THE Sulfation and Glucuronidation post for resveratrol:
Thought I’ld take some time to straighten out the whole resveratrol sulfation, glucuronidation and P450 issue. This post touches on a lot, but I think it helps get to the heart of some of the issues involved. Xenobiotica. 2005 Dec;35(12):1101-19. Links
Sulfation of resveratrol in human liver: evidence of a major role for the sulfotransferases SULT1A1 and SULT1E1……
Sulfation of resveratrol, a polyphenolic compound present in grapes and wine with anticancer and cardioprotective activities, was studied in human liver cytosol. In the presence of 3'-phosphoadenosine-5'-phosphosulfate, three metabolites (M1-3) whose structures were identified by mass spectrometry and NMR as trans-resveratrol-3-O-sulfate, trans-resveratrol-4'-O-sulfate, and trans-resveratrol-3-O-4'-O-disulfate, respectively. ……. Incubation in the presence of human recombinant sulfotransferases (SULTs) demonstrated that M1 is almost exclusively catalysed by SULT1A1 and only to a minor extent by SULT 1A2, 1A3 and 1E1, whereas M2 is selectively formed by SULT1A2. M3 is mainly catalysed by SULT1A2 and 1A3. …………PMID: 16418064
Biochem J. 2007 Jun 1;404(2):207-15. Links
Identification and localization of soluble sulfotransferases in the human gastrointestinal tract
…... SULT1A1, 1A3 and 1B1 were found in all parts of the gastrointestinal tract, often exceeding levels in liver (where these forms were present at high, undetectable and low levels respectively). They were predominantly localized in differentiated enterocytes. SULT1E1 and 2A1 were only detected in liver, jejunum, ileum and cecum. SULT1C1 was readily found in stomach, but was negligible elsewhere. SULT1A2 was present at low levels in individual samples. The remaining forms were not detected with the limitation that only high levels could be recognized with the antisera used. ……………PMID: 17335415
Drug Metab Dispos. 2007 Oct 22; [Epub ahead of print] Links
Effect of Resveratrol on 17{beta}-Estradiol Sulfation by Human Hepatic and Jejunal S9 and Recombinant SULT1E1. ……….. The possible interaction of resveratrol with 17beta-Estradiol (E2), a major estrogen hormone and prototypic substrate for sulfate conjugation was studied. Resveratrol and E2 are both known to undergo sulfate conjugation catalyzed by human sulfotransferases (SULTs). …………sulfate conjugation of E2 and resveratrol were studied individually using S9 fractions from human liver and jejunum as well as recombinant human SULT isoforms. The sulfation of E2 (3 to 20 nM) was then investigated in the presence of various concentrations (0, 0.5, 1, and 2 microM) of resveratrol using the two S9 preparations as well as recombinant SULT1E1, the major isoform responsible for E2 sulfation. Resveratrol inhibited E2 sulfation with estimated Ki values of 1.1 microM (liver), 0.6 microM (jejunum), and 2.3 microM (SULT1E1), concentrations which could be pharmacologically relevant. …….
PMID: 17954528
Pharm Res. 2005 Aug;22(8):1406-10. Epub 2005 Aug 3. Links
Inhibitory effects of various beverages on ritodrine sulfation by recombinant human sulfotransferase isoforms SULT1A1 and SULT1A3……
PURPOSE: …… In this study, we aimed to investigate the activities of ritodrine sulfation by SULT1A1, which is expressed predominantly in the liver, and SULT1A3, which is expressed predominantly in the intestine, as well as the inhibitory effects of beverages on their activities. METHODS: We investigated ritodrine sulfation by using recombinant human sulfotransferase (SULT) 1A1 and SULT1A3 in an in vitro study. Next, we investigated the inhibitory effects of grapefruit juice, orange juice, green tea, and black tea on ritodrine sulfation. RESULTS: ……………. The ritodrine sulfation activities of SULT1A1 and SULT1A3 were significantly inhibited by all beverages examined at a concentration of 10%. Green tea and black tea exhibited potent inhibition; even at a concentration of 5%, they both inhibited SULT1A1 by 100% and SULT1A3 by >or=95%. …. PMID: 16078151
Biopharm Drug Dispos. 2007 Sep 18;28(9):491-500 [Epub ahead of print] Links
Inhibitory effects of various beverages on human recombinant sulfotransferase isoforms SULT1A1 and SULT1A3. …..
Sulfotransferase (SULT) 1A1 and SULT1A3 play important roles in the presystemic inactivation of beta(2) agonists in the liver and intestine, respectively. The study aimed to investigate the inhibitory effects of grapefruit juice, orange juice, green tea, black tea and oolong tea and their constituents on the activities of SULT1A1 and SULT1A3.The activities of both SULT1A1 and SULT1A3 were significantly inhibited by all the beverages investigated at a concentration of 10%. The beverage constituents were tested in concentration ranges considered to be physiologically relevant. The grapefruit constituent, quercetin, completely inhibited SULT1A1 (NOT NARINGIN? CAN ANYONE GET THE FULL TEXT?), while quercetin and naringin both partially inhibited SULT1A3. The orange constituents, tangeretin and nobiletin, also completely inhibited SULT1A1. The tea constituents, (-)-epicatechin gallate and (-)-epigallocatechin gallate, both almost completely inhibited SULT1A1 and SULT1A3. Moreover, the theaflavin and thearubigin fractions of black tea both completely inhibited SULT1A1 and strongly inhibited SULT1A3. The inhibitory action of green tea on SULT1A3 was competitive, while that of black tea and oolong tea was mixed competitive/non-competitive. Mechanism-based inhibition was not observed with any beverage.In conclusion, various beverages, especially teas, inhibit the function of SULT1A3, and therefore may have the potential to increase the bioavailability of orally administered substrates of SULT1A3, such as beta(2) agonists. PMID: 17876860
Biochem J. 2004 Nov 1;383(Pt. 3):543-9. Links
Sulpho-conjugation of ethanol in humans in vivo and by individual sulphotransferase forms in vitro……………. Ten volunteers received a low dose of ethanol (0.1 g/kg of body mass). ………. We have expressed previously all human SULT forms identified in Salmonella typhimurium. Ethanol sulphonation was studied in cytosolic preparations of these strains. The highest activities were observed with SULT1A2, 1B1 and 1C2, followed by 1A3. Activities were markedly lower with SULT1E1, 1A1 and 2A1, and were negligible with SULT1C1, 2B1a, 2B1b and 4A1. If the expression levels in tissues are additionally taken into account, SULT1A3 might be the predominant form for the sulphonation of ethanol in vivo, although a robust estimate requires further studies. With this limitation, urinary ethyl sulphate excretion appears very promising as a biomarker for SULT activity in vivo.
