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DOI: 10.31038/JCRM.2018144

Abstract

The risk of arteriosclerosis may be reduced by increasing the levels of α-linolenic acid (ALA), a omega-3 polyunsaturated fatty acid. Perilla oil contains abundant ALA. This randomized crossover clinical study of perilla oil investigated its safety and effects on the levels of ALA and lipid profile in 10 subjects. Half of the subjects took 1 tablespoon of perilla oil (ALA content = approximately 9.4 g) and the remaining half took 1 tablespoon of olive oil (ALA content = approximately 0.09 g) daily for 1 week. After a 28-day washout period, each group switched and took the other oil for 1 week. Variables were measured before and after each week of oil ingestion. The ratio of low density lipoprotein cholesterol to high density lipoprotein cholesterol significantly decreased after ingestion of perilla oil (2.7 ± 0.6 vs. 2.6 ± 0.6, P = 0.037). The levels of ALA significantly increased after ingestion of perilla oil (31.6 ± 10.32 vs. 67.93 ± 24.35 µg/mL, P = 0.001). There were no adverse effects related to perilla oil. Therefore, as a dietary supplement, perilla oil has beneficial effects on the levels of ALA and lipid profile, suggesting that it contributes to a reduction in the risk of arteriosclerosis.

Keywords

Perilla oil, Olive oil, Arteriosclerosis, Vascular endothelial function, Reactive hyperemia index

Introduction

Arteriosclerosis leads to heart and cerebrovascular diseases and is the leading cause of death worldwide. Risk factors for arteriosclerosis are diabetes (DM), hypertension, dyslipidemia, obesity, and smoking [1]. Omega – 3 polyunsaturated fatty acids have attracted attention for their prophylactic effect against various disorders, including atherosclerosis, coronary artery disease, and inflammatory diseases [2, 3]. There are reports indicating that a high intake of α-linolenic acid (ALA), a plant-derived omega – 3 polyunsaturated fatty acid, is associated with a reduced risk of arteriosclerosis [4, 5]. Perilla oil contains 50%–60% of ALA. This oil can easily be used as a daily dietary supplement. In the human body, ALA synthesizes eicosapentaenoic acid (EPA) [6]. It has been reported that EPA and docosahexaenoic acid (DHA), both omega – 3 polyunsaturated fatty acids contained in fish oil, exhibit antithrombotic and lipid-lowering actions [7, 8]. There have been few studies of perilla oil and its hypothetical effect on reducing arteriosclerosis.

ALA inhibits arteriosclerosis-associated inflammation and reduces oxidative stress, which contributes to improve vascular endothelial function [9, 10]. Reactive hyperemia index (RHI) has been reported to be useful for evaluating vascular endothelial function. Moreover, it is a good predictor of cardiovascular disease [11, 12]. Previous studies have suggested that ALA reduces diastolic blood pressure and increase serum triacylglycerol concentration [13]. Salonen, J.T et al. showed that estimated dietary intake of linolenic acid has an inverse correlation with mean resting blood pressure [14]. However, it must be noted that overdoses of ALA, EPA, and DHA may cause blood coagulation [15].

We conducted a randomized crossover clinical trial of perilla oil to evaluate its safety and effects on the levels of ALA, lipid profile and endothelial function as markers of atherosclerotic risk.

Materials and Methods

Test diets. Perilla oil, extracted from perilla seeds, was used as the study oil. A commercially available olive oil was used as a placebo control. The ALA content of the perilla oil was 62.9 g/100 g, while that of the olive oil was 0.6 g/100 g. The ALA content was measured at the Japan Food Research Laboratories (Tokyo, Japan). Both oils were given in a dose size of 1 tablespoon as a daily supplement at breakfast for 1 week. The estimated content of ALA in each dose was approximately 9.4 g in the perilla oil and 0.09 g in the olive oil.

Subjects. Ten untreated individuals (4 male and 6 female) who had at least two risk factors for arteriosclerosis (aging, first-degree hypertension, dyslipidemia, DM, obesity, and smoking) were enrolled [16]. For the purposes of this study, hypertension was defined as a systolic blood pressure of 140 to 159 mmHg or a diastolic blood pressure of 90 to 99 mmHg. Dyslipidemia was defined as a low-density lipoprotein cholesterol (LDL-C) ≧ 140 mg/dL. Diabetes was defined as a fasting blood glucose concentration ≧ 126 mg/dL, or a hemoglobin A1c (HbA1c) ≧ 6.37%. Obesity was defined as a body mass index (BMI) ≧ 25 kg/m2. Smoking was recorded as a risk factor regardless of whether it was past or present. The definition of aging was 45 years or older men and postmenopausal women. Table 1 shows the subjects’ characteristics. The study was approved by the Ethics Committee of Nanpuh Hospital, Kagoshima Kyosaikai, Public Interest Inc. Association, Japan. Clinical examinations were performed according to the principles of the Declaration of Helsinki. Written informed consent was obtained from all individuals.

