Amazoniac
Member
You must've witnessed at least one person suffering from seneffiosis. It's a debilitating condition that has been taking over alternative wealth circles, the hosts are exposed to a vector (S. seneff) and pathogenesis is immediate if susceptible. What exactly makes it to the brain is still under investigation, but the hosts become wired to sulfur, they're driven to it even when stuffed because the more they has it, the closer they is to solving an issue.
One of the claims is that sulfation makes photosynthesized venom D unique. Below, they found out that killcidiol is sulfated when incubated at civilized concentrations in liver cells and gels.
- 25OHD3-3-O-Sulfate Is the Major Metabolite Formed from 25OHD3 by Human Hepatocytes
It could be argued that it's sulfatization of killciol. It's been mentioned that its presence in milch in this form supports the argument, yet there are publications that haven't detected any and are ignored.
The next experiment shows that in a subject whose contamination was mild, utilization was good judging from the appearance of killcidiol after killciol, therefore it's being metabolized and conjugation is lost for it to happen yet levels are maintained elevated in spite of this, so it could've undergoned processing in liver.
- Vitamin-D Synthesis and Metabolism after Ultraviolet Irradiation of Normal and Vitamin-D-Deficient Subjects
- Bioavailability of Alendronate and Vitamin D3 in an Alendronate/Vitamin D3 Combination Tablet
Oral intoxication differs (it would be better if all metabolites were measured), but what bothers is the selective sulfuroscopic view to form a solid theory, it's highly suspicious and potentially toxic.
--
- Nongenomic actions of steroid hormones
One of the claims is that sulfation makes photosynthesized venom D unique. Below, they found out that killcidiol is sulfated when incubated at civilized concentrations in liver cells and gels.
- 25OHD3-3-O-Sulfate Is the Major Metabolite Formed from 25OHD3 by Human Hepatocytes
"25OHD3-3-O-sulfate is reported to be a major circulating metabolite of 25OHD3 in humans, with an average circulating concentration comparable to that of 25OHD3 (Axelson, 1985; Shimada et al., 1995; Higashi et al., 2014), and thus, the sulfonation metabolic pathway might contribute importantly to vitamin D homeostasis. Surprisingly little is known about how and where 25OHD3-3-O-sulfate is formed. This information is crucial if the contribution from the sulfonation pathway to vitamin D homeostasis is to be fully evaluated."
"The formation of 25OHD3-3-O-sulfate from 25OHD3 could be considered a catabolic process, but some investigators have hypothesized that it also represents an alternative 25OHD3 storage form in the body (Higashi et al., 2010). This is quite plausible because other endogenous steroid sulfate conjugates, such as estradiol-sulfate and dehydroepiandrosterone (DHEA)-sulfate, circulate at relatively high levels, are deconjugated in target tissues, and contribute to certain physiologic functions (Axelson, 1987; Banerjee et al., 2013; Sánchez-Guijo et al., 2015). Similarly, 25OHD3-3-O-sulfate might be retained in the circulation and distributed to different tissues of the body where it could be hydrolyzed to 25OHD3, replenishing the 25OHD3 pool, as needed. With this in mind, we also tested the binding affinity of 25OHD3-3-O-sulfate for DBP and its presence in human urine and bile."
