A novel metabolite of RRR‐α‐tocopherol in human urine

Schönfeld, A.; Schultz, M.; Petrizka, M.; Gaßmann, B.

doi:10.1002/food.19930370514

Cited by 28 publications

(19 citation statements)

References 5 publications

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“…The known homolog, 5-Me LLU-a (a metabolite of a-tocoph- erol), has been isolated from rabbit and human urine (22)(23)(24)(25). However, this latter compound is not natriuretic in our assay (unpublished data), which suggests great specificity in the biology of LLU-a.…”

Section: Discussionmentioning

confidence: 85%

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A new endogenous natriuretic factor: LLU-alpha.

Wechter

Kantoci

Murray

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

179

126

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For over three decades, renal physiology has sought a putative natriuretic hormone (third factor) that might control the body's pool of extracellular fluid, an important determinant in hypertension, congestive heart failure, and cirrhosis. In our search for this hormone, we have isolated several pure natriuretic factors from human uremic urine that would appear, alone or in combination, to mark a cluster of phenomena previously presumed to be that of a single "natriuretic hormone." This paper reports the purification, chemical structure, and total synthesis of the first of these compounds, LLU-a, which proved to be 2,7,8-trimethyl-2-(pcarboxyethyl)-6-hydroxychroman, presumably a metabolite of y-tocopherol. Both natural LLU-a and synthetic material are identical (except for optical activity) with respect to structure and biological activity. It appears that the natriuretic activity of LLU-a is mediated by inhibition of the 70 pS K+ channel in the apical membrane of the thick ascending limb of the kidney.As a result of salt-induced plasma-volume expansion in mammals, three concurrent events have been observed: sustained natriuresis, rising plasma concentration of a Na+ transport inhibitor, and pressor activity. It has been presumed that these effects are due to elaboration of a low-molecular-weight "natriuretic hormone," the putative controller of extracellular fluid (1). Over 30 years of effort have failed to characterize the putative hormone (2, 3). Atrial natriuretic factor, when infused, produces a natriuresis and a decrease in blood pressure that are short-lived (4, 5) and whose physiological role is still undefined (6, 7).The approach of essentially all other workers has been to investigate mammalian-derived isolates that inhibit the Na+ pump (2,8). From these studies, digoxin (9) and "iso-ouabain" (10-13) have been isolated; however, digoxin and ouabain lead to kaliuresis (4,(14)(15)(16)(17). Therefore, we hypothesized that this search tool is an inadequate marker for natriuresis. Consequently, a natriuretic assay has been developed in which the in vivo physiological events, urine volume, K+ and Na+ concentrations, and mean arterial pressure are measured (18).In this paper, we report the isolation of pure LLU-a, the determination of its structure by spectroscopy, its synthesis in racemic form, and its biological characterization. Given its structure, we infer that it is the product of in vivo oxidative metabolism of y-tocopherol, a member of the vitamin E complex. MATERIALS AND METHODSPurification of LLU-a. Human uremic urine (800 liters) was collected, processed by ultrafiltration (3 kDa) and lyophilization, and then chromatographed on Sephadex G-25 to obtain the post-salt fraction as described (18 Step 1. Reversed-phase HPLC was performed by gradient elution with 0.2 M pyridinium acetate, pH 5.5, and methanol as described (4). Based on bioassay data, fractions 50-80 were combined for further purification.Step 2. The next column (5 pm; 10 x 250 mm) was eluted at 2 ml/min with a gradient formed from...

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Section: Discussionmentioning

confidence: 85%

“…However, this latter compound is not natriuretic in our assay (unpublished data), which suggests great specificity in the biology of LLU-a. As with 5-Me LLU-a (22)(23)(24)(25), mild oxidation provides the quinone [1] which is in equilibrium with the lactone [3] (Fig. 3).…”

Section: Discussionmentioning

confidence: 99%

A new endogenous natriuretic factor: LLU-alpha.

Wechter

Kantoci

Murray

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

179

126

View full text Add to dashboard Cite

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“…The ICMs have also been found in cultured HepG2 cells (α-, γ-7'-COOH and α-, γ-5'-COOH [120,140,144] ). The catabolic end-products of vitamin E metabolism are the CEHC (CEHC, sometimes also referred to 3'-COOH or short-chain metabolites, SCM), which were an early focus of research on vitamin E metabolism [145,146] . In the 1980s and 1990s different CEHCs were identified as the first known metabolites of vitamin E degradation: α-CEHC [132,146] , γ-CEHC [147] and δ-CEHC [131] .…”

Section: Metabolism Of Tohmentioning

confidence: 99%

“…The catabolic end-products of vitamin E metabolism are the CEHC (CEHC, sometimes also referred to 3'-COOH or short-chain metabolites, SCM), which were an early focus of research on vitamin E metabolism [145,146] . In the 1980s and 1990s different CEHCs were identified as the first known metabolites of vitamin E degradation: α-CEHC [132,146] , γ-CEHC [147] and δ-CEHC [131] . Shortly after the discovery of the SCMs, it was shown that not only γ-TOH metabolism but also the degradation of γ-T3 results in γ-CEHC [148] .…”