PMID: 15281911 [PubMed - indexed for MEDLINE]
Biochem Pharmacol. 1995 Aug 25;50(5):731-4. Links
Quercetin, a potent and specific inhibitor of the human P-form phenosulfotransferase.
…..
The natural product quercetin was a potent inhibitor of the human P-form phenolsulfo-transferase with an IC50 value of 0.10 +/- 0.03 microM (mean +/- SEM; N = 5), which was three to four orders of magnitude more potent than its inhibition of other human sulfotransferases. The inhibition was noncompetitive with a Ki value of 0.10 microM. …….. Among other flavonoids examined, kaempferol was found to have an IC50 value of 0.39 +/- 0.07 microM, naringenin 10.6 +/- 1.6 microM and naringin 265 +/- 90 microM (N = 3). ……….PMID: 7669078
Kaempferol is a natural flavonoid which has been isolated from tea[1], broccoli, Delphinium, Witch-hazel, grapefruit, and other plant sources.
The myricetin, quercetin and kaempferol contents of a brand of "ban-chá", two brands of green tea and four brands of black tea were determined. Three lots of each brand were analysed in duplicate by high performance liquid chromatography. Quercetin (2.5-3.4 mg/g of dry leaf) predominated in all samples, followed by kaempferol (1.0-2.0 mg/g of dry leaf),
Absorption of kaempferol from endive, a source of kaempferol-3-glucuronide, in humans.
Eur J Clin Nutr. 2004 Jun;58(6):947-54.
To determine the absorption, excretion and metabolism of kaempferol in humans. DESIGN: A pharmacokinetic study of kaempferol from endive over 24 h. SUBJECTS: Four healthy males and four healthy females. RESULTS: Kaempferol, from a relatively low dose (9 mg), was absorbed from endive with a mean maximum plasma concentration of 0.1 microM, at a time of 5.8 h, ……
Content of the flavonols quercetin, myricetin, and kaempferol in 25 edible berries.
J Agric Food Chem. 1999 Jun;47(6):2274-9.
The amounts of quercetin, myricetin, and kaempferol aglycons in 25 edible berries were analyzed by an optimized RP-HPLC method with UV detection and identified with diode array and electrospray ionization mass spectrometry detection. Sixteen species of cultivated berries and nine species of wild berries were collected in Finland in 1997. Quercetin was found in all berries, the contents being highest in bog whortleberry (158 mg/kg, fresh weight), lingonberry (74 and 146 mg/kg), cranberry (83 and 121 mg/kg), chokeberry (89 mg/kg), sweet rowan (85 mg/kg), rowanberry (63 mg/kg), sea buckthorn berry (62 mg/kg), and crowberry (53 and 56 mg/kg). Amounts between 14 and 142 mg/kg of myricetin were detected in cranberry, black currant, crowberry, bog whortleberry, blueberries, and bilberry. Kaempferol was detected only in gooseberries (16 and 19 mg/kg) and strawberries (5 and 8 mg/kg). Total contents of these flavonols (100-263 mg/kg) in cranberry, bog whortleberry, lingonberry, black currant, and crowberry were higher than those in the commonly consumed fruits or vegetables, except for onion, kale, and broccoli.
http://dmd.aspetjour...30/9/977?ck=nckFlavonoids, such as naringin, quercetin, and several prevalent furanocoumarines, especially 6',7'-dihydroxybergamottin, were regarded to be potent components responsible for the clinical effects of grapefruit juice (Edwards et al., 1996; Bellevue et al., 1997). However, direct experimental evidence did not support these conclusions (Edwards and Bernier, 1996; Bailey et al., 1998b; Edwards et al., 1999; Guo et al., 2000). Bergamottin is one of the key compounds causing the drug-grapefruit juice pharmacokinetic interactions (Schmiedlin-Ren et al., 1997; He et al., 1998; Sahi et al., 2002). Some evidence to support this assertion is that bergamottin is more potent than 6',7'-dihydroxybergamottin, with the values of maximal rate constant (kinactiviation) and the concentration of inactivator required for half-maximal rate of inactivation (KI) being 0.3 min1 and 7.7 µM, respectively, for bergamottin (He et al., 1998) and 0.16 min1 and 59 µM, respectively, for 6',7'-dihydroxybergamottin (Schmiedlin-Ren et al., 1997) in the reconstituted CYP3A4 system. In addition, bergamottin inhibits other P450s, such as CYP1A2, 2A6, 2B1, 2C9, 2C19, 2D6, and 2E1 in human liver microsomes (Cai et al., 1996; He et al., 1998; Tassaneeyakul et al., 2000). However, Guo et al. (2000) and Tassaneeyakul et al. (2000) recently showed that two furanocoumarin dimers, GF-I-1 and GF-I-4, caused the most potent inhibition of CYP3A4 in human micosomes, but their presence in the grapefruit is of minor quantity (Fukuda et al., 2000; Guo et al., 2000). A combined action of many furanocoumarins, including bergamottin is likely to be responsible for the overall potent inhibitory effect of grapefruit juice (Guo et al., 2000).
Most of the drugs affected by grapefruit juice are primarily metabolized by CYP3A4, which is the most abundant drug-metabolizing enzyme in both liver and intestine. There is a clear and inverse relationship between bioavailability of individual drugs depending on the first-pass metabolism and the effect of grapefruit juice on AUC and Cmax parameters (reviewed in Fuhr, 1998). Lown et al. (1997) demonstrated that intestinal CYP3A was selectively and post-transcriptionally down-regulated by grapefruit juice. Recurrent grapefruit juice consumption for 6 days resulted in a 62% decrease in the enterocyte CYP3A4 immunoreactive protein concentrations in healthy volunteers, whereas small intestinal CYP3A4 mRNA was unchanged. Schmiedlin-Ren et al. (1997) also observed a 47% reduction in intestinal CYP3A4 content in a healthy volunteer within 4 h after consuming grapefruit juice. In comparison, the intravenous pharmacokinetics of drugs were not significantly altered by oral grapefruit juice (Ducharme et al., 1995; Kupferschmidt et al., 1995; Rashid et al., 1995). However, purified bergamottin given to dogs, either orally or i.v., produced a similar increase in AUC and Cmax of orally administered diazepam indicating that bergamottin can also inhibit the liver-metabolizing enzymes (Sahi et al., 2002). In agreement with this data, we found potent inhibition of CYP3A- and CYP1A1/2-mediated activities by bergamottin in both human and monkey hepatocytes. Bergamottin at 5 µM acutely reduced testosterone 6-hydroxylase activity by 90% in both species compared with the induced level. Bergamottin dose-dependently decreased basal CYP3A activity, as well. Notably the basal activity of testosterone 6-hydroxylase in monkey is approximately 20 times greater than seen in humans. Consequently, treatment with rifampicin, a strong inducer of CYP3A, resulted only in a 2-fold increase in activity suggesting the limited effect on CYP3A induction in monkey. We further characterized the effects of bergamottin on CYP1A1/2. Begamottin was a potent inhibitor of CYP1A1/2-mediated EROD and MROD activities in human hepatocytes. Bergamottin at 5 µM completely inhibited EROD and MROD activities in human cells, similar to the response achieved with 10 µM -NF. These data are in agreement with the inhibition of CYP1A1/2 enzyme activity by bergamottin in human liver microsmes (He et al., 1998; Tassaneeyakul et al., 2000). CYP1A was inhibited by 92% with 1 µM bergamottin as measured by inhibition of phenacetin O-deethylation (He et al., 1998). In addition, bergamottin has been proposed to cause a mechanism-based inactivation of CYP1A2 (Cai et al., 1996). Although the levels of EROD and MROD were similar in human and monkey cells induced with -NF, only EROD was inhibited in monkey cells (Fig. 3). In contrast, 10 µM -NF blocked both activities, suggesting that MROD is catalyzed by other enzyme(s) than CYP1A, which are not inhibited with bergamottin in monkey.
