Bioavailability of quercetin from onion extracts after intraruminal

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Bioactive Constituents, Metabolites, and Functions

Bioavailability of quercetin from onion extracts after intraruminal application in cows Silvia Wein, Birgit Beyer, Benno F. Zimmermann, Ralf Harald Blank, and Siegfreid Wolffram J. Agric. Food Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jafc.8b03049 • Publication Date (Web): 12 Sep 2018 Downloaded from http://pubs.acs.org on September 13, 2018

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Journal of Agricultural and Food Chemistry

Bioavailability of quercetin from onion extracts after intraruminal application in cows

Silvia Wein,† Birgit Beyer, † Benno F. Zimmermann, § Ralf H. Blank, *,† and Siegfried Wolffram †

†

Institute of Animal Nutrition and Physiology, Christian-Albrechts-University of Kiel, Hermann-Rodewald-Straße 9, 24118 Kiel, Germany

§

Institute Prof. Dr. Georg Kurz GmbH, Stöckheimer Weg 1, 50829 Köln, Germany and

Department of Nutritional and Food Sciences - Chair of Food Technology and Biotechnology, University of Bonn, 53117 Bonn, Germany

* Corresponding author: Tel: 0049-431-880-2962 Fax: 0049-431-880-1528 Email: [email protected]

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1

ABSTRACT

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The aim of the present study was to investigate the bioavailability or quercetin from onion

3

bulb (OB) and onion skin (OS) extracts in ruminants. Three non-lactating cows equipped with

4

a permanent rumen fistula intraruminally received equimolar amounts of quercetin either as

5

aglycone, rutin, OB, or OS extract, respectively, at a dose of 50 mg quercetin equivalents/kg

6

body weight. Blood samples were drawn before and frequently within the 24 h period after

7

application of the respective substance. Quercetin and quercetin metabolites with an intact

8

flavonol structure (kaempferol, isorhamnetin, tamarixetin) were analyzed in plasma samples

9

by HPLC with fluorescence detection. All quercetin sources administered resulted in a fast

10

increase of the plasma concentrations of quercetin and total flavonols (sum of quercetin and

11

its metabolites) followed by a rapid decline, whereby significant higher concentrations

12

occurred with OB extract and rutin as compared to quercetin aglycone and OS extract,

13

respectively. The results clearly demonstrate a higher systemic availability of quercetin from

14

OB extract and rutin. Taken together OB extract with a high content of quercetin glucosides is

15

an interesting source for the application of quercetin to ruminants.

16 17

Key Words: quercetin, onion extracts, bioavailability, cow

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INTRODUCTION

20

Flavonoids are natural plant derived polyphenolic compounds, which are widely

21

distributed in feed and feed plants.1 Animals in various amounts ingest them as part of their

22

regular diet, but concentrations in feed plants are generally low. Amounts of 35.3 g total

23

polyphenols/kg of dry matter (DM) in ryegrass and 3.2 g/kg DM in corn silages have been

24

reported. 2 The same authors reported a content of 0.68 g quercetin/kg DM in ryegrass silage.

25

In recent years, biological effects of flavonoids were intensively investigated, and quercetin

26

was found to have strong anti-oxidative and anti-inflammatory capabilities in vitro and in

27

vivo.3 Furthermore, quercetin and other flavonols influence the expression of numerous genes

28

as well as the activity of several key enzymes 4, including enzymes involved in lipid and

29

carbohydrate metabolism.

30

dairy cows might be of special interest due to metabolic disorders such as fatty liver disease

31

and ketosis that often occur in this phase.7,8

5,6

Thus, flavonoids administered in the phase of early lactation in

32

In plants, the flavonol quercetin mainly occurs as various glycosides.9,10 In monogastric

33

species, the sugar moiety of quercetin glycosides is a major determinant of the oral

34

bioavailability of quercetin.

35

quercetin and its bioavailability have been reviewed repeatedly.14–16 The aglycone of most

36

quercetin glycosides must be liberated prior to absorption either by body’s own or bacterial

37

enzymes. Quercetin monoglucosides such as quercetin-3-glucoside and quercetin-4'-glucoside

38

are at least partially de-glycosylated in the small intestine by lactase phloridzin hydrolase.

