Biomedical subjects

K U Ingold

Publications and source records attributed to K U Ingold.

At least 55 records · Page 3Linked to original sources

PubMed1994

Cytochrome P450-catalyzed hydroxylation of hydrocarbons: kinetic deuterium isotope effects for the hydroxylation of an ultrafast radical clock.

The ultrafast radical clock probe trans-1-methyl-2-phenylcyclopropane (1CH3) and its mono-, di-, and trideuteriomethyl analogues were oxidized by phenobarbital-induced rat liver microsomal enzymes. This cytochrome P450-catalyzed hydroxylation of 1CH3 gave three products: the alcohol trans-(2-phenylcyclopropyl)methanol (2), the rearranged alcohol 1-phenylbut-3-en-1-ol (3), and the phenol trans-2-(p-hydroxyphenyl)-1-methylcyclopropane (4). The identification of both the unrearranged and rearranged products of oxidation, 2 and 3, is consistent with the formation of a radical intermediate via a hydrogen atom abstraction from the methyl group by the catalytically active iron-oxo center. Hydroxylation of three deuteriomethyl forms of 1CH3 produced the analogous deuterated products, although in different amounts of each. Perdeuteration of the methyl group (1CD3) disfavored oxidation at the methyl group and caused an increase in the oxidation of the phenyl ring (metabolic switching). By comparing the amounts of alcohols and phenol formed from the individual, noncompetitive oxidation of 1CH3 and 1CD3 the overall (i.e., combined primary and secondary) deuterium kinetic isotope effect (DKIE) was found to be 12.5. Intramolecular DKIEs for 1CHD2 and 1CH2D were 2.9 and 13.2, respectively. From these results, the primary and secondary DKIEs were calculated to be 7.87 and 1.26, respectively, values that indicate that there is extensive C--H bond stretching in the transition state for the rate-controlling step in P450-catalyzed hydroxylation of 1CH3.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

On the mechanism of the nitric oxide synthase-catalyzed conversion of N omega-hydroxyl-L-arginine to citrulline and nitric oxide.

The mechanism of oxidation of N omega-hydroxyl-L-arginine (NHA) by the iron-dioxygen complex in nitric oxide synthase (NOS) is still uncertain. The uncertainty has not been helped by a lack of precision in the notation used to describe the oxidation states and electrical charges on the iron and oxygen in some of the suggested mechanisms. These problems of notation are addressed, and, in addition, a cyclic voltammetric measurement of the oxidation potential of NHA, namely +0.10 +/- 0.04 V versus normal hydrogen electrode, is used to argue that the sometimes postulated oxidation of NHA by the iron-dioxygen complex to form an intermediate radical cation, NHA.+, is very unlikely for thermodynamic reasons. Instead, it is suggested that this oxidation occurs by a thermodynamically favored abstraction of the hydrogen atom from the > C = NOH moiety of NHA to form an intermediate iminoxyl radical, > C = NO(.). A subsequent nucleophilic attack by the iron-hydroperoxide species formed by this H-atom abstraction on the carbon atom of the iminoxyl radical moiety leads to the production of nitric oxide (NO) and citrulline.

Amino Acid Oxidoreductases↗

PubMed1994

Vitamin E for coronary bypass operations. A prospective, double-blind, randomized trial.

BACKGROUND: Free radical lipid peroxidation contributes to the abnormal metabolism and ventricular function frequently seen after cardiac operations. Antioxidants may improve metabolic and functional recovery. METHODS: A prospective, randomized, double-blind clinical trial was conducted to determine the effects of vitamin E (alpha-tocopherol) (n = 14) or a corn oil placebo (n = 14) in patients undergoing elective coronary bypass operations. The RRR-alpha-tocopheryl acetate doubled the alpha-tocopherol levels in the heart. Myocardial metabolism and ventricular function were assessed after the operation. RESULTS: Atrial pacing induced myocardial lactate production in the control patients but lactate consumption in the alpha-tocopherol-treated patients on bypass 25 minutes after crossclamp release. Left ventricular stroke work indices were higher, at similar ventricular volumes, in the alpha-tocopherol-treated group, which indicates improved preload recruitable stroke work, and diastolic compliance was greater 4 hours after the operation. The postoperative creatine kinase cardiac isoenzyme levels were lower in the patients who received alpha-tocopherol. CONCLUSIONS: Pretreatment with alpha-tocopherol sufficient to double the myocardial concentrations had a small but significant metabolic and functional effect after elective coronary bypass operations when compared with placebo. These results do not justify pretreatment of low-risk patients, but they do justify an evaluation in high-risk patients.