Western blot analysis of bergamottin-treated human cultures revealed a small increase in CYP3A4 and CYP1A2 proteins (Fig. 4). In addition, a slight increase in CYP1A1 protein also was observed. This associated with correspondent increases in CYP3A4, CYP1A1, and CYP1A2 (Table 1) mRNAs suggesting that both CYP3A4 and CYP1A1/2 proteins were induced at the transcriptional level. It is well established that potent P450 inhibitors including macrolide antibiotics, protease inhibitors, and omidazole antimycotics can also be inducers of CYP3A protein and mRNA (Wrighton et al., 1985; Hostetler et al., 1989). Thus it appears that bergamottin falls under this category.
We found little effect by bergamottin on conjugation of 4-MU (Fig. 5), a nonspecific substrate for glucuronyl- and sulfotransferase activities. The lack of inhibitory effect of bergamottin on uridine diphosphate glucuronosyltransferases and sulfotransferases suggests that either bergamottin is not a substrate for these enzymes or that the affinity for bergamottin is lower than that for 4-MU.
The results from our studies strongly support the hypothesis that when acutely administered, bergamottin contributes to the grapefruit juice-drug interactions by inhibiting drug-metabolizing enzymes. The minimal effect of grapefruit juice on the liver-metabolizing capacity in human could in part be explained by intestinal metabolism of bergamottin. However, if delivered to the liver it would inhibit phase I enzymes, as was recently demonstrated in dogs (Sahi at al., 2002).
Drug Metab Dispos. 2002 Sep;30(9):977-84. Links
Effects of bergamottin on human and monkey drug-metabolizing enzymes in primary cultured hepatocytes………..We investigated the effect of bergamottin, a major furanocoumarin in grapefruit juice, on phase I and phase II drug-metabolizing enzymes using cultured human and monkey hepatocytes. Both cultured systems were compared and evaluated for the direct effects of bergamottin as well as control treatments on liver enzymes. Treatment of hepatocytes with 0.1, 1, 5, and 10 microM bergamottin resulted in a concentration-dependent reduction in CYP3A4 activity (40-100%) in both human and monkey cells, as measured by testosterone 6 beta-hydroxylase activity. Bergamottin was potent at eliciting these inhibitory effects at both basal and induced states of CYP3A. Bergamottin (5 microM) completely inhibited alpha-naphthoflavone-induced ethoxyresorufin O-dealkylase (EROD) and methoxyresorufin O-dealkylase (MROD) activities in human hepatocytes and caused a 100% decrease in EROD activity in monkey hepatocytes. A 48-h exposure of cultured human hepatocytes to bergamottin resulted in increased levels of immunoreactive CYP3A4, CYP1A1, and CYP1A2 proteins, and CYP3A4, CYP1A1, CYP1A2, CYP2B6, and UDP-glucuronosyl transferase mRNAs. There was only a 20 to 30% reduction in glucuronidation and sulfation of 4-methylumbelliferone in human hepatocytes by 10 microM bergamottin and no effect on conjugation in the monkey hepatocytes. These results suggest that bergamottin causes both inhibition of CYP3A and CYP1A1/2 enzymatic activities and induction of correspondent proteins and mRNAs.
PMID: 12167562
What does it take to get to 10microM bergamottin? = way too much grapefruit juice=1009Liters or 7g of bergamottin
http://www.nature.co...pt2004537a.htmlMethods: In this study 250 mL grapefruit juice; 2-, 6-, or 12-mg capsules of bergamottin plus water; or water was administered with 5 mg extended-release felodipine to 11 volunteers in a partially randomized, 5-way crossover study. Plasma concentrations of felodipine, its primary metabolite (dehydrofelodipine), bergamottin, and 6',7'-dihydroxybergamottin were determined.
Results: Grapefruit juice (containing 1.7 mg bergamottin) increased peak plasma concentration (Cmax) and area under the plasma concentration–time curve (AUC) of felodipine by 89% (P < .025) and 54% (P < .025), respectively, compared with water. With 2 mg bergamottin, felodipine Cmax increased by 33% (P < .05). The increase by bergamottin was markedly variable among individuals (range, -33% to 125%). With 6 mg bergamottin, felodipine Cmax was enhanced by 35% (P < .025), and with 12 mg bergamottin, felodipine Cmax increased by 40% (P < .05) and AUC increased by 37% (P < .05) compared with water. Bergamottin measured in plasma after administration of 6 and 12 mg produced Cmax values of 2.1 and 5.9 ng/mL,=( Molar mass 338.397 g/mol = 0.017microM) respectively, and times to reach Cmax of 0.8 and 1.1 hours, respectively. The bergamottin metabolite 6',7'-dihydroxybergamottin was detected in plasma of some subjects after bergamottin administration.
J Agric Food Chem. 2003 Feb 26;51(5):1474-9. Links
Effects of phenolic acids on human phenolsulfotransferases in relation to their antioxidant activity.