39

Furthermore, a cytosolic ß-glucosidase seems also to be involved in de-glycosylation.

40

This requires uptake of intact quercetin glycosides across the brush-border membrane into the

41

enterocyte. Several authors reported that quercetin glucosides are partially transported by the

42

sodium-dependent glucose transporter SGLT1.

43

sugar moieties like glucorhamnose, galactose, rhamnose, or arabinose are not absorbed in

44

monogastrics until they have reached the large intestine, where hydrolysis of glycosides by

11–13

Current knowledge on intestinal handling and absorption of

19–21

17

17, 18

In contrast, quercetin glycosides with



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14, 15

45

microbial α-rhamnosidases and β-glucosidases releases the aglycone.

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well established that prior to their appearance in the circulation, flavonols are intensively

47

conjugated (sulfatation, glucuronidation, methylation) in the intestinal mucosa and the liver

48

by sulfotransferases, uridin-5‘-diphosphat-glucuronosyl-transferases and catechol-O-methyl-

49

transferases.15, 26, 22 Efflux of some of the flavonol metabolites from small intestinal mucosal

50

cells back into the intestinal lumen is facilitated by multidrug-resistance-protein 2 (MPR2),

51

breast cancer-resistance-protein 1 (BCRP1) and possibly also by the glucose-transporter

52

GLUT 2.

53

flavonol structure (isorhamnetin, tamarixetin, and kaempferol) are mainly present in blood

54

plasma as glucuronidated and sulfated derivatives. 26–28

55

23–25

Furthermore, it is

Thus, after oral application, quercetin and its metabolites with an intact

In monogastric species, the oral bioavailability of quercetin applied as aglycone is 26–28

56

higher than after application of rutin (quercetin-3-O-glucorhamnosid).

57

however, 10-fold higher plasma quercetin concentrations after intraruminal administration of

58

rutin compared with quercetin aglycone, irrespective of the dose applied, was found.

59

contrast, intraduodenal administration of quercetin and rutin, respectively, in cows revealed

60

similar results as in monogastric species.

61

pass the forestomaches, bacterial metabolism within the reticulorumen is an important factor

62

for the bioavailability of flavonoids in ruminants.

63

availability of quercetin in cows after application of the aglycone, rutin and other quercetin

64

glycosides could be interesting quercetin sources in ruminants. To this end, onions having a

65

high content of quercetin glucosides 32 could be of interest. Thus, the aim of the present study

66

was to investigate the bioavailability of quercetin from onions in non-lactating cows using

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either a commercial onion skin and an onion bulb extract as compared to rutin and quercetin

68

aglycone.

30

In ruminants,

29

In

Because flavonoids ingested with feed have to

31

Regarding the rather low systemic

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MATERIALS & METHODS

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Characterization of Onion Extracts

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Pulverized onion bulb and onion skin extract, respectively, purchased from Vivatis

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Pharma GmbH, Hamburg, Germany, were extracted with dimethyl formamide for 10 min in

76

an ultra-sonic bath and then filtered through Chromafil RC-20/15 filters (0.2 µm pore size,

77

Macherey and Nagel, Düren, Germany). The instrumentation for UHPLC-DAD-MS analysis

78

of the onion extracts was the same as previously described.

79

150 mm; Waters, Milford, MA, USA) was used at a temperature of 40 °C. Injection volume

80

was 2 µL. A gradient elution with water (A) and acetonitrile (B) both containing 0.1% formic

81

acid was applied with the following time program: 0 min: 2% B; 20 min: 45% B; 21-23 min:

82

100% B; 25-27 min: 2% B at a flow rate of 0.4 mL/min. A MS scan from m/z 160 to m/z

83

1050 detected the [M–H]--ions and allowed to identify the compounds visible in the UV

84

chromatogram. The flavonols and flavonol glycosides were detected at 350 nm and quantified

85

by external calibration using quercetin and rutin, respectively, as standards applying a mass

86

correction.