Adult↗

PubMed1993

Cytochrome P450 hydroxylation of hydrocarbons: variation in the rate of oxygen rebound using cyclopropyl radical clocks including two new ultrafast probes.

The oxidation of eight methyl-substituted and three alkyl-substituted cyclopropanes by rat liver microsomal cytochrome P450 and pure reconstituted rabbit P450 2B4 was studied. Alkane hydroxylation catalyzed by P450 is generally believed to proceed by hydrogen abstraction followed by reaction of the carbon-centered radical with an iron-bound hydroxyl radical, a process called oxygen rebound. Hydrogen abstraction from methylcyclopropanes generates cyclopropylcarbinyl radicals whose solution rate constants for ring opening are known [Bowry, V.W., et al. (1991) J. Am. Chem. Soc. 113, 5687-5698]. Rearranged products were only observed with the five substrates which, upon hydrogen abstraction, would generate a cyclopropylcarbinyl radical that undergoes ring opening with a rate constant > or = 2.0 x 10(9) s-1 in solution. Values of the rate constants for oxygen rebound (kOH) were calculated by determining the ratio of unrearranged products (cyclopropylmethanols) to rearranged products (alkenols). For each substrate this ratio was generally about the same for the oxidations catalyzed by microsomal P450 and by P450 2B4. It is concluded that all of the substrates are oxidized via an intermediate cyclopropylcarbinyl radical. Two ultrafast probes, trans-1-methyl-2-phenylcyclopropane and 1,1-diphenyl-2-methylcyclopropane, gave alcohol product ratios which yielded unreasonably high values for kOH, viz., ca. 1.5 x 10(12) and ca. 7 x 10(12) s-1, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

Autoxidation of lipids and antioxidation by alpha-tocopherol and ubiquinol in homogeneous solution and in aqueous dispersions of lipids: unrecognized consequences of lipid particle size as exemplified by oxidation of human low density lipoprotein.

Recent studies on the initial stages in oxidation of low density lipoprotein (LDL) have revealed certain previously unrecognized similarities to emulsion polymerization and some quite unexpected features including the following: (i) ascorbate is an extremely effective antioxidant for LDL containing alpha-tocopherol (alpha-TOH); (ii) in the presence of alpha-TOH and in the absence of both ascorbate and ubiquinol 10 (Q10H2), oxidation of LDL occurs via a free radical chain; (iii) Q10H2 is a much better antioxidant for LDL than alpha-TOH, although the reverse is true in homogeneous systems. We show here that these problems can be solved on the basis of three simple hypothesis, each of which is based on known chemistry: (i) alpha-TOH in LDL can be regenerated from its radical, alpha-TO., by ascorbate; (ii) in the absence of ascorbate and Q10H2, the alpha-TOH in LDL acts as a chain-transfer agent rather than as a radical trap; (iii) Q10H2 is a much more effective chain-breaking antioxidant than alpha-TOH in LDL because the semiquinone radical Q10H. exports its radical character from the LDL into the aqueous phase. Our conclusions imply that the search for better antiatherosclerotic drugs might profitably focus on antioxidants capable of exporting radicals from LDL particles or otherwise increasing the traffic of radicals between particles.

Antioxidants↗

PubMed1992

Vitamin E in human low-density lipoprotein. When and how this antioxidant becomes a pro-oxidant.