…... There are two forms of PST that are specific for the sulfation of small phenols (PST-P) and monoamines (PST-M). Phenoilc acids have been reported to have important biological and pharmacological properties and may have benefits to human health. In the present study, human platelets were used as a model to investigate the influence of 13 phenolic acids on human PST activity and to evaluate the relationship to their antioxidant activity. The results showed that chlorogenic acid (The primary dietary source of chlorogenic acid is coffee; the green coffee beans typically contain 6-7% of this component (range: 4-10%); roasted coffee beans contain somewhat less…. In Chinese medicine, the primary source is lonicera flowers (jinyinhua); extracts are standardized according to chlorogenic acid content, often at 25% of the extract. Eucommia bark and gardenia fruit are also major sources, with extracts standardized to 20% chlorogenic acid. These extracts would yield a dose of about 1 gram of chlorogenic acids in 4-5 grams of extract, a rather large amount. Other Chinese herbs known for their chlorogenic acid content include chrysanthemum flower, crataegus fruit (hawthorne berries!) , artemisia leaves, and epimedium leaves. ……..In Western herbal medicine, an herb especially known for its chlorogenic acid content is artichoke leaves; the extracts are usually standardized to 15% of this compound. Other medicinal herbs known for content of chlorogenic acid include burdock root, dandelion root, and echinacea root.) , syringic acid (grapes), protocatechuic acid (colored onions contained 1 to 2 g protocatechuic acid per 100 g), vanillic acid (it’s oxidized Vanillin, the primary component of the extract of the vanilla bean), sinapic acid (Sinapine is found in cruciferous plants), and caffeic acid (Caffeic acid and its derivative caffeic acid phenethyl ester (CAPE) are produced in many plants including: pears, basil, thyme, verbena, tarragon, oregano, wood betony, burning bush, turmeric, dandelion, yarrow, horsetail, rosemary, hawthorn and coffee.) significantly (p < 0.05) inhibited the activities of both forms of PST by 21-30% at a concentration of 6.7 microM. The activity of PST-P was enhanced (p < 0.05) by p-hydroxybenzoic acid, gallic acid, gentisic acid, o-coumaric acid, p-coumaric acid, and m-coumaric acid at a concentration of 6.7 microM, whereas the activity of PST-M was enhanced by gentisic acid, gallic acid, p-hydroxybenzoic acid, and ferulic acid. The phenolic acids exhibited antioxidant activity as determined by the oxygen radical absorbance capacity (ORAC) assay and Trolox equivalent antioxidant capacity (TEAC) assay, especially gallic acid, p-hydroxybenzoic acid, gentisic acid, and coumaric acid, which had strong activity. The overall effect of phenolic acids tested on the activity of PST-P and PST-M was well correlated to their antioxidant activity of ORAC value ….
PMID: 12590501
So add some hawthorne berries, red onion, and vanilla to the resveratrol mix? And stay away from these immediately after…:
Free Radic Res. 2005 Aug;39(8):893-904. Links
Effect of vegetables on human phenolsulfotransferases in relation to their antioxidant activity and total phenolics……………The result showed that PST-P activity was significantly (p < 0.01) induced by asparagus, broccoli, cauliflower, celery and eggplant, whereas PST-M activity was induced by asparagus, broccoli, carrot, eggplant and potato at a concentration of 100 microg/ml. The vegetable extracts that induced both forms of PSTs activities were found to have higher antioxidant capacities and total phenolic content in the oxygen radical absorbance capacity (ORAC) and Folin-Ciocalteu assay. The major polyphenols in broccoli, the most potential inducer in both forms of PSTs activities, was antioxidant phenolic acids. HPLC retention times and standard spiked indicated the presence of gallic acid, p-hydroxybenzoic acid, p-coumaric acid, gentisic acid and ferulic acid in broccoli. The overall effect of vegetables tested on the activity of PST-P was well correlated to their ORAC value and total phenolics content (r= 0.82, p < 0.05 and r = 0.78, p < 0.05). These results imply that vegetables have a capability of inducing PST activity, and the PST induction may be possibly ascribed to antioxidant phenolic acids in vegetable extracts. PMID: 16036370
Phytomedicine. 2001 Nov;8(6):481-8.Links
Natural products isolated from Mexican medicinal plants: novel inhibitors of sulfotransferases, SULT1A1 and SULT2A1……..
Calophyllum brasiliense, Lonchocarpus oaxacensis, and Lonchocarpus guatemalensis are used in Latin American folk medicine. Four natural xanthones, an acetylated derivative, and two coumarins were obtained from C. brasiliense. Two flavanones were extracted from L. oaxacensis and one chalcone from L guatemalensis. These compounds were tested as substrates and inhibitors for two recombinant sulfotransferases (SULTs) …….. The natural xanthones reversibly inhibited SULT1A1 with IC50 values ranging from 1.6 to 7 microM whereas much higher amounts of these compounds were required to inhibit SULT2A1 (IC50 values of 26-204 microM). The flavonoids inhibited SULT1A1 with IC50 values ranging from 9.5 to 101 microM, which compared with amounts needed to inhibit SULT2A1 (IC50 values of 11 to 101 microM). ……….PMID: 11824526
Drug Metab Dispos. 1996 Feb;24(2):232-7. Links
Flavonoids, potent inhibitors of the human P-form phenolsulfotransferase. Potential role in drug metabolism and chemoprevention.
….. The common dietary constituent quercetin was a potent inhibitor of sulfoconjugation of acetaminophen and minoxidil by human liver cytosol, partially purified P-form phenolsulfotransferase (PST), and recombinant P-form PST, with IC50 values of 0.025-0.095 microM. Quercetin inhibition of acetaminophen was noncompetitive with respect to acceptor substrate, with a Ki value of 0.067 microM. A number of other flavonoids, such as fisetin (Fisetin is reported to be included in onion (5 mg/kg), apple (27 mg/kg) and strawberry (160 mg/kg).) , galangin (from galangal), myricetin (found mostly in walnuts), kaempferol (foods rich in kaempferol are Green tea, red wine (and presumably red grapes,) red onions and the skin of red apples.) , chrysin (high in Parsley, thyme, celery), and apigenin (high in parsley), were also potent inhibitors of P-form PST-mediated sulfation, with IC50 values < 1 microM. Studies of structural analogs indicated the flavonoid 7-hydroxyl group as particularly important for potent inhibition. Potential human metabolites of quercetin were poor inhibitors. Curcumin, genistein, and ellagic acid (other polyphenolic natural products) were also inhibitors of P-form PST, with IC50 values of 0.38-34.8 microM. …………
PMID: 8742236 [PubMed - indexed for MEDLINE]
Xenobiotica. 2000 Jun;30(6):609-17.Links
Sulphation of resveratrol, a natural product present in grapes and wine, in the human liver and duodenum……………. IC50 of resveratrol sulphation for quercetin was 12 +/- 2 pM (liver) and 15 +/- 2 pM (duodenum), those for mefenamic acid were 24 +/- 3 nM (liver) and 11 +/- 0.6 nM (duodenum), and those for salicylic acid were 53 +/- 9 microM (liver) and 66 +/- 4 microM (duodenum). 5. PMID: 10923862
Xenobiotica. 2000 Sep;30(9):857-66.Links
Sulphation of resveratrol, a natural compound present in wine, and its inhibition by natural flavonoids
………..Resveratrol is sulphated, and the hepatic and duodenal sulphation might limit the bioavailability of this compound. …….. In the liver, IC50 for the inhibition of resveratrol sulphation was 12+/-2 pM (quercetin), 1.0+/-0.04 microM (fisetin), 1.4+/-0.1 microM (myricetin), 2.2+/-0.1 microM (kaempferol) and 2.8+/-0.2 microM (apigenin). Similarly, in the duodenum, IC50 was 15+/-2 pM (quercetin), 1.3+/-0.1 microM (apigenin), 1.3+/-0.5 microM (fisetin), 2.3+/-0.1 microM (kaempferol) and 2.5+/-0.3 microM (myricetin). 3. ………..PMID: 11055264
Toxicol In Vitro. 2006 Mar;20(2):187-210. Epub 2005 Nov 11. Links
Dietary flavonoids: effects on xenobiotic and carcinogen metabolism.
