The modern chemical environment is detrimental to thiamine status. Many, if not most, environmental pharmaceutical, and food related chemicals and compounds, impact thiamine status directly by derailing gut microbiota to prevent absorption and/or endogenous synthesis, by blocking thiamine transporters, and/or by changing the shape of the molecule itself so it cannot be activated. Other chemicals simply damage the mitochondria more broadly, thereby increasing demand.
Even diets high in carbohydrates, in otherwise healthy individuals, can evoke deficiency if intake is not increased relative to demand. Then there is alcohol, coffee, or tea. Regular alcohol intake, well below what might considered excessive or warrant consideration for alcoholism, reduces thiamine availability by over 50% in some cases. The caffeic, chlorogenic, and tannic acids in coffee, tea, and energy drinks change the thiamine molecule, impairing its absorption. A couple cups of coffee per day and a glass of wine or a beer at night slowly but surely triggers problems with thiamine.
The High Fructose Oxythiamine Connection
A few years back, I found another mechanism for thiamine disruption excessive fructose consumption. A diet laden with high fructose corn syrup not only blocks a key thiamine enzyme, the transketolase enzyme, but over time, upregulates the endogenous synthesis of an the anti-thiamine molecule called oxythiamine.
Oxythiamine is one of two chemicals used experimentally to induce thiamine deficiency in rodents and other animals. Pyrithiamine is the other, and while there is no evidence yet of its endogenous synthesis, I would not be surprised if it too is upregulated relative to certain modern processed foods or other chemicals.
Oxythiamine blocks the transketolase enzyme, inducing a functional thiamine deficiency when intake is sufficient, and frank deficiency when it is not.
A Few More Roads to Thiamine Problems
Just recently, I have found a few more ways to disrupt thiamine status: pyruvate dehydrogenase kinase (PDK) upregulation and/or pyruvate dehydrogenase phosphatase downregulation (PDP). PDK blocks the thiamine dependent subunit of the pyruvate dehydrogenase complex (PDHC) and PDP removes the blockade. The triad of enzymes works together to ensure an appropriate balance between energy synthesis and cell substrate synthesis and each is affected by environmental exposures and nutrient deficiencies.
Last week, I published an entire post on PDK regulation, and so I won’t detail all of the mechanisms by which PDK becomes persistently upregulated, but I would like to delve more deeply into two particularly widespread exposures that keep most of population in a negative energy state via the thiamine pathway: soybean oil and plasticizers like phthalates and bisphenols (BPAs). I would also connect a few more dots regarding PDP downregulation to this pattern.
The PDK and Dietary Soybean Oil Connection
Soybean oil is the most common seed oil in vegetable oils. It is used by millions of households for everyday cooking, and because it is cheap and has a high smoke point, has replaced other fats in most processed foods, whether fried or not. According the USDA, in 2023-2024, Americans consumed over 27 million pounds of soy oil. This is approximately 13 pounds per person per year.
Despite marketing attempts by industry and physicians promoting its healthiness, SO, especially in the quantities currently consumed, is anything but healthy. Indeed, it is clearly metabolically disastrous by multiple pathways. One such pathway, and arguably the most important, is via the persistent upregulation of the PDK enzyme, which in turn, downregulates the primary driver of mitochondrial glucose metabolism – the PDHC. Soybean oil upregulates PDK 4, which blocks the thiamine-dependent subunit of the PDHC enzyme, and thus redirects glucose metabolism away from mitochondrial ATP production towards the induction excessive lactate and cell growth and proliferation pathways.
Simultaneously, fatty acid metabolism is upregulated, which is not necessarily a bad thing. Fatty acid metabolism through the mitochondria yields more ATP per molecule than glucose (~100 versus ~32) and many tissues like muscle, the heart, and even kidneys, favor fats over carbs for energy. The problem with SO based induction of PDK > fatty acid metabolism pathway is that SO upregulates PDK at 4x the rate of other fats. This makes it particularly difficult to consume enough thiamine to the keep the PDHC open for business (low thiamine allosterically upregulates the PDK) and to manage, not only fatty and amino acid metabolism, both of which require thiamine, but also, handle the surplus lactate, the upregulation of HIFs and other hypoxia related proteins, and the shift towards cell growth/proliferation pathways simultaneously. There is just not enough thiamine to go around. Inasmuch as SO is consumed mostly with other processed foods, which tend to be higher in carbohydrates and mitochondrial toxicants, this is a metabolic disaster.
This shift makes SO not only obesogenic, but also potentially oncogenic, especially over the longer term and when combined with other toxicants. Through the upregulated PDK pathway, we get the characteristic Warburg effect underlying cancer and many female reproductive disorders associated with excessive cell growth, like adenomyosis, endometriosis, fibroids, and the like.
To summarize, soybean oils forcefully and persistently upregulate PDK enzyme, which blocks the thiamine dependent subunit of the PDHC, increasing the demand for thiamine. Lower thiamine, both in absolute terms and relative to need feeds back and upregulates PDK enzyme further, continuing the blockade the PDHC. Lower thiamine then, derails other key enzymes in each of the other nutrient pathways. This precipitates an energetic crisis within the cells, effectively forcing the upregulation of Warburg type metabolism and cell growth to compensate.
