Dose-dependent shifts in the sulfation and glucuronidation of phenolic compounds in the rat in vivo and in isolated hepatocytes

Koster, Henk; Halsema, Ina; Scholtens, Egbert; Knippers, Marjan; Mulder, Gerard J.

doi:10.1016/0006-2952(81)90584-0

Cited by 93 publications

(40 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Many recommend the daily consumption of polyphenols based on the consumption of soy products in Japan or of grapes or wine in some European countries [66,80]. Typical doses are 50 mg per day (mg/d) for isoflavones or 100-300 mg/d grape seed extracts rich in proanthocyanidins.…”

Section: Bioefficacy and Safety Of Polyphenol Consumptionmentioning

confidence: 99%

“…Therefore, the isoforms that are specifically involved in the conjugation of polyphenols have yet been clearly identified. However, sulfation still can account for a large percentage of the phase II metabolism at lower concentration [75,79], and may serve as the primary metabolic pathway for selected polyphenols such as resveratrol [80].…”

Section: Conjugation Enzymesmentioning

confidence: 99%

“…This O-methylation reaction is subjected to strong inhibitory regulation by S-adenosyl-L-homocyteine, which is formed in large quantities during the O-methylation of tea polyphenols. Although methylation may not be the major metabolic pathway, its importance in the mechanisms of action of tea polyphenols cannot be underestimated as methylated metabolites tend to have different activities and some may resist inactivation via UGTs and SULTs [80][81][82][83][84].…”

Section: Conjugation Enzymesmentioning

confidence: 99%

See 2 more Smart Citations

Natural polyphenol disposition via coupled metabolic pathways

Liu¹,

Hu²

2007

Expert Opinion on Drug Metabolism & Toxicology

126

View full text Add to dashboard Cite

A major challenge associated with the development of chemopreventive polyphenols is the lack of bioavailability in vivo, which are primarily the result of coupled metabolic activities of conjugating enzymes and efflux transporters. These coupling processes are present in most of tissues and organs in mammals and are efficient for the purposes of drug metabolism, elimination and detoxification. Therefore, it was expected that these coupling processes represent a significant barrier to the oral bioavailabilities of polyphenols. In various studies of this coupling process, it was identified that various conjugating enzymes such as UGT and SULT are capable of producing very hydrophilic metabolites of polyphenols, which cannot diffuse out of the cells and needs the action of efflux transporters to pump them out of the cells. Additional studies have shown that efflux transporters such as MRP2, BCRP and OAT appear to serve as the gate keeper when there is an excess capacity to metabolize the compounds. These efflux transporters may also act as the facilitator of metabolism when there is a product/metabolite inhibition. For polyphenols, these coupled processes enable a duo recycling scheme of enteric and enterohepatic recycling, which allows the polyphenols to be reabsorbed and results in longer than expected apparent plasma half-lives for these compounds and their conjugates. Since the vast majority of polyphenols in plasma are hydrophilic conjugates, more research is needed to determine if the metabolites are active or reactive, which will help explain their mechanism of actions.

show abstract

Section: Bioefficacy and Safety Of Polyphenol Consumptionmentioning

confidence: 99%

Section: Conjugation Enzymesmentioning

confidence: 99%

Section: Conjugation Enzymesmentioning

confidence: 99%

See 1 more Smart Citation

Natural polyphenol disposition via coupled metabolic pathways

Liu¹,

Hu²

2007

Expert Opinion on Drug Metabolism & Toxicology

126

View full text Add to dashboard Cite

show abstract

“…Phenolic drugs are known to be preferentially sulfated in hepatocytes at low concentrations although the shift from glucuronidation to sulfation occurs at considerably high concentrations of more than 100 mM. [14][15][16] It has been considered that the sulfate conjugation pathway of phenolic compounds is limited, probably due to the poor capacity of PAPS in cells. [14][15][16] We kinetically characterized the glucurono-and sulfo-conjugation of kaempferol using liver subcellular preparations.…”

Section: Discussionmentioning

confidence: 99%

“…[14][15][16] It has been considered that the sulfate conjugation pathway of phenolic compounds is limited, probably due to the poor capacity of PAPS in cells. [14][15][16] We kinetically characterized the glucurono-and sulfo-conjugation of kaempferol using liver subcellular preparations. A markedly large proportion of the V max value for mG3/cS supported the preferential production of hG3 in the cultured hepatocytes.…”

Section: Discussionmentioning

confidence: 99%

Glucurono- and Sulfo-Conjugation of Kaempferol in Rat Liver Subcellular Preparations and Cultured Hepatocytes