…………….
……….This review focuses on the flavonoid effects on cytochrome P450 (CYP) enzymes involved in the activation of procarcinogens and phase II enzymes, largely responsible for the detoxification of carcinogens. A number of naturally occurring flavonoids have been shown to modulate the CYP450 system, including the induction of specific CYP isozymes, and the activation or inhibition of these enzymes. Some flavonoids alter CYPs through binding to the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, acting as either AhR agonists or antagonists. Inhibition of CYP enzymes, including CYP 1A1, 1A2, 2E1 and 3A4 by competitive or mechanism-based mechanisms also occurs. Flavones (chrysin, baicalein, and galangin), flavanones (naringenin) and isoflavones (genistein, biochanin A) inhibit the activity of aromatase (CYP19), thus decreasing estrogen biosynthesis and producing antiestrogenic effects, important in breast and prostate cancers. Activation of phase II detoxifying enzymes, such as UDP-glucuronyl transferase, glutathione S-transferase, and quinone reductase by flavonoids results in the detoxification of carcinogens and represents one mechanism of their anticarcinogenic effects. A number of flavonoids including fisetin, galangin, quercetin, kaempferol, and genistein represent potent non-competitive inhibitors of sulfotransferase 1A1 (or P-PST); this may represent an important mechanism for the chemoprevention of sulfation-induced carcinogenesis. ……….PMID: 16289744
Phase I dose escalation pharmacokinetic study in healthy volunteers of
resveratrol, a potential cancer chemopreventive agent.
Cancer Epidemiol Biomarkers Prev. 2007 Jun;16(6):1246-52.
PMID: 17548692
……………. A phase I study of oral resveratrol (single doses of
0.5, 1, 2.5, or 5 g) was conducted in 10 healthy volunteers per dose level.
………………Resveratrol and six metabolites were recovered from plasma and urine. Peak plasma levels of resveratrol at the highest dose were 539 +/- 384 ng/mL (2.4 mumol/L, mean
+/- SD; n = 10), which occurred 1.5 h post-dose. Peak levels of two
monoglucuronides and resveratrol-3-sulfate were 3- to 8-fold higher. The
area under the plasma concentration curve (AUC) values for
resveratrol-3-sulfate and resveratrol monoglucuronides were up to 23 times
greater than those of resveratrol. ………………..
High absorption but very low bioavailability of oral resveratrol in humans.
Drug Metab Dispos. 2004 Dec;32(12):1377-82. Epub 2004 Aug 27.
PMID: 15333514…………… The absorption of a
dietary relevant 25-mg oral dose was at least 70%, with peak plasma levels
of resveratrol and metabolites of 491 +/- 90 ng/ml (about 2 microM) and a
plasma half-life of 9.2 +/- 0.6 h. However, only trace amounts of unchanged
resveratrol (<5 ng/ml) could be detected in plasma. Most of the oral dose
was recovered in urine, and liquid chromatography/mass spectrometry analysis
identified three metabolic pathways, i.e., sulfate and glucuronic acid
conjugation of the phenolic groups and, interestingly, hydrogenation of the
aliphatic double bond, the latter likely produced by the intestinal
microflora. Extremely rapid sulfate conjugation by the intestine/liver
appears to be the rate-limiting step in resveratrol's bioavailability. ………..
And on to glucoronidation:
Glucuronidation of resveratrol, a natural product present in gape and wine, in the human liver.
Anno 2000
…….. It has been previously shown that this compound is sulfated in human liver and the aims of the present investigation were to study resveratrol glucuronidation in human liver microsomes and to determine whether flavonoids inhibit resveratrol glucuronidation…………… The flavonoid quercetin inhibited resveratrol glucuronidation and its IC50 (mean+SD; No=3) value was 10+1 uM. Twenty uM myricetin, catechin, kaempferol, fisetin and apigenin inhibited resveratrol glucuronidation and the percent of control ranged between 46% (catechin) to 72% (apigenin). …………..
Original Paper
Resveratrol is efficiently glucuronidated by UDP-glucuronosyltransferases in the human gastrointestinal tract and in Caco-2 cells
……………. The aim of this study was to determine the contribution of the gastrointestinal (GI) tract to the glucuronidation of this compound and its cis-isomer, which also occurs naturally. For this purpose, glucuronidation of the two resveratrol isomers was investigated in human microsomes prepared from: stomach, duodenum, four segments of the remaining small intestine (S-1 to S-4) and colon, and from the human intestinal cell lines Caco-2 and PD-7. cis- and trans-Resveratrol were efficiently glucuronidated in the GI tract with the formation of both 3-O- and 4-O-glucuronides, however, the two stereoisomers were glucuronidated at different rates depending on the donor and the segment considered. Microsomes prepared from Caco-2 and PD-7 cells also efficiently glucuronidated cis-resveratrol and, to a lesser extent, the trans-isomer, however, only the 3-O-glucuronide was formed. Among the UDP-glucuronosyltransferases (UGT) that are known to be expressed in the GI tract, the isoforms UGT1A1, 1A6, 1A8, 1A9 and 1A10 were active in glucuronidating trans- and/or cis-resveratrol. The results demonstrate that the GI tract may contribute significantly to the first pass metabolism of these naturally occurring polyphenols. Copyright © 2006 John Wiley & Sons, Ltd.