"Previous studies have demonstrated that at nonphysiologic concentrations (1–5 mM), 25OHD3 is metabolized to 1a,25(OH)2D3, 24R,25(OH)2D3, 4a,25(OH)2D3, 4b,25(OH)2D3, 25OHD3-3-O-glucuronide, 25OHD3-25-O-glucuronide, and putative 5,6-trans-25OHD3-25-O-glucuronide when incubated with human hepatocytes (Wang et al., 2014). However, formation of 25OHD3-3-O-sulfate in human hepatocytes was not determined. For this investigation, a more physiologic concentration of 25OHD3 (50 nM) was applied to cultured human hepatocytes to generate a metabolite profile. As shown in Fig. 3A, all major metabolites of 25OHD3, except 1a,25(OH)2D3, were detected in the incubations. 25OHD3-3-O-sulfate was the most abundant product observed, followed by 24R,25(OH)2D3, 4,25(OH)2D3 [4a,25(OH)2D3 and 4b,25(OH)2D3], and 25OHD3-glucuronides. Formation of these 25OHD3 metabolites occurred in a linear, time-dependent manner, except for 4b,25(OH)2D3 and 4a,25(OH)2D3 formation, which underwent extensive sequential glucuronidation, as previously reported (Wang et al., 2013a). By comparison, renal tubule epithelial cells and LS180 intestinal epithelial cells showed no detectable formation of 25OHD3-3-O-sulfate during a 24-hour incubation with 50 nM 25OHD3 (data not shown). These cells have previously been shown to catalyze the 24-hydroxylation of 25OHD3 under similar culture conditions (Zheng et al., 2012; Weber et al., 2016). Based on the assay limit of detection, culture conditions, and the approximate number of cells per well, it was estimated that 25OHD3 sulfonation activity per renal tubule epithelial cell or LS180 cell was ,10% that of cryopreserved human hepatocytes."
"Herein, we confirm that 25OHD3-3-O-sulfate is [] a quantitatively important circulating product of 25OHD3 (Axelson, 1985; Shimada et al., 1995) and we report for the first time that it is generated primarily in the liver by the enzyme SULT2A1." "Thus, interindividual differences in sulfonation activity may be a major source of variation in circulating blood 25OHD3 concentrations(Fig 8), assuming that hepatic clearance of 25OHD3 is an important determinant of 25OHD3 accumulation in the body."
"SULT2A1 is known to metabolize hydroxysteroids, such as estradiol, DHEA and bile acids (Chatterjee et al., 2005). That it also catalyzes 25OHD3 sulfonation is not surprising, considering structural similarities. The regiospecificity of SULT2A1 toward 25OHD3 sulfonation, almost exclusively at the 3-position, is similar to that observed for hydroxysteroids and oxysterols. Interestingly, the related SULT isoform, SULT2B1, showed little activity toward 25OHD3, which is in contrast to its ability to generate sulfate metabolites of hydroxysteroids and oxysterols that are substrates for SULT2A1 (Falany and Rohn-Glowacki, 2013). SULT2B1 is expressed primarily in extrahepatic tissues (Falany and Rohn-Glowacki, 2013), whereas SULT2A1 is highly expressed in the liver and adrenal cortex and less so in the gastrointestinal tract (Chatterjee et al., 2005). This distribution pattern suggests that there will be limited 25OHD3 sulfonation activity outside of the liver. Consistent with these findings, no detectable 25OHD3 sulfonation was observed in either human intestinal LS180 cells or renal epithelial cells incubated with a physiologically relevant concentration of 25OHD3."
"25OHD3-3-O-sulfate was found to have a high binding affinity for DBP, which explains its relatively high abundance in plasma and absence from urine. The crystal structure of DBP indicates that the vitamin D binding site is a cleft, which can easily accommodate large substituents at the C-3 position of 25OHD3 (e.g., conjugated moieties) (Verboven et al., 2002). High binding affinity to DBP would reduce the renal excretion of 25OHD3-3-O-sulfate into urine. We speculate that the complex of 25OHD3-3-O-sulfate and DBP is filtered and then reabsorbed in renal proximal tubules by megalin/cubilin-mediated endocytosis, as shown for the 25OHD3-DBP complex (Rowling et al., 2006)."
