz, Steven.
Inhibition of δ - Aminolevulinic Acid Synthesis by Glyphosate. Lynn M. Kitchen, William W. Witt and Charles E. Rieck. JOURNAL ARTICLE. Weed Science. Vol. 29, No. 5 (Sep., 1981), pp. 571-577 (7 pages). Published By: Cambridge University Press
Salicylic acid induces mitochondrial injury by inhibiting ferrochelatase heme biosynthesis activity. Vipul Gupta 1, Shujie Liu. Mol Pharmacol . 2013 Dec;84(6):824-33.
Adherence modifies the regulation of gene expression induced by interleukin-10. Anne-France Petit-Bertron a, Thierry Pedron. Cytokine. Volume 29, Issue 1, 7 January 2005, Pages 1-12. https://doi.org/10.1016/j.cyto.2004.09.001
Antagonism of ALAS1 by the Measles Virus V protein contributes to degradation of the mitochondrial network and promotes interferon response. Pierre Khalfi, Rodolphe Suspène. PLoS Pathog. . 2023 Feb 21;19(2):e1011170. doi: 10.1371/journal.ppat.1011170. eCollection 2023 Feb. PMID: 36802406. PMCID: PMC9983871. DOI: 10.1371/journal.ppat.1011170
C-terminal deletions in the ALAS2 gene lead to gain of function and cause X-linked dominant protoporphyria without anemia or iron overload. Sharon D Whatley, Sarah Ducamp, et al.. Am J Hum Genetics. . 2008 Sep;83(3):408-14. doi: 10.1016/j.ajhg.2008.08.003. Epub 2008 Sep 4. PMID: 18760763. PMCID: PMC2556430. DOI: 10.1016/j.ajhg.2008.08.003
Molecular expression, characterization and mechanism of ALAS2 gain-of-function mutants.
Protoporphyrin IX: the Good, the Bad, and the Ugly. Madhav Sachar, Karl E. Anderson, and Xiaochao Ma. The Journal of Pharmacology and Experimental Therapeutics. American Society for Pharmacology and Experimental Therapeutics. J Pharmacol Exp Ther. 2016 Feb; 356(2): 267–275. Published online 2016 Feb. doi: 10.1124/jpet.115.228130
Erythropoietic Protoporphyria and X-Linked Protoporphyria: Pathophysiology, Genetics, Clinical Manifestations, and Management. Manisha Balwani, MD, MS
A possible role of copper in the regulation of heme biosynthesis through ferrochelatase. By G S Wagner, T R Tephly. Adv Exp Med Biology. 1975;58(00):343-54.  doi: 10.1007/978-1-4615-9026-2_24.
Biochemistry Cobalt inhibition of synthesis and induction of 6-aminolevulinate synthase in liver (trace metals/hepatic porphyria/hemoproteins/heme oxygenase/drug metabolism) M. D. MAINES, V. JANOUSEK*, J. M. TOMIO, AND A. KAPPAS The Rockefeller University, New York, N.Y. 10021 Communicated by E. H. Ahrens, Jr., February 13, 1976. Proc. Natl. Acad. Sci. USA Vol. 73, No. 5, pp. 1499-1503, May 1976
Lead, arsenic and manganese metal mixture exposures: focus on biomarkers of effect. VL Andrade, et. al. Biol Trace Elem Res. Author manuscript; available in PMC 2016 Jul 1. Published in final edited form as: Biol Trace Elem Res. 2015 Jul; 166(1): 13–23. Published online 2015 Feb 20. doi: 10.1007/s12011-015-0267- x PMCID: PMC4470849 NIHMSID: NIHMS665841 PMID: 25693681
Maines MD. Regional distribution of the enzymes of haem biosynthesis and the inhibition of 5-aminolaevulinate synthase by manganese in the rat brain. Biochem J. 1980;190:315–321.
Hift RJ, Thunell S, Brun A. Drugs in porphyria: From observation to a modern algorithm-based system for the prediction of porphyrogenicity. Pharmacol Ther. 2011;132(2):158–169
The in vitro effects of selected environmental toxicants on two heme synthesis enzymes. By D J Johnson. J Environ Pathol Toxicol Oncology. 1985 Nov-Dec;6(2):211-8. PMID:Â 4078689
Environmental Chemical Exposures and Disturbances of Heme Synthesis . By William E. Daniell. Environmental Health Perspectives * Vol 105, Supptement 1 - February 1997.
Cobalt inhibition of synthesis and induction of 6-aminolevulinate synthase in liver (trace metals/hepatic porphyria/hemoproteins/heme oxygenase/drug metabolism) M. D. MAINES. Proc. Natl. Acad. Sci. USA Vol. 73, No. 5, pp. 1499-1503, May 1976 Biochemistry
Nutritional Factors That Affect The Formation of 5-Aminolevulinic, A Key Intermediate Metabolyte of Heme BioSynthesis. By Imi, et. al. Journal Of Nutritional Science, Vitaminol, Vol 67, 339-350, 2021.
