A reductive state (high GSH, NAC, NADH/NAD+ ratio, etc), activates the cortisol/estrogen pathways; oxidizing/ pro-metabolic agents block them
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Ray mentioned in a few of his articles that a reductive state, characterized by a buildup of sulfhydryl (SH) groups, is a key characteristic hypothyroidism and of many chronic diseases, especially chronic inflammatory states, diabetes, cancer, neurodegenerative conditions, heart disease (CVD), etc.
https://raypeat.com/articles/articles/cancer-progesterone.shtml
“…One of the basic reactions to injury is to shift the cell away from oxidative metabolism to glycolytic metabolism, which is inefficient, but can support cell division. Chemical stains show that during cell division cells are in a reduced state, with abundant sulfhydryl groups including reduced glutathione and protein sulfhydryls. This shift in itself increases the formation of active estradiol from estrone.”
https://raypeat.com/articles/articles/fatigue-aging-recuperation.shtml
“…Thyroid stimulation of oxygen consumption tends to prevent lactic acid production, because it keeps the cytoplasm in a state of relative oxidation, i.e., it keeps the concentration of NAD+ hundreds of times higher than that of NADH. NADH is required for the conversion of pyruvate to lactate. It is also the source of reducing potential in many kinds of toxic redox cycling, that generate lipid peroxides, and it maintains the sulfhydryl system, involving the balance of reduced glutathione (GSH) with the sulfhydryl-disulfide system of protein bonds, which governs the cell’s electronic state and affects its balance of hydrophobicity and hydrophilicity.”
Conversely, shifting the state away from reduction and towards oxidation has many beneficial effects that are not explainable by a single pathway or mechanism. The study below demonstrates that an intact SH group on the GR receptor is essential for the activation of the GR and thus the stress response/cascade. Conversely, blocking access to the SH group of the GR by either binding it or oxidizing it into a disulfide group blocks the activation of the GR by known glucocorticoid ligands such as the endogenous cortisol, or synthetic glucocorticoids. Thus, SH binding or oxidizing agents act as “silent” GR antagonists and as such are expected to have a variety of beneficial effects considering that cortisol is (relatively) elevated in virtually all chronic diseases and also in general aging. This is due to the fact that the relative “stress” signalling characterized by ratios such as cortisol/DHEA, cortisol/androgens, cortisol/progesterone increases with disease/age due to decline of anti-cortisol factors such as DHEA, androgens, progesterone, etc. The study looked specifically at beta-lapachone, a powerful ortho-naphthoquinone, and found it to be such a silent GR antagonist, which probably explains a good deal of the benefits seen from usage of this quinone. However, the mechanism of action is general in nature and suggests that all oxidizing agents capable of oxidizing the SH group of the GR would also have similar anti-cortisol effects. In addition to the role of intact SH group in GR activation, the study also cites other studies demonstrating that intact SH group is crucial for the activation of the estrogen receptor (ER) as well. As such, oxidizing agents are likely to also act as ER antagonists. There is already published evidence demonstrating that vitamin K (a para-naphthoquinone) has anti-estrogenic effects, and the findings of the study below probably explain why. Under the same logic, it is expected that other powerful quinones such as COQ10, idebenone, thymoquinone, emodin, aloe, emodin, methylene blue (MB), etc. would also have anti-cortisol and anti-estrogenic effects. In addition, non-oxidizing but pro-metabolic agents such as aspirin, thyroid and progesterone would also function as indirect cortisol/estrogen antagonists because they all result in increased metabolism, which results in a more oxidized state (lower NADH/NAD+ ratio) and a decrease in the amount of SH groups. There is already plenty of evidence for the anti-cortisol and anti-estrogenic effects of progesterone directly at the receptor level, while the evidence for aspirin is also strong, but medicine has so far failed to explain the mechanism behind aspirin’s endocrine effects. Conversely, accumulation of intact SH groups such as seen in virtually all chronic conditions or as a result of supplementation with SH donors such as GSH, N-acetyl-cysteine (NAC), methionine, cysteine, etc would be expected to promote both cortisol and estrogen signalling. This strongly suggests that supplementing with reducing agents such as GSH, NAC, cysteine, methionine, etc would not be beneficial in healthy people and can be quite dangerous in people with compromised health. I did a post just a few days ago on a study that found GSH to be a key driver of cancer growth, by enabling the survival and growth of cells under a state of hypoxia (a key characteristic of cancer and other chronic diseases). Estrogen excess is both a key driver of hypoxia and a result of it, which once again confirms the key role metabolism plays in endocrine disturbances that have mystified medicine for decades and are thought to this day to not be related to metabolism.