"Although 25OHD3-3-O-sulfate is a major circulating form of vitamin D3, whether it possesses biologic activity directly or indirectly is unclear. A number of studies have been conducted to understand the biologic activities of vitamin D3-sulfate, a conjugated metabolite of vitamin D3 (Higaki et al., 1965; Sahashi et al., 1967a,b, 1969). Vitamin D3-sulfate was synthesized previously (Reeve et al., 1981) and its biologic activity was determined in a vitamin D–deficient rat model. Activity was observed, but only at doses higher than what can be elicited by vitamin D3 (Nagubandi et al., 1981). Later studies also showed less biologic activity of vitaminD3-sulfate than free vitaminD3 in vivo (Cancela et al., 1985). However, in each of these studies, vitamin D3-sulfate was administered, rather than having the metabolite generated in situ, with the uncertainties of bioavailability and access to cellular sites that complicate quantitative comparisons. Thus, it is possible that 25OHD3-3-O-sulfate might undergo hydrolysis, catalyzed by ubiquitous sulfatases and regenerate 25OHD3. This type of hormone conjugate cycling is observed for estrogen and DHEA (Mueller et al., 2015), where the sulfoconjugates are the dominant form in blood circulation and are distributed to peripheral tissues where desulfonation can occur. In the case of DHEA-3-O-sulfate, conversion to DHEA is followed by metabolism to androstenedione and downstream androgens and estrogens (Strott, 2002)."
"Finally, given the detection of 25OHD3-3-O-sulfate in bile, we are intrigued by the possibility that preferential delivery of the hormone conjugate to the duodenum and upper small intestine might explain the preferential expression of vitamin D receptor target genes, such as CYP3A4, transient receptor potential cation channel subfamily V member 6 (TRPV6), and calbindin D9K, in the upper small intestine (Wang et al., 2013b). Results from unpublished studies indicate that 25OHD3-3-O-sulfate is a substrate for the cell uptake transporter, organic anion transporting polypeptide 2B1 (OATP2B1), which is expressed in the intestinal epithelia (Drozdzik et al., 2014). Once absorbed into mucosal epithelial cells, 25OHD3-3-O-sulfate could be hydrolyzed to 25OHD3 and then undergo 1a-hydroxylation to the active hormone and contribute to the regulation of TPRV6, calbindin D9K, and CYP3A4 (Wang et al., 2013b). With regard to the kidney, 25OHD3-3-O-sulfate bound to the DBP in blood could be filtered in the glomerulus and then reabsorbed in the proximal tubular epithelium through the action of megalin/cubilin, similar to what occurs for the 25OHD3-DBP complex (Negri, 2006). Again, intracellular hydrolysis of the conjugate and bioactivation to 1a,25(OH)2D3 could contribute to the known biologic effects of vitamin D in this tissue. Further work is needed to explore these mechanistic hypotheses."
"The formation of 25OHD3-3-O-sulfate from 25OHD3 could be considered a catabolic process, but some investigators have hypothesized that it also represents an alternative 25OHD3 storage form in the body (Higashi et al., 2010). This is quite plausible because other endogenous steroid sulfate conjugates, such as estradiol-sulfate and dehydroepiandrosterone (DHEA)-sulfate, circulate at relatively high levels, are deconjugated in target tissues, and contribute to certain physiologic functions (Axelson, 1987; Banerjee et al., 2013; Sánchez-Guijo et al., 2015). Similarly, 25OHD3-3-O-sulfate might be retained in the circulation and distributed to different tissues of the body where it could be hydrolyzed to 25OHD3, replenishing the 25OHD3 pool, as needed. With this in mind, we also tested the binding affinity of 25OHD3-3-O-sulfate for DBP and its presence in human urine and bile."
"Previous studies have demonstrated that at nonphysiologic concentrations (1–5 mM), 25OHD3 is metabolized to 1a,25(OH)2D3, 24R,25(OH)2D3, 4a,25(OH)2D3, 4b,25(OH)2D3, 25OHD3-3-O-glucuronide, 25OHD3-25-O-glucuronide, and putative 5,6-trans-25OHD3-25-O-glucuronide when incubated with human hepatocytes (Wang et al., 2014). However, formation of 25OHD3-3-O-sulfate in human hepatocytes was not determined. For this investigation, a more physiologic concentration of 25OHD3 (50 nM) was applied to cultured human hepatocytes to generate a metabolite profile. As shown in Fig. 3A, all major metabolites of 25OHD3, except 1a,25(OH)2D3, were detected in the incubations. 25OHD3-3-O-sulfate was the most abundant product observed, followed by 24R,25(OH)2D3, 4,25(OH)2D3 [4a,25(OH)2D3 and 4b,25(OH)2D3], and 25OHD3-glucuronides. Formation of these 25OHD3 metabolites occurred in a linear, time-dependent manner, except for 4b,25(OH)2D3 and 4a,25(OH)2D3 formation, which underwent extensive sequential glucuronidation, as previously reported (Wang et al., 2013a). By comparison, renal tubule epithelial cells and LS180 intestinal epithelial cells showed no detectable formation of 25OHD3-3-O-sulfate during a 24-hour incubation with 50 nM 25OHD3 (data not shown). These cells have previously been shown to catalyze the 24-hydroxylation of 25OHD3 under similar culture conditions (Zheng et al., 2012; Weber et al., 2016). Based on the assay limit of detection, culture conditions, and the approximate number of cells per well, it was estimated that 25OHD3 sulfonation activity per renal tubule epithelial cell or LS180 cell was ,10% that of cryopreserved human hepatocytes."