UDP glucuronosyltransferases (UGTs)1 are a superfamily of membrane-
bound enzymes located in the endoplasmic reticulum that catalyze
the conjugation of endogenous substances (e.g., bilirubin, steroids,
thyroid hormone) and xenobiotics with D-glucuronic acid.
UGTs catalyze the conversion of lipophilic molecules into more polar
hydrophilic glucuronides, thereby facilitating their elimination via
bile, feces, and urine. The role of hepatic and extrahepatic UGT
enzymes and their expression in gastrointestinal tract are described by
Fisher et al. (2001). In this review, the authors reported the presence
of UGT1A1, UGT1A3, UGT1A4, UGT2B7, and UGT2B15 in human
liver and small intestine.
Biochem Pharmacol. 2004 Jan 1;67(1):191-9. Links
Evidence that unsaturated fatty acids are potent inhibitors of renal UDP-glucuronosyltransferases (UGT): kinetic studies using human kidney cortical microsomes and recombinant UGT1A9 and UGT2B7.
………Renal ischaemia is associated with accumulation of fatty acids (FA) and mobilisation of arachidonic acid (AA). Given the capacity of UDP-glucuronosyltransferase (UGT) isoforms to metabolise both drugs and FA, we hypothesised that FA would inhibit renal drug glucuronidation. …….. FA (C16:1-C20:5) significantly inhibited (25-93%) HKCM, UGT1A9 or UGT2B7 catalysed 4-MU glucuronidation. Although linoleic acid (LA) and AA were both competitive inhibitors of 4-MU glucuronidation by HKCM (K(i)(app) 6.34 and 0.15 microM, respectively), only LA was a competitive inhibitor of UGT1A9 (K(i)(app) 4.06 microM). In contrast, inhibition of UGT1A9 by AA exhibited atypical kinetics. These data indicate that LA and AA are potent inhibitors of 4-MU glucuronidation catalysed by human kidney UGTs and recombinant UGT1A9 and UGT2B7. …….. PMID: 14667942
Can J Physiol Pharmacol. 2006 Dec;84(12):1259-65. Links
Influence of curcumin, capsaicin, and piperine on the rat liver drug-metabolizing enzyme system in vivo and in vitro.
………… The effect of dietary supplementation of spice-active principles, curcumin (0.2%), capsaicin (0.015%), and piperine (0.02%) on the activities of the liver drug-metabolizing enzyme system was examined. …………. Uridine dinucleotide phosphate (UDP)-glucuronyl transferase activity was decreased by dietary piperine and the combination of curcumin and capsaicin. NADPH-cytochrome c reductase activity was significantly decreased by dietary piperine. The levels of hepatic microsomal cytochrome P450 and cytochrome b5 were not influenced by any of the dietary spice-active principles. ………….. Hepatic microsomal glucuronyl transferase activity was significantly decreased in vitro by addition of capsaicin or piperine. Capsaicin and piperine brought about significant decrease in liver microsomal cytochrome P450 when included at 1 x 10(-6) mol/L and 1 x 10(-5) mol/L, the effect being much higher in the case of piperine. The results suggested that whereas the 3 spice principles have considerable similarity in structure, piperine is exceptional in its influence on the liver drug-metabolizing enzyme system. The study also indicated that a combination of curcumin and capsaicin does not produce any significant additive effect on the liver drug-metabolizing enzyme system. PMID: 17487234
Biochem Pharmacol. 1993 Jul 20;46(2):229-38.Links
Impairment of UDP-glucose dehydrogenase and glucuronidation activities in liver and small intestine of rat and guinea pig in vitro by piperine.
….. The effects of piperine, a major ingredient of black pepper, on UDP-glucose dehydrogenase (UDP-GDH) and glucuronidation potentials of rat and guinea pig liver and intestine were studied. Piperine caused a concentration-related strong inhibition of UDP-GDH (50% at 10 microM) reversibly and equipotently, in both tissues. ………… In guinea pig small intestine, both these activities were inhibited significantly requiring less than 25 microM piperine to produce a more than 50% inhibition of UGT(s). The results suggested that (i) piperine is a potent inhibitor of UDP-GDH, (ii) inhibition is offered exclusively by the conjugated double bonds of the molecule, and (iii) piperine exerts stronger effects on intestinal glucuronidation than in rat liver.PMID: 8347144 [PubMed - indexed for MEDLINE]
J Nutr. 2004 Aug;134(8):1948-52. Links
Piperine enhances the bioavailability of the tea polyphenol (-)-epigallocatechin-3-gallate in mice.Lambert ………..
Intragastric coadministration of 163.8 micromol/kg EGCG and 70.2 micromol/kg piperine to male CF-1 mice increased the plasma C(max) and area under the curve (AUC) by 1.3-fold compared to mice treated with EGCG only. Piperine appeared to increase EGCG bioavailability by inhibiting glucuronidation and gastrointestinal transit. Piperine (100 micromol/L) inhibited EGCG glucuronidation in mouse small intestine (by 40%) but not in hepatic microsomes. Piperine (20 micromol/L) also inhibited production of EGCG-3"-glucuronide in human HT-29 colon adenocarcinoma cells. Small intestinal EGCG levels in CF-1 mice following treatment with EGCG alone had a C(max) = 37.50 +/- 22.50 nmol/g at 60 min that then decreased to 5.14 +/- 1.65 nmol/g at 90 min; however, cotreatment with piperine resulted in a C(max) = 31.60 +/- 15.08 nmol/g at 90 min, and levels were maintained above 20 nmol/g until 180 min. This resulted in a significant increase in the small intestine EGCG AUC (4621.80 +/- 1958.72 vs. 1686.50 +/- 757.07 (nmol/g.min)).
PMID: 15284381 [PubMed - indexed for MEDLINE]
http://www.resveratr....com/page40.htmBioavailability
For example, Thomas Walle and colleagues at the University of South Carolina confirm that a minimum of 70 percent of oral resveratrol, as a small molecule, is absorbed in the human digestive tract, but thereafter most resveratrol in blood plasma is conjugated with (complexed with) sulfur and glucuronic acid as it passes through the liver. [Drug Metabolism Disposition 32:1377-82, 2004] Other studies also indicate that gastric absorption of resveratrol in-vivo may be high but there is limited bioavailability due to efficient sulfate conjugation. [J Pharmacy Pharmacology 55:307-12, 2003] Researchers in Britain also maintain that oral resveratrol is not bio-available and that an aerosol delivery system would be required to treat lung diseases. [Am J Physiology Lung Cell Molecular Physiology 287:L774-83, 2004]
…………..