Section: Metabolism Of Tohmentioning

confidence: 99%

Complexity of vitamin E metabolism

Schmölz¹,

Birringer²,

Lorkowski³

et al. 2016

WJBC

168

138

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Bioavailability of vitamin E is influenced by several factors, most are highlighted in this review. While gender, age and genetic constitution influence vitamin E bioavailability but cannot be modified, life-style and intake of vitamin E can be. Numerous factors must be taken into account however, i.e. , when vitamin E is orally administrated, the food matrix may contain competing nutrients. The complex metabolic processes comprise intestinal absorption, vascular transport, hepatic sorting by intracellular binding proteins, such as the significant α-tocopherol-transfer protein, and hepatic metabolism. The coordinated changes involved in the hepatic metabolism of vitamin E provide an effective physiological pathway to protect tissues against the excessive accumulation of, in particular, non-α-tocopherol forms. Metabolism of vitamin E begins with one cycle of CYP4F2/CYP3A4-dependent ω-hydroxylation followed by five cycles of subsequent β-oxidation, and forms the water-soluble end-product carboxyethylhydroxychroman. All known hepatic metabolites can be conjugated and are excreted, depending on the length of their sidechain, either via urine or feces. The physiological handling of vitamin E underlies kinetics which vary between the different vitamin E forms. Here, saturation of the side-chain and also substitution of the chromanol ring system are important. Most of the metabolic reactions and processes that are involved with vitamin E are also shared by other fat soluble vitamins. Influencing interactions with other nutrients such as vitamin K or pharmaceuticals are also covered by this review. All these processes modulate the formation of vitamin E metabolites and their concentrations in tissues and body fluids. Differences in metabolism might be responsible for the discrepancies that have been observed in studies performed in vivo and in vitro using vitamin E as a REVIEW

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“…Although an important factor involved in this selectivity is the hepatic atocopherol transfer protein (a-TTP) (21)(22)(23)(24), differential rates of postabsorptive metabolism of the tocopherols and tocotrienols to water-soluble metabolites appear to be ultimately responsible for the dramatic differences in biological half-lives between the various vitamers. The tocopherols and tocotrienols are metabolized to water-soluble urinary metabolites with the side chain shortened to the 3 ¶ carbon (25)(26)(27)(28)(29). We demonstrated that this occurs by an initial v-hydroxylation at a terminal methyl group of the hydrophobic side chain, followed by sequential b-oxidation to the 3 ¶ carboxychromanol, or 2,7,8-trimethyl-2-(b-carboxyethyl)-6-hydroxychroman (CEHC) (30).…”

mentioning

confidence: 99%

Influence of major structural features of tocopherols and tocotrienols on their ω-oxidation by tocopherol-ω-hydroxylase

Sontag

Parker

2007

Journal of Lipid Research

173

157

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Human cytochrome P450 4F2 (CYP4F2) catalyzes the initial v-hydroxylation reaction in the metabolism of tocopherols and tocotrienols to carboxychromanols and is, to date, the only enzyme shown to metabolize vitamin E. The objective of this study was to characterize this activity, particularly the influence of key features of tocochromanol substrate structure. The influence of the number and positions of methyl groups on the chromanol ring, and of stereochemistry and saturation of the side chain, were explored using HepG2 cultures and microsomal reaction systems. Human liver microsomes and microsomes selectively expressing recombinant human CYP4F2 exhibited substrate activity patterns similar to those of HepG2 cells. Although activity was strongly associated with substrate accumulation by cells or microsomes, substantial differences in specific activities between substrates remained under conditions of similar microsomal membrane substrate concentration. Methylation at C5 of the chromanol ring was associated with markedly low activity. Tocotrienols exhibited much higher V max values than their tocopherol counterparts. Side chain stereochemistry had no effect on v-hydroxylation of a-tocopherol (a-TOH) by any system. Kinetic analysis of microsomal CYP4F2 activity revealed Michaelis-Menten kinetics for a-TOH but allosteric cooperativity for other vitamers, especially tocotrienols. Additionally, a-TOH was a positive effector of v-hydroxylation of other vitamers. These results indicate that CYP4F2-mediated tocopherol-vhydroxylation is a central feature underlying the different biological half-lives, and therefore biopotencies, of the tocopherols and tocotrienols.-Sontag, T. J., and R. S. Parker. Influence of major structural features of tocopherols and tocotrienols on their v-oxidation by tocopherol-v-hydroxylase. J. Lipid Res. 2007. 48: 1090-1098. Supplementary key words vitamin EVitamin E is the generic term for the tocopherols and tocotrienols, which differ in the number and positions of methyl groups around the chromanol ring and in the saturation and stereochemistry of the phytyl tail (Fig. 1).These subtle structural variations are associated with substantial differences in their biopotency in vivo. Although a-tocopherol (a-TOH) has been studied most intensively, recent research has also suggested important roles for the non-a vitamers of vitamin E. Bioactivities of tocopherols and tocotrienols include the more familiar trapping of radical species, including nitric oxide (1-9), as well as more provocative activities, such as the regulation of gene transcription (10-13), anti-inflammation (14), inhibition of cholesterol synthesis (15), and apoptosis (16-18).The superior activity of RRR-a-TOH in vivo appears to result from its superior retention in the body relative to other forms of vitamin E (19, 20). Although an important factor involved in this selectivity is the hepatic atocopherol transfer protein (a-TTP) (21-24), differential rates of postabsorptive metabolism of the tocopherols and tocotrienols to w...

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A novel metabolite of RRR‐α‐tocopherol in human urine

Cited by 28 publications

References 5 publications

A new endogenous natriuretic factor: LLU-alpha.

A new endogenous natriuretic factor: LLU-alpha.

Complexity of vitamin E metabolism

Influence of major structural features of tocopherols and tocotrienols on their ω-oxidation by tocopherol-ω-hydroxylase

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