"Herein, we confirm that 25OHD3-3-O-sulfate is [] a quantitatively important circulating product of 25OHD3 (Axelson, 1985; Shimada et al., 1995) and we report for the first time that it is generated primarily in the liver by the enzyme SULT2A1." "Thus, interindividual differences in sulfonation activity may be a major source of variation in circulating blood 25OHD3 concentrations
"SULT2A1 is known to metabolize hydroxysteroids, such as estradiol, DHEA and bile acids (Chatterjee et al., 2005). That it also catalyzes 25OHD3 sulfonation is not surprising, considering structural similarities. The regiospecificity of SULT2A1 toward 25OHD3 sulfonation, almost exclusively at the 3-position, is similar to that observed for hydroxysteroids and oxysterols. Interestingly, the related SULT isoform, SULT2B1, showed little activity toward 25OHD3, which is in contrast to its ability to generate sulfate metabolites of hydroxysteroids and oxysterols that are substrates for SULT2A1 (Falany and Rohn-Glowacki, 2013). SULT2B1 is expressed primarily in extrahepatic tissues (Falany and Rohn-Glowacki, 2013), whereas SULT2A1 is highly expressed in the liver and adrenal cortex and less so in the gastrointestinal tract (Chatterjee et al., 2005). This distribution pattern suggests that there will be limited 25OHD3 sulfonation activity outside of the liver. Consistent with these findings, no detectable 25OHD3 sulfonation was observed in either human intestinal LS180 cells or renal epithelial cells incubated with a physiologically relevant concentration of 25OHD3."
This is related to what it was posted on the ex-nutrient thread:
- From Performance Management System to Menopause: Female Hormones in Context
- From Performance Management System to Menopause: Female Hormones in Context
"Radioactive estrogen has been shown to accumulate selectively in (liver) cancer cells, which is remarkable since that behavior is so untypical of liver cells. One of my first research projects had to do with the fact that estrogen promotes the formation of beta-glucuronidase, an enzyme which can reverse the reaction which normally occurs in the liver, detoxifying estrogen by combining it with glucuronic acid . Irritated tissues, and all cancers, contain beta-glucuronidase, with the capacity to 're-toxify" estrogen in the irritated or cancerous site, depositing it locally and negating the liver's protective function. More recently, breast cancer cells have been found to contain sulfatase enzymes, with the same kind of function, since the liver's other main route of estrogen detoxication is by combining it with sulfate. A systematic anti-estrogen program (including adequate protein to sustain liver function) would help to minimize the cancer-promoting action of this locally deposited estrogen. I think of the appearance of these estrogen-releasing enzymes in irritated tissue as part of a system for promoting regeneration. In the uterus, estrogen promotes simple growth, and progesterone promotes differentiation. I think something analogous happens in other tissues, with a variety of substances supporting differentiation."
"25OHD3-3-O-sulfate was found to have a high binding affinity for DBP, which explains its relatively high abundance in plasma and absence from urine. The crystal structure of DBP indicates that the vitamin D binding site is a cleft, which can easily accommodate large substituents at the C-3 position of 25OHD3 (e.g., conjugated moieties) (Verboven et al., 2002). High binding affinity to DBP would reduce the renal excretion of 25OHD3-3-O-sulfate into urine. We speculate that the complex of 25OHD3-3-O-sulfate and DBP is filtered and then reabsorbed in renal proximal tubules by megalin/cubilin-mediated endocytosis, as shown for the 25OHD3-DBP complex (Rowling et al., 2006)."