Uptake of oxidatively modified low-density lipoprotein (LDL) by cells in the arterial wall is believed to be an important early event in the development of atherosclerosis. Because vitamin E is the major antioxidant present in human lipoproteins, it has received much attention as a suppressor of LDL lipid oxidation and as an epidemiological marker for ischaemic heart disease. However, a careful examination of lipid peroxidation in LDL induced by a steady flux of aqueous peroxyl radicals has demonstrated that, following consumption of endogenous ubiquinol-10, the rate of peroxidation (i) declines as vitamin E is consumed, (ii) is faster in the presence of vitamin E than following its complete consumption, (iii) is substantially accelerated by enrichment of the vitamin in LDL, either in vitro or by diet, and (iv) is virtually independent of the applied radical flux. We propose that perodixation is propagated within lipoprotein particles by reaction of the vitamin E radical (i.e. alpha-tocopheroxyl radical) with polyunsaturated fatty acid moieties in the lipid. This lipid peroxidation mechanism, which can readily be rationalized by the known chemistry of the alpha-tocopheroxyl radical and by the radical-isolating properties of fine emulsions such as LDL, explains how reagents which reduce the alpha-tocopheroxyl radical (i.e. vitamin C and ubiquinol-10) strongly inhibit lipid peroxidation in vitamin E-containing LDL.

Fatty Acids, Unsaturated↗

PubMed1992

Discrimination between forms of vitamin E by humans with and without genetic abnormalities of lipoprotein metabolism.

To study the mechanisms of discrimination between various forms of vitamin E, four normal subjects, one patient with lipoprotein lipase deficiency, and three patients with abnormal apolipoprotein B-100 production were given an oral dose containing three tocopherols labeled with differing amounts of deuterium (2R,4'R,8'R-alpha-(5,7-(C2H3)2)tocopheryl acetate (d6-RRR-alpha-tocopheryl acetate), 2S,4'R,8'R-alpha-5-(C2H3)tocopheryl acetate (d3-SRR-alpha-tocopheryl acetate), and 2R,4'R,8'R-gamma-(3,4-2H)tocopherol (d2-RRR-gamma-tocopherol). The tocopherol contents of plasma, red cells, and lipoproteins were measured up to 76 h after the dose. In normal subjects all three tocopherols were absorbed and secreted in chylomicrons with equal efficiencies. Both d2-gamma- and d3-SRR-alpha-tocopherols peaked at similar concentrations in the other lipoprotein fractions, then decreased similarly, but 2-4 times more rapidly than did d6-RRR-alpha-tocopherol. A lipoprotein lipase-deficient patient and a patient with prolonged production of chylomicrons with absent apolipoprotein B-100 also demonstrated the lack of discrimination between tocopherols during absorption. Despite abnormal apolipoprotein B-100 production in two patients, the "VLDL" was preferentially enriched in d6-RRR-alpha-tocopherol. Our results show that there is no discrimination between the three tocopherols during absorption and secretion in chylomicrons, but subsequently there is a preferential enrichment of very low density lipoprotein (VLDL) with RRR-alpha-tocopherol. Catabolism of this VLDL results in the maintenance of plasma RRR-alpha-tocopherol concentrations.

Administration, Oral↗

PubMed1991

Effect of orally administered alpha-tocopheryl acetate on human myocardial alpha-tocopherol levels.