A Problem with Plastics
Adding insult to injury, another widely pervasive and almost inescapable exposure wreaking havoc on thiamine homeostasis are the chemicals used in plastics: phthalates and BPA/BPA metabolites or substitutes.
Phthalates, a class of chemicals used in plasticizers to make PVC more pliable. They are especially problematic because not only are they everywhere, but they may bioaccumulate in fat cells, making them persistent threats to PDK/PDHC regulation. Phthalates are in home products (vinyl flooring, adhesives and synthetic leather products), toys, personal care products (nail polish, perfumes, deodorants, hair gels, shampoos, soaps, hair sprays, and body lotions, to help lubricate other substances in the formula and to carry fragrances), food packaging, and medical devices (IV tubing, blood bags, and catheters). Exposure comes from skin absorption, ingestion, or injection (leaching from plastic containers/medical products), and inhalation. The highest exposure for most people, outside of chemical factories or medical exposures, is off-gassing from products within the home, particularly during hot and humid months. Oh, and phthalates are also endocrine disruptors, obesogenic, oncogenic and linked to neurodegeneration. Similarly pervasive are the BPA and BPA alternatives used to make the plastic resins for food/drink packaging, to line metal food cans, in eyewear, and in thermal receipts. Oh, and just like the phthalates, BPA and its analogues are also endocrine disruptors, obesogenic, oncogenic and linked to neurodegeneration.
Unlike soybean oil that directly upregulates PDK, plasticizers take a more circuitous route. Both the phthalates and BPA and BPA-like chemicals upregulate a group of nuclear proteins called peroxisome proliferator activated receptors (PPARs). PPARs upregulate PDK. Despite the more indirect pathway, these compounds are just as problematic, if not more so, for thiamine status, mitochondrial capacity, and health. Moreover, both phthalates and BPA are mitochondrial toxicants via multiple pathways, making these exposures especially problematic.
And Then There Is This: A Broken Off-Switch
The pyruvate dehydrogenase phosphatase (PDP) is responsible for removing the PDK induced blockade of the PDHC – and it is likely ‘broken’ in large swathes of the population because of key mineral deficiencies rampant with modern diets. Changes to PDP activity is linked to Warburg like cell behaviors in cancer, but the patterns are inconsistent and more complicated than can be outlined in a few paragraphs. That said, for this paper, I would like to focus solely on three minerals critical to thiamine stability that also govern PDP activity: magnesium, calcium and manganese.
Magnesium is required to activate dietary or free thiamine into a form that enzymes like the PDHC can use. It is also a required cofactor in the PDP enzyme responsible for removing the PDK induced blockade of the PDHC. Roughly 60% of the adult population does not meet the daily recommended intake of magnesium. This means that we have three hits from magnesium: 1) low magnesium > low bioactive thiamine reducing PDHC capacity directly; 2) low thiamine upregulates PDK activity allosterically; and 3) low magnesium prevents the appropriate upregulation of PDP needed to remove the PDK blockade.
Calcium influx and mitochondrial sequestration are critical components of cell activity and must be regulated precisely. Thiamine deficiency negatively influences calcium regulation (here, here). Calcium is also a required cofactor for the PDP enzyme. Its absence or dysregulation will limit PDP activity. Approximately 40% of the population is deficient. This represents another two hits to PDP activity.
Manganese is the third cofactor required for PDP activation. Its role is less clear, however. That said, manganese influences calcium flux either in conjunction with thiamine and/or because of its ability to improve thiamine storage and synthesis. Although much of the research manganese focuses upon its toxicity parameters, accumulating evidence suggests that low manganese is more common than recognized, particularly in the neurodegenerative disorders. Manganese and magnesium are similar in shape and thus share binding sites on many enzymes, including PDP and others that influence thiamine.
The Modern Environment Is Detrimental to Thiamine
These are but a few more variables to add to the ever-increasing list of environmental exposures that derail thiamine status and mitochondrial energetics. As I continue to dig into the PDK/PDP regulation of the PDHC, I become increasingly convinced that this is the pattern underlying most disease processes but especially those associated with excessive cell growth. A while back, I discovered research from the stem cell side of things showing that stem cells adopt proliferative and migratory patterns when nutrients are lacking. This is a survival mechanism. When one cell cannot meet its own needs, it signals the nucleus to make more cells in order to share the load and if that does not work, migration is initiated. Underlying this pattern is the Warburg effect noted in cancer cells but also in adenomyosis and endometriosis, and even in Alzheimer’s disease. I would argue it is present in every other disease of metabolic dysfunction, perhaps just not as visibly as with cancer. And all of this comes back to an interplay between environmental demands and nutrient intake, availability, and usability, which has become inherently disrupted by modern chemical exposures. The modern chemical environment is killing us and these are some of the mechanisms involved.
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