But an important biochemical aspect of why resveratrol exerts seemingly magical properties has been overlooked. The metabolic process of glucuronidation in the liver actually appears to protect resveratrol from degradation, extending its half life and maintaining its biological properties for up to nine hours. [Biochemistry Journal 374 (Pt 1):157-63, 2003]
J Pharmacol Exp Ther. 2002 Jul;302(1):369-73. Links
Metabolism and disposition of resveratrol in rats: extent of absorption, glucuronidation, and enterohepatic recirculation evidenced by a linked-rat model.
………… Pharmacokinetics of trans-resveratrol in its aglycone (RES(AGL)) and glucuronide (RES(GLU)) forms were studied following intravenous (15 mg/kg i.v.) and oral (50 mg/kg p.o.) administration of trans-resveratrol in a solution of beta-cyclodextrin to intact rats. In addition, the enterohepatic recirculation of RES(AGL) and RES(GLU) was assessed in a linked-rat model. Multiple plasma and urine samples were collected and concentrations of RES(AGL) and RES(GLU) were determined using an electrospray ionization-liquid chromatography/tandem mass spectrometry method. After i.v. administration, plasma concentrations of RES(AGL) declined with a rapid elimination half-life (T(1/2), 0.13 h), followed by sudden increases in plasma concentrations 4 to 8 h after drug administration. These plasma concentrations resulted in a significant prolongation of the terminal elimination half-life of RES(AGL) (T(1/2TER), 1.31 h). RES(AGL) and RES(GLU) also displayed sudden increases in plasma concentrations 4 to 8 h after oral administration, with T(1/2TER) of 1.48 and 1.58 h, respectively. RES(AGL) bioavailability was 38% and its exposure was approximately 46-fold lower than that of RES(GLU) (AUC(inf), 7.1 versus 324.7 micromol.h/l). Enterohepatic recirculation was confirmed in the linked-rat model since significant plasma concentrations of RES(AGL) and RES(GLU) were observed in bile-recipient rats at 4 to 8 h. The percentages of the exposures of RES(AGL) and RES(GLU) that were due to enterohepatic recirculation were 24.7 and 24.0%, respectively. The fraction of drug excreted in the urine over a period of 12 h was negligible. These results confirm that RES(AGL) is bioavailable and undergoes extensive first-pass glucuronidation, and that enterohepatic recirculation contributes significantly to the exposure of RES(AGL) and RES(GLU) in rats.
PMID: 12065739 [PubMed - indexed for MEDLINE]
J Pharm Pharmacol. 2003 Mar;55(3):307-12. Links
Resveratrol transport and metabolism by human intestinal Caco-2 cells.
….Resveratrol is a dietary constituent suggested to have protective effects against cancer as well as cardiovascular disease. The purpose of the study was to learn whether this agent could be absorbed in man and enter the systemic circulation. This was examined by measuring transport and metabolism of resveratrol (5-40 microM) by the human intestinal epithelial cell line Caco-2 cultured in Transwells. Transport across the Caco-2 monolayer occurred in a direction-independent manner with P(app) values of approximately 7 x 10(-6) cm s(-1), much higher than for the paracellular transport marker mannitol (approximately 0.4 x 10(-6) cm s(-1)), suggesting efficient absorption in-vivo. At the highest resveratrol concentration, the absorption increased, possibly due to saturation of metabolism. In sharp contrast to previous findings in the rat, the metabolism of resveratrol in Caco-2 cells involved mainly sulfation and, to a minor extent, glucuronidation. At low resveratrol concentrations, most of the sulfate conjugate was exported to the apical side, presumably by MRP2, which is well expressed in these cells. At high concentrations, there was a shift towards the basolateral side, possibly involving MRP3, which was recently shown also to be expressed in Caco-2 cells. These results indicate that absorption of resveratrol in-vivo may be high but with limited bioavailability due to efficient sulfate conjugation. Extensive accumulation of resveratrol in the Caco-2 cells, demonstrated in additional experiments, suggests enterocytes as a major target site for this cancer preventive agent. PMID: 12724035
Pharm Res. 2006 Sep;23(9):2107-15. Epub 2006 Aug 9. Links
Increased transport of resveratrol across monolayers of the human intestinal Caco-2 cells is mediated by inhibition and saturation of metabolites.
………….. PURPOSE: The study's aim was to investigate the dose-dependent effect of sulfation and glucuronidation on intestinal absorption of resveratrol, a dietary constituent found in grapes and various medical plants. MATERIALS AND METHODS: The intestinal epithelial membrane transport kinetics and metabolism of resveratrol (10-200 microM) was studied using Caco-2 monolayers cultured in Transwells. RESULTS: Along with resveratrol it was possible to identify three metabolites, namely, resveratrol-4'-O-glucuronide (M1), resveratrol 3-O-gucuronide (M2), and resveratrol-3-O-sulfate (M3) by LC/MS and NMR. Efflux of the glucuronides M1 and M2 followed Michaelis-Menten kinetics significantly favouring basolateral efflux. The predominant metabolite was the monosulfate M3, however, its formation was strongly inhibited at higher resveratrol concentrations. As biotransformation was either inhibited or saturated, total amount of resveratrol transported across the Caco-2 monolayers increased as much as 3.5-fold at 200 microM resveratrol. This value might be even higher when taking into account the high intracellular concentration of resveratrol, which accounted for up to 61% of the applied dose. CONCLUSIONS: Our data demonstrate a concentration-dependent biotransformation of resveratrol in Caco-2 cells, which may also apply to human enterocytes affecting oral bioavailability.
PMID: 16952002
Researchers at the Institute of Human Virology, University of Maryland Biotechnology Institute, have written an extensive report describing the biological aspects of liver metabolism and resveratrol. Here is an excerpt paraphrased from their paper:
What is the biological function of glucuronidation of resveratrol in humans? What is the real bioactive form of resveratrol in living organisms? …There are examples showing that liver metabolism (glucuronidation) has a role in drug disposition and drug targeting in humans. It is known that beta-glucuronidase, the enzyme that breaks down glucuronide, is widely expressed in organs, tissues, and body fluids in humans. Therefore, this enzyme may release a drug or bound molecule like resveratrol locally or systemically from a glucuronide conjugate (such as resveratrol glucuronide). In fact, many glucuronide prodrugs have been designed and are under development that bind a synthetic drug molecule to glucuronide which subsequently depends upon the beta-glucuronidase enzyme to release it into living tissues.