Free radical injury may contribute to the delayed postoperative recovery of myocardial metabolism and ventricular function after elective coronary artery revascularization. This clinical study was designed to evaluate, in stable angina patients having aortocoronary bypass surgery, whether orally administered alpha-tocopheryl acetate was effective in increasing myocardial alpha-tocopherol levels and the effect of cardioplegic arrest followed by reperfusion on the myocardial alpha-tocopherol levels. Twenty-four patients with stable angina pectoris for elective revascularization received preoperatively the natural stereoisomer of alpha-tocopheryl acetate labelled with deuterium (D3) and six patients were used as controls. Since four patients who received 300 mg of D3-alpha-tocopheryl acetate preoperatively for 1 and 2 days did not have significant increases in their myocardial total or D3-tocopherol levels, the remaining 20 patients received 100 mg (n = 6), 300 mg (n = 8), or 900 mg (n = 6) of D3-alpha-tocopheryl acetate for 14 consecutive preoperative days. The left ventricular deuterated and nondeuterated alpha-tocopherol levels were measured by gas chromatography/mass spectrometry. Although there was a decrease (p less than 0.05) in myocardial alpha-tocopherol levels with the onset of reperfusion (cross-clamp removal), the myocardial tocopherol levels were not statistically different from preoperative levels by 20 minutes of reperfusion. At least 300 mg of alpha-tocopherol must be taken orally for 14 consecutive days to double the myocardial alpha-tocopherol levels.

Administration, Oral↗

PubMed1990

Further studies of a new vitamin E analogue more active than alpha-tocopherol in the rat curative myopathy bioassay.

The bioactivities of the acetates of 2R,4'R,8'R- and 2S,4'R,8'R-2,4,6,7-tetramethyl-2-(4',8',12'-trimethyltridecyl)-5-h ydroxy-3,4- dihydrobenzofuran (RRR- and SRR-1-Ac) have been measured in the rat curative myopathy bioassay and compared with the RRR and SRR stereoisomers of alpha-tocopheryl acetate (RRR- and SRR-2-Ac). Each stereoisomer of 1 is only slightly more active than the corresponding stereoisomer of 2(RRR-1-Ac/RRR-2-Ac = 1.10; SRR-1-Ac/SRR-2-Ac = 1.16). This finding contrasts with our earlier finding [(1986) FEBS Lett. 205, 117-120], confirmed in the present study, that all-rac-1-Ac is 1.5-1.9 as active as all-rac-2-Ac. We suggest that the stereochemistry (S vs R) at the 4' and 8' tail carbons is of less biological importance in 1 than in 2.

Animals↗

PubMed1990

Studies on the hyperplasia ('regeneration') of the rat liver following partial hepatectomy. Changes in lipid peroxidation and general biochemical aspects.

Using the experimental model of partial hepatectomy in the rat, we have examined the relationship between cell division and lipid peroxidation activity. In rats entrained to a regime of 12 h light/12 h dark and with a fixed 8 h feeding period in the dark phase, partial hepatectomy is followed by a rapid regeneration of liver mass with cycles of synchronized cell division at 24 h intervals. The latter phenomenon is indicated in this study by pulses of thymidine kinase activity having maxima at 24 h, 48 h and 72 h after partial hepatectomy. Microsomes prepared from regenerating livers show changes in lipid peroxidation activity (induced by NADPH/ADP/iron or by ascorbate/iron), which is significantly decreased relative to that in microsomes from sham-operated controls, again at 24 h, 48 h and 72 h after the operation. This phenomenon has been investigated with regard to possible underlying changes in the content of microsomal fatty acids, the microsomal enzymes NADPH:cytochrome c reductase and cytochrome P-450, and the physiological microsomal antioxidant alpha-tocopherol. The cycles of decreased lipid peroxidation activity are apparently due, at least in part, to changes in microsomal alpha-tocopherol content that are closely associated in time with thymidine kinase activity.

Animals↗

PubMed1990

Biokinetics of dietary RRR-alpha-tocopherol in the male guinea pig at three dietary levels of vitamin C and two levels of vitamin E. Evidence that vitamin C does not "spare" vitamin E in vivo.