Yodogawa

Arakawa

Sugihara

et al. 2003

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

The health benefits of flavonoids as preventive nutrition from coronary heart disease and cancer have received considerable attention since they occur naturally in dietary plants. 1,2) For a better understanding of the pharmacological activity of flavonoids, a thorough knowledge of their metabolism in the body is required. Flavonoids are polyphenols and, therefore, considered to be metabolized mainly as conjugated derivatives by coupling with a glucuronic acid or a sulfuric acid during the phase II biotransformation pathway in vertebrates. There have been several reports [3][4][5][6] on the conjugative metabolism of flavonoids, particularly quercetin which is one of the most widely distributed flavonoids found in fruits and vegetables. 7,8) The conjugation of quercetin is somewhat complicated since it also undergoes methylation of its catechol moiety on the B-ring in addition to glucurono-and sulfo-conjugation in the body. Quercetin metabolites are found as glucurono-or sulfo-conjugates of quercetin and isorhamnetin, a 3Ј-O-methylated form of quercetin, in the plasma of rats and humans administered quercetin.3-6) However, details of the different glucurono-and sulfo-conjugated forms of quercetin and isorhamnetin are still poorly understood. In the present studies, the metabolism of kaempferol lacking one of the ortho-dihydroxyl substitutions on the Bring of quercetin was investigated using rat liver subcellular preparations and cultured hepatocytes. Kaempferol was only glucurono-and sulfo-conjugated but not o-methyl-conjugated in the cultured hepatocytes. Thus, kaempferol appeared to be a more suitable model than quercetin for studying glucurono-and sulfo-conjugated forms of flavonols. Glucurono-and Sulfo-Conjugation by Liver Preparations Liver microsomes and cytosol were prepared in 0.25 M sucrose from male Wistar rats weighing 180-220 g provided with standard rat chow and water ad libitum as described by De Duve et al. MATERIALS AND METHODS Materials9) The reaction mixtures for glucurono-conjugation consisted of 100 mM flavonoid, 50 mM Tris-HCl buffer pH 7.4, 5 mM MgCl 2 , 0.02% Brij, 3 mM UDPGA, and 100 mg microsomes in a final volume of 0.5 ml. The reaction mixtures for sulfo-conjugation consisted of 100 mM flavonoid, 50 mM Tris-HCl buffer pH 7.4, 5 mM MgCl 2 , 10 mM dithiothreitol, 600 mM PAPS, and 1 mg cytosol in a final volume of 0.5 ml. Incubations were at 37°C with shaking for 30-120 minutes. Protein was determined by the method of Lowry et al. 10)Glucurono-and Sulfo-Conjugation by Cultured Hepatocytes Hepatocytes were isolated by the collagenase perfusion method 11) from male Wistar rats maintained as described above. These cells were resuspended in Eagle's MEM containing dexamethasone (1 mM), insulin (0.1 mM), triiodothyronine (1 mg/ml), d-aminolevulinic acid hydrochloride (0.2 mM) and 10% fetal calf serum. The cells were seeded in 35 mm plastic culture dishes at a density of 1ϫ10 6 cells/dish, and placed in an incubator in an atmosphere of 5% CO 2 95% air at 37°C. The monolayers of hepatocytes were *...

show abstract

Phenol and Phenolics

Cavender,

O'Donoghue

2023

Patty's Toxicology

View full text Add to dashboard Cite

The phenolics used for industrial and commercial purposes are a large and diverse group of chemicals as the six‐member ring of phenolics can be methylated, halogenated or include other moieties that add properties or toxicological potential that is not observed with simple phenolics. For simple dihydroxy phenolics, the largest exposure potential can be through their presence naturally in foods. Low concentrations of chlorophenols are commonly found in drinking water due to water chlorination processes. Simple methyl phenols are commonly used as disinfectants. More complex phenolics such as creosote and pentachlorophenol are used as wood preservatives. The acute toxicity of phenolics at relatively high doses is manifested as excitation of the nervous system causing muscle tremors, salivation, and in severe cases, convulsions. The excitatory phase of phenolic intoxication gives way to depression of the nervous system and can result in mortality. Acute and repetitive exposure to phenolics can result in liver and kidney toxicity. A number of phenolics can be absorbed through skin and are readily absorbed after ingestion. Major metabolites of phenols are sulfates and glucuronide conjugates that are excreted through the kidneys. First pass metabolism present on ingestion is not a factor for phenols absorbed through the skin. Therefore, the toxicity of phenolics may differ depending on route of exposure.

show abstract

Dose-dependent shifts in the sulfation and glucuronidation of phenolic compounds in the rat in vivo and in isolated hepatocytes

Cited by 93 publications

References 21 publications

Natural polyphenol disposition via coupled metabolic pathways

Natural polyphenol disposition via coupled metabolic pathways

Glucurono- and Sulfo-Conjugation of Kaempferol in Rat Liver Subcellular Preparations and Cultured Hepatocytes

Phenol and Phenolics

Contact Info

Product

Resources

About