Therefore, it is likely that at least a portion of resveratrol is unzipped from its protective carrier by the glucuronidase enzyme and could be converted back to free resveratrol. Since tissue or serum beta-glucuronidase enzyme activity is elevated in certain diseased tissues, such as cancer, liver diseases, and AIDS, resveratrol would be targeted and released more so in these tissues than in healthy ones. Researchers state that “these observations… raise the possibility that glucuronidation of resveratrol may have a role in detoxification, disposition, and prolongation of the effectiveness of resveratrol in humans.” [Journal Pharm Science 93:2448–2457, 2004]
Mol Ther. 2001 Jun;3(6):875-81. Links
Primary adult human astrocytes as an ex vivo vehicle for beta-glucuronidase delivery in the brain.
…Astrocytes are a good candidate cell type for brain transplantation: They are endogenous to the CNS, they have efficient secretory machinery, and they play a major role in neuronal support. We assessed the potential of genetically modified primary adult human astrocytes as vehicles for the delivery of secreted molecules in the mammalian CNS. ……... These experiments document the grafting of engineered primary adult human astrocytes, allowing the release of a secreted therapeutic factor throughout the brain.
PMID: 11407901 [PubMed - indexed for MEDLINE]
J Pharm Sci. 2004 Oct;93(10):2448-57. Links
Resveratrol glucuronides as the metabolites of resveratrol in humans: characterization, synthesis, and anti-HIV activity…….Whereas resveratrol was cytotoxic at > or =30 microM, no cytotoxicity was observed for the metabolites at concentrations as high as 300 microM. However, resveratrol showed strong synergistic anti-HIV activity with didanosine at 10 microM, but no synergistic effects were observed for either of the metabolites at up to 300 microM. Nevertheless, the in vitro activity of the metabolites (resveratrol glucuronides) may not necessarily reflect their in vivo function, given the fact that the ubiquitously existing human beta-glucuronidase could convert the metabolites back to resveratrol locally or systematically in vivo. The present studies have implications for future development of resveratrol and/or its derivatives as a chemotherapeutic agent. PMID: 15349955
J Endocrinol. 2004 Jun;181(3):393-400. Links
Activities of UDP-glucuronyltransferase, beta-glucuronidase and deiodinase types I and II in hyper- and hypothyroid rats.
,,,,,,…… We have investigated the hypothesis that uridine 5'-diphosphate (UDP)-glucuronyltransferases (UGTs) and beta-glucuronidase are jointly involved in a mechanism for the storage and mobilization of iodothyronine metabolites in liver, kidney, heart and brain. Specifically, we predicted UGT activities to decrease and increase respectively, and beta-glucuronidase activity to increase and decrease respectively in hypo- and hyperthyroidism. To this end we have studied the effects of thyroid status on the activities of different enzymes involved in thyroid hormone metabolism in liver, kidney, heart and brain from adult rats with experimentally induced hypo- and hyperthyroidism. ………… Hepatic phenol-UGT as well as androsteron-UGT activities were decreased in hypothyroid rats, with specific androsteron-UGT activities two to three orders of magnitude lower than phenol-UGT activities. Both UGT isozymes were well above detection limits in heart, but appeared to be insensitive to thyroid status. In contrast, cardiac beta-glucuronidase activity decreased in hypothyroid tissue, whereas the activity of this enzyme in the other organs investigated did not change significantly.In summary, cardiac beta-glucuronidase, albeit in low levels, and hepatic phenol-UGT activities were responsive only to experimental hypothyroidism. Although a high basal activity of the pleiotropic beta-glucuronidase masking subtle activity changes in response to thyroid status cannot be ruled out, we conclude that hepatic, renal and cardiac UGT and beta-glucuronidase activities are not regulated reciprocally with thyroid status. PMID: 15171687 [PubMed - indexed for MEDLINE] =one more reason to go on CR?
And in summary:
Sulfation is the conjugation of toxins with sulfur-containing compounds. The sulfation system is important for detoxifying several drugs, food additives, and, especially, toxins from intestinal bacteria and the environment. In addition to environmental toxins, sulfation is also used to detoxify some normal body chemicals and is the main pathway for the elimination of steroid and thyroid hormones. Since sulfation is also the primary route for the elimination of neurotransmitters, dysfunction in this system may contribute to the development of some nervous system disorders.
Many factors influence the activity of sulfate conjugation. For example, a diet low in methionine and cysteine has been shown to reduce sulfation. Sulfation is also reduced by excessive levels of molybdenum or vitamin B6 (over about 100 mg/day). In some cases, sulfation can be increased by supplemental sulfate, extra amounts of sulfur-containing foods in the diet, and the amino acids taurine and glutathione.
Inhibitors of sulfation:
• Insufficient intake of sulfur-containing amino acids (cysteine and methionine) from the diet
• Excessive non-steroidal anti-inflammatory intake, including aspirin
• High tartrazine intake
• Excessive molybdenum or vitamin B6 (over 100mg/ day) intake
• Molybdenum deficiency
Increase low allergy potential protein in the diet to ensure adequate intake of sulfur amino acids
• Ensure molybdenum levels are optimal as the enzyme sulfite oxidase, which is necessary for the
conversion of cysteine/ methionine to sulfate, is dependent upon this trace mineral.
Excessive molybdenum, however can inhibit sulfation
• Supplementing L-cysteine, inorganic sulfate, N-acetyl-cysteine, glutathione, taurine will all increase
sulfation (glutathione taken orally is not cleaved by digestive enzymes and will raise levels)
• Ensure adequate intake of sulfur-containing foods such as egg yolks, red peppers, garlic, onions,
broccoli and Brussels sprouts
Also to inhibit glucoronidation, go on CR to lower T3 levels, take aspirin, and stay away from cymarin in artichoke leaf and linonene rich foods such as citrus peel, dill weed seeds and caraway seeds and fish oils at the same time:
Inhibitors of Glucuronidation
• Fluoride is thought to inhibit the enzyme responsible for glucuronidation, UDP-glucuronosyltransferase
• Decreased levels of beneficial bacteria and/ or fibre in the colon, as bacterial fermentation can also
influence the activity of the above enzyme
• Excessive aspirin or probenecid intake
• Vitamin A deficiency
• Low T3 levels
Action:
• Ensure sufficient glucuronic acid levels.
• Supplement N-acetyl-cysteine (NAC) which helps
increase glutathione levels
• Increase sources of limonene, sulfur-rich foods
(as above) and citrus fruits (but not grapefruit)
• Methionine administered as SAMe has been shown
to be beneficial in treating Gilbert’s Syndrome
Action
• Cymarin from artichoke leaf can induce
glucuronidation
• Ensure optimal vitamin A levels
• Assess thyroid function
• Supply non-digestible fibre and replenish
beneficial flora
• Limonene rich foods, fish oils and cymarin
(artichoke) can induce glucuronidation
LongeCity