33

A HSS-T3 column (2.1 mm x

87 88

Animal Experiments

89

For the experiments, 3 ruminally fistulated non-lactating cows (Jersey × German

90

Black Pied) with an average body weight (BW) of 537 ± 37 kg (mean ± SD) were used in a

91

randomized crossover design with a 2-d wash-out period between each application. Animals

92

were surgically equipped with an indwelling catheter (WVI Jugularis Teflon catheter, C.

93

Walter, Baruth/Mark, Germany) in the right or left jugular vein and were fed a ration

94

consisting of 1.5 kg of hay and 1.5 kg of concentrate twice daily supplemented 75 g of

95

mineral vitamin premix. The composition of the concentrate and mineral vitamin premix has

96

been previously described29. Animals had free access to tap water. Animals were adapted to 5 ACS Paragon Plus Environment


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diets for seven days prior to the start of the experiments. The experiment was approved by the

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Ministry of Agriculture, the Environment and Rural Areas of the state Schleswig-Holstein,

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Germany (permission no. V242-7224.121-25) and were in accordance with the guidelines

100

issued by the German authorities for care and treatments of animals 34.

101

Three days after implantation of the catheter, the test substances quercetin aglycone

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(Carl Roth GmbH & Co. KG, Karlsruhe, Germany), rutin (Carl Roth GmbH & Co. KG,

103

Karlsruhe, Germany), onion bulb extract, or onion skin extract, each suspended in 500 mL of

104

physiological saline, were administered at a dosage of 50 mg quercetin equivalents per kg of

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BW via the rumen fistula during morning feeding. After application ruminal contents were

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gently mixed by hand through the fistula to achieve a better distribution of the test substances

107

within the ruminal contents. Blood samples (9 mL) were collected via jugular catheters into

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lithium-heparinized monovettes (Sarstedt, Nümbrecht, Germany) before (time point zero) as

109

well as 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 h after intraruminal application of the

110

respective test substance. Blood samples were immediately centrifuged (1,100 × g, 10 min, 4

111

°C) and aliquots of plasma were stored at -80 °C upon analysis.

112 113

Analysis of Flavonols

114

Flavonols were extracted from plasma as previously reported. 35 The HPLC analysis of

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flavonols with an intact flavonol structure (quercetin, kaempferol, isorhamnetin, tamarixetin)

116

was performed according to Hollman et al. 36 with minor modifications 29.

117 118

Pharmacokinetic Calculation and Statistics

119

All data presented are mean values ± SEM. Plasma concentrations of individual

120

flavonols at each time point were corrected for basal plasma concentration already present

121

prior to the application of test substances (time point zero). Concentrations of total plasma

122

flavonols at each time point are the sum of the concentrations of individual plasma flavonols 6 ACS Paragon Plus Environment

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(quercetin, kaempferol, isorhamnetin, and tamarexitin). Pharmacokinetic parameters (Cmax =

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maximum plasma concentration, Tmax = time to achieve maximum plasma concentration,

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AUC = area under the curve) were calculated for individual as well as for total flavonols

126

using GraphPad-Prism (version 4.01, GraphPad Software Inc., San Diego, CA). The AUCs

127

were calculated according to the trapezoidal rule for the time period 0-24 h. Statistical

128

differences were assessed using a one-factorial ANOVA followed by Tukey Kramer post hoc

129

test using PROC MIXED of SAS (SAS Institute, Inc. Version 9.2, Cary, NC, USA). A P-value

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≤ 0.05 was considered to be significant.

131 132

RESULTS

133 134 135

In the present study we investigated the relative bioavailabilities of quercetin from

136

four different sources (quercetin aglycone, rutin, onion bulb extract, and onion skin extract) in

137

non-lactating cows. In a previous study

138

than in monogastric species, rutin (quercetin-3-O-glucorhamnoside) is a much better source

139

for oral application of quercetin (about 10-fold higher bioavailability of quercetin) than the

140

quercetin aglycone. Onions contain considerable amounts of quercetin, whereas quercetin in

141

the non-pigmented parts mainly consists of various quercetin glucosides (e.g., quercetin-4'-O-

142

ß-monoglucosides and quercetin-3,4'-O-ß-diglucosides); In contrast, the outer pigmented parts

143

of onions mainly contain the quercetin aglycone

144

the onion bulb and onion skin extracts, used in the present study, are presented in table 1.