"Although 25OHD3-3-O-sulfate is a major circulating form of vitamin D3, whether it possesses biologic activity directly or indirectly is unclear. A number of studies have been conducted to understand the biologic activities of vitamin D3-sulfate, a conjugated metabolite of vitamin D3 (Higaki et al., 1965; Sahashi et al., 1967a,b, 1969). Vitamin D3-sulfate was synthesized previously (Reeve et al., 1981) and its biologic activity was determined in a vitamin D–deficient rat model. Activity was observed, but only at doses higher than what can be elicited by vitamin D3 (Nagubandi et al., 1981). Later studies also showed less biologic activity of vitaminD3-sulfate than free vitaminD3 in vivo (Cancela et al., 1985). However, in each of these studies, vitamin D3-sulfate was administered, rather than having the metabolite generated in situ, with the uncertainties of bioavailability and access to cellular sites that complicate quantitative comparisons. Thus, it is possible that 25OHD3-3-O-sulfate might undergo hydrolysis, catalyzed by ubiquitous sulfatases and regenerate 25OHD3. This type of hormone conjugate cycling is observed for estrogen and DHEA (Mueller et al., 2015), where the sulfoconjugates are the dominant form in blood circulation and are distributed to peripheral tissues where desulfonation can occur. In the case of DHEA-3-O-sulfate, conversion to DHEA is followed by metabolism to androstenedione and downstream androgens and estrogens (Strott, 2002)."
"Finally, given the detection of 25OHD3-3-O-sulfate in bile, we are intrigued by the possibility that preferential delivery of the hormone conjugate to the duodenum and upper small intestine might explain the preferential expression of vitamin D receptor target genes, such as CYP3A4, transient receptor potential cation channel subfamily V member 6 (TRPV6), and calbindin D9K, in the upper small intestine (Wang et al., 2013b). Results from unpublished studies indicate that 25OHD3-3-O-sulfate is a substrate for the cell uptake transporter, organic anion transporting polypeptide 2B1 (OATP2B1), which is expressed in the intestinal epithelia (Drozdzik et al., 2014). Once absorbed into mucosal epithelial cells, 25OHD3-3-O-sulfate could be hydrolyzed to 25OHD3 and then undergo 1a-hydroxylation to the active hormone and contribute to the regulation of TPRV6, calbindin D9K, and CYP3A4 (Wang et al., 2013b). With regard to the kidney, 25OHD3-3-O-sulfate bound to the DBP in blood could be filtered in the glomerulus and then reabsorbed in the proximal tubular epithelium through the action of megalin/cubilin, similar to what occurs for the 25OHD3-DBP complex (Negri, 2006). Again, intracellular hydrolysis of the conjugate and bioactivation to 1a,25(OH)2D3 could contribute to the known biologic effects of vitamin D in this tissue. Further work is needed to explore these mechanistic hypotheses."
It could be argued that it's sulfatization of killciol. It's been mentioned that its presence in milch in this form supports the argument, yet there are publications that haven't detected any and are ignored.
The next experiment shows that in a subject whose contamination was mild, utilization was good judging from the appearance of killcidiol after killciol, therefore it's being metabolized and conjugation is lost for it to happen yet levels are maintained elevated in spite of this, so it could've undergoned processing in liver.
- Vitamin-D Synthesis and Metabolism after Ultraviolet Irradiation of Normal and Vitamin-D-Deficient Subjects
- Bioavailability of Alendronate and Vitamin D3 in an Alendronate/Vitamin D3 Combination Tablet
Oral intoxication differs (it would be better if all metabolites were measured), but what bothers is the selective sulfuroscopic view to form a solid theory, it's highly suspicious and potentially toxic.
--
- Nongenomic actions of steroid hormones
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