The net rates of uptake of "new" and loss of "old" 2R,4'R,8'R-alpha-tocopherol (RRR-alpha-TOH, which is natural vitamin E) have been measured in the blood and in nine tissues of male guinea pigs over an eight week period by feeding diets containing deuterium-labelled alpha-tocopheryl acetate (d6-RRR-alpha-TOAc). There was an initial two week "lead-in" period during which 24 animals [the "high" vitamin E (HE) group] received diets containing 36 mg of unlabelled (d0) RRR-alpha-TOAc and 250 mg of ascorbic acid per kg diet, while another 24 animals [the "low" vitamin E (LE) group] received diets containing 5 mg d0-RRR-alpha-TOAc and 250 mg ascorbic acid per kg diet. The HE group was then divided into three equal subgroups, which were fed diets containing 36 mg d6-RRR-alpha-TOAc and 5000 mg [the "high" vitamin C (HEHC) subgroup], 250 mg [the "normal" vitamin C (HENC) subgroup] and 50 mg [the "low" vitamin C (HELC) subgroup] ascorbic acid per kg diet. One animal from each group was sacrificed each week and the blood and tissues were analyzed for d0- and d6-RRR-alpha-TOH by gas chromatography-mass spectrometry. The LE group was similarly divided into three equal subgroups with animals receiving diets containing 5 mg d6-RRR-alpha-TOAc and 5,000 mg (LEHC), 250 mg (LENC) and 50 mg (LELC) ascorbic acid per kg diet with a similar protocol being followed for sacrifice and analyses. In the HE group the total (d0(-) + d6-) RRR-alpha-TOH concentrations in blood and tissues remained essentially constant over the eight week experiment, whereas in the LE group the total RRR-alpha-TOH concentrations declined noticeably (except in the brain, an organ with a particularly slow turnover of vitamin E). There were no significant differences in the concentrations of "old" d0-RRR-alpha-TOH nor in the concentrations of "new" d6-RRR-alpha-TOH found in any tissue at a particular time between the HEHC, HENC and HELC subgroups, nor between the LEHC, LENC and LELC subgroups. We conclude that the long-postulated "sparing" action of vitamin C on vitamin E, which is well documented in vitro, is of negligible importance in vivo in guinea pigs that are not oxidatively stressed in comparison with the normal metabolic processes which consume vitamin E (e.g., by oxidizing it irreversibly) or eliminate it from the body.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1990

Simon metabolites of alpha-tocopherol are not formed via a rate-controlling scission of the 3'C-H bond.

The major in vivo oxidation products of alpha-tocopherol, alpha-T, are the Simon metabolites, 1 and 2. For these compounds to be formed from alpha-T the polyisoprenoid tail of alpha-T must be oxidatively cleaved at the 3' carbon atom. Comparison of the levels of 2R,4'R,8'R-alpha-(3',3'-2H2)-T and 2R,4'R,8'R-alpha-[5,7-(C2H3)2]-T remaining in various tissues of rats which had been preloaded with equal quantities of these two forms of vitamin E following a change to a vitamin E-free diet has shown that there is no statistically significant difference in the rates of loss of these two deuterium-labeled alpha-T's. This demonstrates that the Simon metabolites are not formed by a rate-controlling scission of the 3'C-H bond of alpha-T.

Animals↗

PubMed1990

Is methyl-branching in alpha-tocopherol's "tail" important for its in vivo activity? Rat curative myopathy bioassay measurements of the vitamin E activity of three 2RS-n-alkyl-2,5,7,8-tetramethyl-6-hydroxychromans.

The vitamin E activity of the acetates of three 2RS-n-alkyl-2,5,7,8-tetramethyl-6-hydroxychroman analogs of alpha-tocopherol have been measured and compared directly with all-rac-alpha-tocopheryl acetate, or indirectly via 2R,4'R,8'R-alpha-tocopheryl acetate, using the rat curative myopathy, plasma pyruvate kinase assay. The analogs with alkyl chain lengths of 11 and 13 carbons have activities which not only do not differ significantly (p greater than 0.05) from each other but also do not differ from that of all-rac-alpha-tocopheryl acetate. This finding indicates that methyl branching in the phytyl tail at the 4', 8', and 12' positions has little if any influence upon vitamin E activity. Thus physical interactions involving the methyl branches of the phytyl tail and the polyunsaturated moieties of membrane phospholipids are unimportant in vivo, insofar as this bioassay is concerned. However, the length of the hydrocarbon tail is important. This is indicated by the result obtained with the acetate of the analog with an alkyl chain length of 15 carbon atoms which had only 15% of the activity of 2R,4'R,8'R-alpha-tocopheryl acetate, i.e., 22% of the activity of all-rac-alpha-tocopheryl acetate since this form is 1.47 times less active than 2R,4'R,8'R-alpha-tocopheryl acetate in the curative myopathy bioassay (Weiser, Vecchi, & Schlachter, Internat. J. Vit. Nutr. Res. 55:149-158, 1985).