145

Whereas the onion bulb extract contained about 52 % or total quercetin equivalents in form of

146

various glucosides, almost 100 % of the quercetin within the onion skin extract were present

147

as aglyone (Tab. 1).

29

, we have already shown, that in ruminants, other

37

. The analysis of the quercetin content in



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148

As already described 29, quercetin and its derivatives with an intact flavonol structure

149

were mainly present as conjugates (glucuronides and/or sulfates, > 90 % for each individual

150

flavonol, data not shown) after intraruminal application of quercetin or rutin. Thus, data

151

concerning plasma flavonol concentrations presented here were all obtained from plasma

152

samples treated with glucuronidase/sulfatase prior to HPLC analyses. Irrespective of the

153

quercetin source applied, quercetin was always the main plasma metabolite and only small

154

amounts of isorhamnetin and kaempferol could be found, whereas tamarixetin was not

155

detected in plasma samples or was in the range of the detection limit (data not shown). With

156

respect to the AUC, the percentage of quercetin, kaempferol, and isorhamnetin, respectively,

157

amounted to 85, 8, and 7 % of the AUC of total flavonols.

158

Figure 1 depicts plasma concentration time curves of total flavonols after intraruminal

159

application of 50 mg quercetin equivalents/kg BW either as aglycone, rutin, onion bulb

160

extract, or onion skin extract.. All quercetin sources tested resulted in a fast increase in total

161

plasma flavonols followed by a rapid subsequent decline (Fig. 1). Maximum concentrations of

162

total flavonols were already achieved within one hour after intraruminal application of test

163

substances (Fig. 1, Tab. 2). Maximum plasma concentration (Cmax) was highest with onion

164

bulb extract, followed by rutin and considerably lower values for onion skin extract as well as

165

quercetin aglycone (Tab. 1). Bioavailability of quercetin calculated as the AUC of total

166

plasma flavonols, was significantly higher after rutin and onion bulb extract compared to the

167

aglycone and onion skin extract (Figure 1, inset).

168 169

DISCUSSION

170 171 29

, we showed, that unlike in monogastric species

26, 27, 38

172

In a preceding paper

plasma

173

quercetin concentration in ruminants were about 10-fold higher after intraruminal 8 ACS Paragon Plus Environment

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administration of rutin compared with quercetin aglycone, irrespective of the dose applied 29.

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Data from the present study substantiate these results; application of rutin compared with

176

quercetin aglycone as a source of quercetin resulted in approximately 10-times higher

177

maximum total flavonol plasma concentrations and an 3 to 4- times greater AUC. The reasons

178

therefore were already discussed by Berger at al.29. The authors concluded, that the sugar

179

moiety of rutin may somehow protect quercetin from bacterial breakdown within the rumen.

180

Here we speculate, that the better water solubility of rutin and hence a better distribution as

181

compared to the rather lipophilic quercetin aglycone might contribute to a significantly higher

182

bioavailability of quercetin after intraruminal application in cows. As a consequence, the

183

chance for quercetin liberated from rutin by rumen microorganisms to get in contact with the

184

absorptive surface should be improved and would increase ruminal absorption of quercetin.

185

This may equally apply for that part of quercetin present as glucosides within the onion bulb

186

extract, explaining the higher bioavailability of quercetin from the onion bulb extract as

187

compared to onion skin extract and quercetin aglycone. The low bioavailability of quercetin

188

from onion skin extract might be best explained by the dominance of the rather lipophilic

189

quercetin aglycone within this preparation and further shows that additional matrix effects of

190

the powdery oninon skin extract used do not substantially influence quercetin’s bioavailability

191

from this source.