https://pubmed.ncbi.nlm.nih.gov/7336464/
https://www.jstor.org/stable/58687
https://pubmed.ncbi.nlm.nih.gov/5484467/
https://pubmed.ncbi.nlm.nih.gov/6746659/
“…The data presented demonstrate that beta-lapachone can be utilized as a specific probe for the ligand-binding site of the glucocorticoid receptor. The effects of beta-lapachone on the ligand-binding site are rapid (Fig. 4) and competitive in nature (Fig. 5 and Tables I1 and 111). Despite the fact that the structure of this 1,2-naphthoquinone derivative (Fig. 1) is unlike that of a glucocorticoid, this compound appears to specifically interact with the ligand-binding site of unpurified and highly purified glucocorticoid receptor (Table VI) and not with the ligand-binding sites of estrogen, progesterone, androgen, and mineralocorticoid receptors or serum transcortin (Table V). Thus, when compared with other known inhibitors of steroid binding such as sulfhydryl oxidizing agents (6, 18-20), serine protease inhibitors (21,22), and alkaline phosphatase (23, 24), beta-lapachone is uniquely specific. Although beta-lapachone is a competitive inhibitor of [6,7-3H]TA binding (Fig. 5), the precise mechanism by which this compound interacts with the ligand-binding site is unclear. The ability of DTT and mercaptoethanol (reducing agents) to block (Fig. 2B) and reverse (Table I) the betalapachone-mediated inhibition suggests that this compound may interact in some unspecified way with sulfhydryl groups at the ligand-binding site.”
“…Kalimi and Love (25) have recently reported that two oxidizing agents, N-ethylmaleimide and iodoacetamide, block the activation of hepatic glucocorticoid receptor complexes. These authors speculated that sulfhydryl groups, in addition to being required at the ligandbinding site, also may be required for the conformational change which occurs during activation. Also, the glucocorticoid receptor appears to be several orders of magnitude more sensitive to beta-lapachone, which is effective in the micromolar range, than to most oxidizing agents, which are effective in the millimolar range.”
“…Leach et al. (4) have presented data which suggest that molybdate may actually bind to sulfhydryl or phosphate moieties on the receptor protein. Housley et al. (28) have also reported that rat liver glucocorticoid receptors which have been inactivated (rendered unable to bind steroid) by phosphatases in the presence of molybdate can be reactivated to the steroid-binding state by addition of dithiothreitol (a reducing agent).”
“…Likewise diphenylhydantoin has been reported to bind to the unpurified glucocorticoid receptor and, like glucocorticoids themselves, it has been shown to inhibit the production of prostaglandins in thymocytes (30). In contrast, beta-lapachone competes for the steroid-binding site but the compound does not appear to facilitate the conformational change associated with activation of the receptor complex (Fig. 6) and hence would theoretically be incapable of eliciting a glucocorticoid-like response. In light of these observations, it would be tempting to classify this compound as a glucocorticoid antagonist.”
“…Although the common sensitivities of DNA polymerase (Y and the glucocorticoid receptor to beta-lapachone may be fortuitous, this compound is a highly specific competitive inhibitor of the glucocorticoid receptor which should be useful as a probe of the steroid-binding site. A complete understanding of the biochemical mechanism underlying (beta-lapachone’s inhibitory effect depends on the further characterization of the structure and environment of the steroid-binding site. Such studies are now feasible in light of recent advances in the purification of unactivated glucocorticoid receptors. “
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I find it hard to reconcile the need for a high GSSG/GSH state to have an oxidative state for high energy production characteristic of efficient mitochondrial metabolism via a vis a need for having a high GSH/GSSG ratio to give the body the antioxidant capacity to counter oxidative stresses that are inflammatory and destructive of tissues which leads to a state that favors infection.
So I asked Delphi AI to weigh and the answer makes sense to me:
The balance between the oxidized (GSSG) and reduced (GSH) forms of glutathione is indeed a nuanced aspect of cellular metabolism, particularly in the context of mitochondrial function and oxidative stress. The apparent contradiction you’ve raised—needing a high GSSG/GSH ratio for optimal mitochondrial oxidation while also requiring a low ratio to protect against oxidative stress—can be reconciled by understanding the dynamic and compartmentalized nature of redox regulation in the cell.