Acetates↗

PubMed1990

Impaired ability of patients with familial isolated vitamin E deficiency to incorporate alpha-tocopherol into lipoproteins secreted by the liver.

Plasma and lipoprotein alpha-tocopherol concentrations of four patients with familial isolated vitamin E deficiency and six control subjects were observed for 4 d after an oral dose (approximately 15 mg) of RRR-alpha-tocopheryl acetate labeled with six deuterium atoms (d6-tocopherol). Chylomicron d6-tocopherol concentrations were similar in the two groups. d6-Tocopherol concentrations of plasma, very low (VLDL), low (LDL), and high (HDL) density lipoproteins were similar in the two groups only during the first 12 h; then these were significantly lower, and the rate of disappearance faster, in the patients. The times (tmax) of the maximum chylomicron d6-tocopherol concentrations were similar for the two groups, but tmax values in the controls increased in the order: chylomicrons less than VLDL less than or equal to LDL approximately HDL, while the corresponding values in the patients were similar to the chylomicron tmax. Thus, plasma d6-tocopherol in controls increased during chylomicron and VLDL catabolism, whereas in patients it increased only during chylomicron catabolism, thereby resulting in a premature and faster decline in the plasma tocopherol concentration due to a lack of d6-tocopherol secretion from the liver. We suggest that these patients are lacking or have a defective liver "tocopherol binding protein" that incorporates alpha-tocopherol into nascent VLDL.

Absorption↗

PubMed1990

Vitamin E activity of 1-thio-alpha-tocopherol as measured by the rat curative myopathy bioassay.

The bioactivity of the acetate of the all-racemic, 1-thio analog of alpha-tocopherol (all-rac-1-thio-alpha-tocopheryl acetate) has been determined by measuring its ability to decrease plasma levels of pyruvate kinase in vitamin E deficient rats using the curative myopathy bioassay. The thio analog is only 0.22 times as active as RRR-alpha-tocopheryl acetate and is therefore approximately 0.33 times as active as all-rac-alpha-tocopheryl acetate, since the latter has been shown to be 1.47 times less active than RRR-alpha-tocopheryl acetate in the same bioassay (H. Weiser, M. Vecchi and M. Schlachter, Internat. J. Vit. Nutr. Res., 55, 149-158 (1985)). The 0.33:1.0 ratio is similar to the ratio of 0.41:1.0 measured for the in vitro antioxidant activities of the corresponding free phenols. This finding lends further support to our view that the vitamin E activity in the curative myopathy bioassay of close structural analogs of alpha-tocopherol is determined primarily by the in vitro antioxidant activity of the analog relative to alpha-tocopherol, consistent with the belief that vitamin E functions primarily as a general purpose, lipid-soluble antioxidant in mammals.

Animals↗

PubMed1990

Application of deuterated alpha-tocopherols to the biokinetics and bioavailability of vitamin E.

alpha-Tocopherol, a superior chain-breaking, peroxyl radical-trapping antioxidant and the most active component of vitamin E, is elevated in liver tumor cells, contributing to their greater resistance towards lipid peroxidation compared to cells from normal tissues. Also, in regenerating rat liver the level of vitamin E has been found to fluctuate in phase with the rate of cell division. In order to study the biokinetics and mechanisms of the distribution of vitamin E in organs and within tissues of animals, deuterated forms of alpha-tocopherol have been synthesized and their uptake into blood and tissues has been measured by gas chromatography-mass spectrometry. Measurement of the competitive uptake from a mixture of the RRR- and SRR-alpha-tocopherol stereoisomers labelled with different amounts of deuterium shows that the liver exerts a strong preference for secretion of the natural (RRR) stereoisomer into the plasma. It is suggested that a tocopherol-binding protein plays a key role in this process.

