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. “