192

The early appearance of flavonols in the circulation with maximum plasma concentrations

193

already achieved within one hour after intraruminal application of various quercetin sources

194

found in the present as well as in the preceding study

195

quercetin. Alternatively, the early appearance of quercetin (from all sources applied) may be

196

attributable to a rapid transfer of liquid material from the rumen to the small intestine with

197

subsequent absorption there. If this would be the case, the higher plasma concentrations of

198

individual as well as of total flavonols, achieved after application of rutin and the onion bulb

199

extract, respectively, compared to the quercetin aglycone and the onion skin extract, again

29

points to ruminal absorption of



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200

could be explained by the better water solubility of the glycosides (rutin and quercetin

201

glucosides of the onion bulb extract, respectively) eventually resulting in higher

202

concentrations of free quercetin within the ruminal fluid. Transfer of intact quercetin

203

glycosides to the small intestine with subsequent liberation and absorption of the aglycone can

204

be ruled out due to the fact that at least in the case of rutin microbial liberation of quercetin

205

will only occur after rutin has reached the large intestine

206

from the rumen to the large intestine within one hour or less is hardly conceivable,

207

considering an intestinal mean retention time of liquid and solid digesta in the range of 20.5 h

208

at low dry matter intake (6.5 kg/d) and of 8 h at an increased dry matter intake of 23.7 kg/d 39.

209

This conclusion is also substantiated by the finding, that quercetin was not bioavailable after

210

application of rutin into the duodenum of lactating dairy cows 30.

211

It is important to keep in mind, that quercetin-mono- and di-glucosides contained in the onion

212

bulb extract used in the present study only accounted for about 50 % of the total quercetin, the

213

remaining part being present as quercetin aglycone. Thus, it can be speculated, that the

214

application of pure quercetin glucosides would result in an even higher bioavailability of

215

quercetin than from rutin.

216

From the present study we conclude, that in cows the bioavailability of quercetin following

217

intraruminal administration is highest from the onion bulb extract followed by rutin. The

218

bioavailablility after the application of equimolar amounts of quercetin either as an onion skin

219

extract (containing quercetin aglycone) or as quercetin aglycone, however, is much lower

220

compared to the sources mentioned above. The reason for these results is most likely due to

221

the better solublization and distribution of the more hydrophilic sources (rutin, quercetin

222

glucosides of the onion bulb extract) within the rumen contents, hence resulting in a better

223

absorption. Absorption occurs most likely from the rumen because maximum plasma

224

concentrations of quercetin and quercetin metabolites were already achieved within one hour.

14, 15

. Transfer of intact glycosides

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Funding: This work is part of the joint research project Food Chain Plus (FoCus) financially

227

supported by the Federal Ministry of Education and Research, Germany (BMBF grant no.

228

0315538A)

229 230

Authors have nothing to disclose.

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FIGURE CAPTIONS

Figure 1: Plasma concentration–time curves of total flavonols after intraruminal application of 50 mg of quercetin equivalents/kg body weight as rutin, quercetin aglycone, onionskin extract (OS) and onion bulb extract (OB), respectively. Plasma samples were analyzed after β-glucuronidase/sulfatase treatment. Values are means ± SEM, n = 3. Inset: Bars represent means ± SEM (n = 3) of AUC (area under the curve) of total plasma flavonols; significant differences (P < 0.05) are indicated by different small letters; a-bdifferent superscripts differ (P < 0.05)



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Table 1: Concentration of Quercetin in Extracts of Onion Bulb (OB) and Onionskin (OS) OB

OS

µmol quercetin equivalents/g dry matter Quercetin-aglycone

436

843

Quercetin-monoglycoside

301

2

Quercetin-diglycoside

98

0.3


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Table 2: Selected Pharmacokinetic Parametersa of Total Flavonols in Plasma after Intraruminal Application of Quercetin (50 mg Quercetin Equivalents/kg Body Weight) from Rutin (R), Quercetin Aglycone (Q), Onionskin Extract (OS) and Onion Bulb Extract (OB), respectively. Q

R

OS

OB

Cmax, nmol/Lb

110 ± 43A

951 ± 256B

97 ± 11A

1648 ± 196C

Tmax, hc

0.8 ± 0.17

1.0 ± 0.0

0.8 ± 0.3

0.7 ± 0.2

a

Data are means ± SEM, n = 3

b

Cmax = maximum plasma concentration

c

Tmax = time to achieve maximum plasma concentration

A-C

Means within a row with different superscripts differ (P < 0.05)



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FIGURE 1


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TOC graphic


Bioavailability of quercetin from onion extracts after intraruminal

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