Animals↗

PubMed1990

RRR- and SRR-alpha-tocopherols are secreted without discrimination in human chylomicrons, but RRR-alpha-tocopherol is preferentially secreted in very low density lipoproteins.

Five subjects ingested in a single oral dose containing 50 mg each of 2R,4'R,8'R-alpha-(5,7-(C2H3)2)tocopheryl acetate (d6-RRR-alpha-tocopheryl acetate) with natural stereochemistry, and of 2S,4'R,8'R-alpha-(5-C2H3)tocopheryl acetate (d3-SRR-alpha-tocopheryl acetate). These are two of eight stereoisomers in synthetic vitamin E. By day 1 the plasma and red blood cells were enriched fourfold with d6-RRR-alpha-tocopherol (P less than 0.004). The ratio of d6-RRR-/d2-SRR- further increased over the succeeding 4 days, because the d3-SRR- decreased at a faster rate than did the d6-RRR-stereoisomer. Plasma and lipoproteins were isolated at intervals during the first day, and daily for 3 days, from four additional subjects fed a mixture of equal amounts of the deuterated tocopherols. The plasma contained similar concentrations of the two forms until 11 h, when the d6-RRR-alpha-tocopherol concentration became significantly greater (P less than 0.05). The chylomicrons contained similar concentrations of the two deuterated tocopherols, but the VLDL (very low density lipoproteins) became preferentially enriched in d6-RRR-alpha-tocopherol by 11 h. The pattern of the deuterated tocopherols shows that during chylomicron catabolism all of the plasma lipoproteins were labeled equally with both tocopherols, but that during the subsequent VLDL catabolism the low and high density lipoproteins became enriched in d6-RRR-alpha-tocopherol. These results suggest the existence of a mechanism in the liver for assembling VLDL preferentially enriched in RRR- relative to SRR-alpha-tocopherol.

Chylomicrons↗

PubMed1990

Nascent VLDL from liver perfusions of cynomolgus monkeys are preferentially enriched in RRR- compared with SRR-alpha-tocopherol: studies using deuterated tocopherols.

The transport and secretion of vitamin E in lipoproteins have been studied in cynomolgus monkeys fed tocopherols labeled with different amounts of deuterium. The animals were fed a single dose of vitamin E containing 60 mumol of each 2R,4'R,8'R-alpha-(5,7-(C2H3)2)tocopheryl acetate (d6-RRR-alpha-tocopheryl acetate; alpha-tocopherol with natural stereochemistry), 2S,4'R,8'R-alpha-5-(C2H3)tocopheryl acetate (d3-SRR-alpha-tocopheryl acetate; alpha-tocopherol with unnatural stereochemistry), and 2R,4'R,8'R-gamma-(3,4-2H)tocopherol (d2-RRR-gamma-tocopherol; gamma-tocopherol with natural stereochemistry). Chylomicrons, as well as the other plasma lipoproteins, contained equal concentrations of all three tocopherols at the earliest time points after feeding suggesting that all three tocopherols were absorbed equally. At later times plasma lipoproteins became preferentially enriched in d6-RRR-alpha-tocopherol. This is likely to be due to hepatic secretion of VLDL (very low density lipoproteins) and other lipoproteins, which were enriched in d6-RRR-alpha-tocopherol, as demonstrated in the lipoproteins isolated from perfused livers that had been obtained 24 h following the administration of the deuterated tocopherols. Taken together these data demonstrate that the liver, not the intestine, is the likely site of discrimination between tocopherol isomers and that the liver secretes nascent lipoproteins preferentially enriched in d6-RRR-alpha-tocopherol.

Animals↗