1. The Role of GSSG/GSH in Mitochondrial Oxidation
Mitochondrial Oxidation and the Redox State:
A relatively oxidized redox environment (higher GSSG/GSH ratio) within the mitochondria is necessary for efficient oxidative phosphorylation. This is because the electron transport chain (ETC) relies on a flow of electrons from reduced substrates (like NADH) to oxygen, and an overly reduced state can impair this process by creating a bottleneck in electron flow.
A higher GSSG/GSH ratio in the mitochondria reflects active energy production, as electrons are being transferred efficiently through the ETC, generating ATP and carbon dioxide. This oxidized state is a marker of healthy mitochondrial respiration and metabolic activity [3][6].
2. The Role of GSSG/GSH in Protecting Against Oxidative Stress
Antioxidant Defense and Cellular Protection:
Glutathione in its reduced form (GSH) is a critical antioxidant that neutralizes reactive oxygen species (ROS) and prevents oxidative damage to lipids, proteins, and DNA. A low GSSG/GSH ratio in the cytoplasm is essential for maintaining this protective function.
When ROS levels rise, GSH is oxidized to GSSG, temporarily increasing the GSSG/GSH ratio. However, the cell’s glutathione reductase enzyme quickly regenerates GSH from GSSG, restoring the reduced state and ensuring continued protection against oxidative stress [5][7].
3. Reconciling the Two Needs
The key to resolving this apparent contradiction lies in recognizing that the GSSG/GSH ratio is not uniform throughout the cell. Instead, it is tightly regulated and compartmentalized:
Mitochondrial Compartment:
Within the mitochondria, a slightly more oxidized environment (higher GSSG/GSH ratio) supports efficient electron transport and ATP production. This is a localized adaptation to the high metabolic activity and ROS generation in this organelle.
The mitochondria have their own pool of glutathione, which is regulated independently of the cytoplasmic pool. This allows the mitochondria to maintain an oxidized redox state for respiration while still having enough GSH available to neutralize ROS and prevent damage to mitochondrial components [3][6].
Cytoplasmic Compartment:
In the cytoplasm, a low GSSG/GSH ratio is maintained to protect the cell from oxidative stress and to support various enzymatic processes that require a reduced environment. This ensures that ROS generated by the mitochondria or external stressors do not overwhelm the cell’s defenses [5][7].
Dynamic Regulation:
The cell dynamically adjusts the GSSG/GSH ratio in response to metabolic demands and stress. For example:
During periods of high energy production, the mitochondrial GSSG/GSH ratio may increase to facilitate oxidative phosphorylation.
If oxidative stress becomes excessive, the cell prioritizes antioxidant defense, increasing the activity of glutathione reductase and other protective systems to restore a reduced state.
4. Practical Implications for Health and Metabolism
Support Mitochondrial Function:
Ensure adequate glucose oxidation, as this produces more carbon dioxide and less ROS compared to fat oxidation. Carbon dioxide itself helps regulate calcium and oxygen utilization, reducing the likelihood of oxidative stress [1][3][6].
Avoid excessive intake of polyunsaturated fats, which are prone to peroxidation and can exacerbate oxidative stress [3][7].
Enhance Antioxidant Capacity:
Provide the nutrients needed for glutathione synthesis and recycling, such as glycine, cysteine, selenium, and riboflavin. These support the cell’s ability to maintain a low GSSG/GSH ratio in the cytoplasm while allowing for localized oxidation in the mitochondria [5][7].
Vitamin E and progesterone can stabilize mitochondrial membranes and reduce the production of ROS, indirectly supporting a balanced redox state [7][8].
Monitor Thyroid Function:
Optimal thyroid function supports mitochondrial biogenesis and glucose oxidation, improving the cell’s ability to produce energy efficiently without excessive ROS generation [6][7].
Final Thoughts
The GSSG/GSH ratio is a dynamic and compartmentalized system that reflects the cell’s ability to balance energy production with antioxidant defense. By supporting mitochondrial function and providing the nutrients needed for glutathione recycling, you can optimize both aspects of this balance. Let me know if you’d like to explore specific strategies or nutrients further. There’s always more to uncover in optimizing your health.
