Quercetin, a potent and specific inhibitor of the human P-form phenolsulfotransferase

Walle, Thomas; Eaton, E A; Walle, U K

doi:10.1016/0006-2952(95)00190-b

Cited by 72 publications

(51 citation statements)

References 25 publications

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“…6; they demonstrate that 4-n-nonylphenol acts as a partial mixed inhibitor of SULT1A1/2-mediated 17␤-estradiol sulfation. This behavior is similar to that of several other known inhibitors of SULT1A1/2 activity including vanillin (58) and quercetin (59). We suggest that the most likely explanation of this complex enzymatic behavior is that 4-n-nonylphenol can bind to free SULT1A1/2 yielding an enzyme-inhibitor complex (dissociation constant K i ϭ 2.8 M) and also bind to the SULT1A1/2-17␤-estradiol complex giving an unreactive enzyme-substrate/inhibitor complex (dissociation KЈ i ϭ 5.4 M).…”

Section: ␤-Estradiol Is Sulfated In Human Platelet Cytosol By Two Ssupporting

confidence: 78%

Sulfation of “Estrogenic” Alkylphenols and 17β-Estradiol by Human Platelet Phenol Sulfotransferases

Harris

Waring

Kirk

et al. 2000

Journal of Biological Chemistry

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We have investigated the ability of alkylphenols to act as substrates and/or inhibitors of phenol sulfotransferase enzymes in human platelet cytosolic fractions. Our results indicate: (i) straight chain alkylphenols do not interact with the monoamine-sulfating phenol sulfotransferase (SULT1A3); (ii) short chain 4-n-alkylphenols (C < 8) are substrates for the phenol-sulfating enzymes (SULT1A1/2), which exhibit two activity maxima against substrates with alkyl chain lengths of C1-2 and C4 -5; (iii) long chain 4-n-substituted alkylphenols (C > 8) are poor substrates and act as inhibitors of SULT1A1/2; (iv) human platelets contain two activities, of low and high affinity, capable of sulfating 17␤-estradiol, and 4-n-nonylphenol is a partial mixed inhibitor of the low affinity form of this activity. We conclude that by acting either as substrates or inhibitors of SULT1A1/2, alkylphenols may influence the sulfation, and hence the excretion, of estrogens and other phenol sulfotransferase substrates in humans.

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Section: ␤-Estradiol Is Sulfated In Human Platelet Cytosol By Two Ssupporting

confidence: 78%

Sulfation of “Estrogenic” Alkylphenols and 17β-Estradiol by Human Platelet Phenol Sulfotransferases

Harris

Waring

Kirk

et al. 2000

Journal of Biological Chemistry

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“…On initial screening with cDNA-expressed enzymes, multiple SULTs (SULT1A1, SULT1A2, SULT1A3, SULT1E, and SULT2A1) were capable of forming O-demethyl apixaban sulfate; however, SULT1A1 and SULT1A2 had a higher catalytic efficiency than other enzymes tested. Quercetin and DCNP were selective inhibitors of SULT1A1 with IC 50 values of approximately 100 nM (Walle et al, 1995;Schrag et al, 2004). In the present study, results showed that quercetin (1 M) and DCNP (0.5 M) selectively inhibited the formation of O-demethyl apixaban sulfate by Ͼ90% in human liver S9 incubations at 20 and 100 M of O-demethyl apixaban (Fig.…”