Aluminum triggers decreased aconitase activity via Fe-S cluster disruption and the overexpression of isocitrate dehydrogenase and isocitrate lyase: a metabolic network mediating cellular survival. By Jeffrey Middaugh, et. al. . J Biol Chem. 2005 Feb 4;280(5):3159-65.  doi: 10.1074/jbc.M411979200. Epub 2004 Nov 17. PMID: 15548528. DOI: 10.1074/jbc.M411979200
Heme biosynthesis depends on previously unrecognized acquisition of iron-sulfur cofactors in human amino-levulinic acid dehydratase. By Gang Liu. Nature Communications. Published: 09 December 2020
Elevated Nitric Oxide/Peroxynitrite Theory of Multiple Chemical Sensitivity: Central Role of N-Methyl-D-Aspartate Receptors in the Sensitivity Mechanism Martin L. Pall School of Molecular Biosciences, Washington State University, Pullman, Washington, USA Environmental Health Perspectives • VOLUME 111 | NUMBER 12 | September 2003
Peroxynitrite and Nitric Oxide Differently Target the Iron−Sulfur Cluster and Amino Acid Residues of Human Iron Regulatory Protein 1. By Soum, et. al. August 2003. Biochemistry 42(25):7648-54 DOI:10.1021/bi030041i.
Artemisia annua L. Extracts Irreversibly Inhibit the Activity of CYP2B6 and CYP3A4 Enzymes by Martin Kondža, et. al. Biomedicines 2023, 11(1), 232; https://doi.org/10.3390/biomedicines11010232 Submission received: 7 December 2022 / Revised: 12 January 2023 / Accepted: 13 January 2023 / Published: 16 January 2023
The effect of aluminum chloride on some steps of heme biosynthesis in rats after oral exposure. By Jadwiga Chmielnicka, et. al. Volume 40, pages 127–136, (1994). Published: June 1994. Biological Trace Element ResearchAims and scopeSubmit manuscript
Inherited Porphyrias R.J. Desnick, ... Karl E. Anderson, in Emery and Rimoin's Principles and Practice of Medical Genetics (Sixth Edition), 2013. Science Direct.
The association between chemical-induced porphyria and hepatic cancer Andrew G. Smith and John R. Foster. Toxicology Research REVIEW Cite this: Toxicol. Res., 2018, 7, 647 Received 12th January 2018, Accepted 4th April 2018 DOI: 10.1039/c8tx00019k rsc.li/toxicology-research
Structure and function of ferrochelatase G C Ferreira, et. al. J Bioenerg Biomembr . 1995 Apr;27(2):221-9.  doi: 10.1007/BF02110037. PMID: 7592569 . DOI: 10.1007/BF02110037
Modifications of Mitochondrial Function by Toxicants☆ A. Al Maruf, ... P.J. O’Brien, in Reference Module in Biomedical Sciences, 2014.
Cobalt induces neurodegenerative damages through impairing autophagic flux by activating hypoxia-inducible factor-1α triggered ROS overproduction Author links open overlay panel. Jianping Tang. Science of The Total Environment Volume 857, Part 2, 20 January 2023, 159432. Mendeley. https://doi.org/10.1016/j.scitotenv.2022.159432
Inhibition of haem synthesis caused by cobalt in rat liver. Evidence for two different sites of action F De Matteis, A H Gibbs. Biochem J . 1977 Jan 15;162(1):213-6.  doi: 10.1042/bj1620213. PMID: 849279. PMCID: PMC1164588. DOI: 10.1042/bj1620213
Methyl Phenyl Selenide Causes Heme Biosynthesis Impairment and Its Toxicity Is Not Modified by Dimethyl Sulphoxide In Vivo. By Vanderlei Folmer et. al. Drug and Chemical Toxicology Volume 27, 2004 - Issue 4. Pages 331-340 | Published online: 26 Oct 2004 . https://doi.org/10.1081/DCT-200039720
Regulation of cadmium induced porphyria by ascorbic acid in chick embryos. B V Somashekharaiah. Indian J Med Res. . 1991 Oct:94:387-90. PMID: 1794897
Inhibitory Effect of Selenium on Enzymes Involved in Heme Biosynthetic Pathway in Chick Embryos. By K. Padmaja. R. Ramamurthi, A. R. K. Prasad Pages 1-11 | Received 22 May 1995, Accepted 22 Jan 1996, Published online: 27 Sep 2008. Journal Of Enzyme Inhibition. https://doi.org/10.3109/14756369609038217
Biotin deficiency inhibits heme synthesis and impairs mitochondria in human lung fibroblasts. By Hani AtamnaJ Nutrition. . 2007 Jan;137(1):25-30.  doi: 10.1093/jn/137.1.25. PMID: 17182796. DOI: 10.1093/jn/137.1.25
37. Regulation of Heme Synthesis and Proteasomal Activity by Copper: Possible Implications for Wilson's Disease, Volume 28, Issue 3, 2009, pp. 209-221. DOI: 10.1615/JEnvironPatholToxicolOncol.v28.i3.20
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