Section: Discussionmentioning

confidence: 99%

Sulfation of O-Demethyl Apixaban: Enzyme Identification and Species Comparison

Wang¹,

Raghavan²,

He³

et al. 2009

Drug Metab Dispos

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ABSTRACT:Apixaban, a potent and highly selective factor Xa inhibitor, is currently under development for treatment of arterial and venous thrombotic diseases. The O-demethyl apixaban sulfate is a major circulating metabolite in humans but circulates at lower concentrations relative to parent in animals. The aim of this study was to identify the sulfotransferases (SULTs) responsible for the sulfation reaction. Apixaban undergoes O-demethylation catalyzed by cytochrome P450 enzymes to O-demethyl apixaban, and then is conjugated by SULTs to form O-demethyl apixaban sulfate. Of the five human cDNA-expressed SULTs tested, SULT1A1 and SULT1A2 exhibited significant levels of catalytic activity for formation of O-demethyl apixaban sulfate, and SULT1A3, SULT1E1, and SULT2A1 showed much lower catalytic activities. In human liver S9, quercetin, a highly selective inhibitor of SULT1A1 and SULT1E1, inhibited O-demethyl apixaban sulfate formation by 99%; 2,6-dichloro-4-nitrophenol, another inhibitor of SULT1A1, also inhibited this reaction by >90%; estrone, a competitive inhibitor for SULT1E1, had no effect on this reaction. The comparable K m values for formation of O-demethyl apixaban sulfate were 41.4 M (human liver S9), 36.8 M (SULT1A1), and 70.8 M (SULT1A2). Because of the high level of expression of SULT1A1 in liver and its higher level of catalytic activity for formation of O-demethyl apixaban sulfate, SULT1A1 might play a major role in humans for formation of O-demethyl apixaban sulfate. O-Demethyl apixaban was also investigated in liver S9 of mice, rats, rabbits, dogs, monkeys, and humans. The results indicated that liver S9 samples from dogs, monkeys, and humans had higher activities for formation of O-demethyl apixaban sulfate than those of mice, rats, and rabbits.

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“…These included vanillin (a naturally occurring flavoring), octyl gallate (an antioxidant), and tartrazine (a synthetic colorant). A number of flavonoids, such as quercetin, are also potent inhibitors of ST activity (90); and red wine, which contains very high levels of polyphenolic compounds, is a very potent and selective inhibitor of human P-PST with a 2000-fold dilution resulting in 50% inhibition of this enzyme activity (91). The importance of these dietary inhibitors may lie in their ability to inhibit the bioactivation of dietary procarcinogens by STs (particularly P-PST) and thus act as natural chemoprotectants.…”

Section: Known Polymorphisms Of Sulfation In Manmentioning

confidence: 99%

Genetic and environmental factors associated with variation of human xenobiotic glucuronidation and sulfation.

Burchell

Coughtrie

1997

Environ Health Perspect

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Glucuronidation and sulfation are phase 2 metabolic reactions catalyzed by large families of different isoenzymes in man. The textbook view that glucuronidation and sulfation lead to the production of harmless conjugates for simple excretion is not valid. Biologically active and toxic sulfates and glucuronides are produced and lead to adverse drug reactions, including immune hypersensitivity. Considerable variation in xenobiotic conjugation is observed as a result of altered expression of UDP-glucuronosyltransferases (UGTs) and sulfotransferases (STs). Recent cloning and expression of human cDNA encoding UGTs and STs has facilitated characterization of isoform substrate specificity, which has been further validated using specific antibodies and human tissue fractions. The availability of cloned/expressed human enzymes and specific antibodies has enabled the investigation of xenobiotic induction and metabolic disruption leading to adverse responses. Genetic polymorphisms of glucuronidation and sulfation are known to exist although the characterization and assessment of the importance of these variations are hampered by appropriate ethical studies in man with suitable safe model compounds. Genetic analysis has allowed molecular identification of defects in well-known hyperbilirubinemias. However, full characterization of the specific functional roles of human UGTs and STs requires rigorous kinetic and molecular analyses of the role of each enzyme in vivo through the use of specific antibodies and inhibitors. This will lead to the better prediction of variation of xenobiotic glucuronidation and sulfation in man. Environ Health Perspect 1 05(Suppl 4): 739-747 (1997)

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Quercetin, a potent and specific inhibitor of the human P-form phenolsulfotransferase

Cited by 72 publications

References 25 publications

Sulfation of “Estrogenic” Alkylphenols and 17β-Estradiol by Human Platelet Phenol Sulfotransferases

Sulfation of “Estrogenic” Alkylphenols and 17β-Estradiol by Human Platelet Phenol Sulfotransferases

Sulfation of O-Demethyl Apixaban: Enzyme Identification and Species Comparison

Genetic and environmental factors associated with variation of human xenobiotic glucuronidation and sulfation.

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