Table 1. Characteristics of subjects taking perilla oil or olive oil supplements

No

Age

Sex

hypertension

dyslipidemia

diabetes

obesity

Smoking

1

55

Male

No

Yes

No

No

No

2

56

Female

No

Yes

No

No

No

3

44

Male

No

Yes

No

No

Yes

4

57

Female

Yes

Yes

No

No

No

5

59

Female

No

Yes

No

No

No

6

47

Male

No

No

No

Yes

Yes

7

50

Female

Yes

Yes

No

No

No

8

56

Female

No

No

No

Yes

No

9

42

Male

Yes

Yes

No

Yes

Yes

10

56

Female

Yes

Yes

No

Yes

No

Study design. This study was designed as a crossover method. The 10 subjects were randomly divided into two groups of 5, the first group took perilla oil daily for 1 week and the second group took olive oil. After a 28-day washout period, the groups were reversed, with the first group took olive oil daily for 1 week and the second group took perilla oil (Table 2).

Table 2. Protocol of clinical study design

1st period

WO 3 term

2nd period

Day 1

Day 2–7

Day 8

Day 9–35

Day 36

Day 37–42

Day 43

Examination

BMI 1

Blood pressure

Blood test

RHI 2

Intake

1 Body mass index (kg/m2), 2 Reactive hyperemia index (-), 3 Washout

Variables were measured before and after each 1-week period of oil ingestion. All measurements at the beginning of each period were completed on the first day of the period before the supplement was given. The measurements after each period were taken the next day of the last oil supplement.

Physical parameters were measured including blood pressure, BMI, RHI, and blood examinations. RHI, a measure of peripheral endothelial function, was assessed using peripheral arterial tonometry (EndoPAT 2000; Itamar Medical, Caesarea, Israel) according to the manufacturer’s instructions. Serum levels of aspartate and alanine aminotransferase, total protein, γ-glutamyl transferase, and C-reactive protein were determined by latex agglutination using a BM6050 analyzer (Kyowa-Medex Co., Ltd., Tokyo, Japan). Serum levels of uric acid, blood urea nitrogen, glucose, triglycerides, high density lipoprotein cholesterol (HDL-C), LDL-C, and HbA1c were measured using a BioMajesty JCA-BM6050 analyzer (JEOL Ltd., Tokyo, Japan). The white blood cell (WBC), red blood cell (RBC), and platelet counts were measured with an XE-5000 Hematology Analyzer (Sysmex, Co., Hyogo, Japan). Plasma fatty acids (lauric, myristic, myristoleic, myristoleic, palmitic, palmitoleic, stearic, oleic, linoleic, γ-linolenic, α-linolenic, arachidic, eicosenoic, eicosadienoic, 5–8-11 eicosatrienoic, dihomo-γ-linolenic, arachidonic, eicosapentaenoic, behenic, erucic, docosatetraenoic, docosapentaenoic, lignoceric, docosahexaenoic, and nervonic acids) were measured by SRL Inc (Tokyo, Japan).

Subjects were interviewed regarding their intake of the test oils and any symptoms they experienced during the study.

Statistical analysis. Measured values are expressed as means ± standard deviation. The data were assessed using a paired t-test to compare results before and after ingestion of each oil. Data were analyzed using SPSS Version 25 (IBM Co., Armonk, NY, USA). A value of P <0.05 was considered statistically significant.

Results

Physical parameters. There were no significant differences in blood pressure, BMI, or RHI before and after the week-long interventions with perilla oil or olive oil (Table 3).

Table 3. Physical parameters in subjects taking perilla oil or olive oil

Test oils

Before

After

P-value

Systolic blood pressure (mmHg)

Perilla oil

138.6 ± 17.2

139.4 ± 19.0

0.739

Olive oil

138.5 ± 12.0

135.5 ± 12.5

0.380

Diastolic blood pressure (mmHg)

Perilla oil

87.7 ± 12.6

85.4 ± 14.0

0.090

Olive oil

84.8 ± 10.7

84.0 ± 7.9

0.658

Body Mass Index (kg/m2)

Perilla oil

23.5 ± 2.7

23.6 ± 2.8

0.711

Olive oil

23.5 ± 2.9

23.4 ± 2.9

0.136

Reactive hyperemia index (-)

Perilla oil

1.59 ± 0.41

1.68 ± 0.50

0.571

Olive oil

1.57 ± 0.32

1.76 ± 0.58

0.100

Values are presented as mean ± standard deviation; n = 10.

Biochemical markers. After a week of perilla oil, the LDL-C/HDL-C ratio decreased significantly from 2.7 ± 0.6 to 2.6 ± 0.6
(P = 0.037, Fig. 1A). There was no statistically significant difference in the LDL-C / HDL-C ratio after subjects ingested olive oil (2.9 ± 0.8 before vs. 2.8 ± 0.7 after, P = 0.314, Fig. 1B). Perilla oil thus improved the LDL-C / HDL-C ratio.

PowerPoint プレゼンテーション

Figure 1. Ratios of low density lipoprotein cholesterol (LDL-C) to high density lipoprotein cholesterol (HDL-C) before and after 1 week of intake of perilla oil (A) or olive oil (B). Values are presented as mean ± standard deviation; n = 10.

With the exception of significant decrease of the platelet count after a week of olive oil, none of the other biochemical or hematologic markers differed significantly before and after either perilla oil or olive oil (Table 4).

Fatty acids. We compared the levels of ALA before and after test oil intake. Fig. 2 shows the result of the levels of ALA before and after 1 week of intake of perilla oil or olive oil, respectively. The levels of ALA increased significantly after intake of perilla oil (31.60 ± 10.32 vs. 67.93 ± 24.35 μg/mL, P = 0.001, Fig. 2A), while the levels did not change after intake of olive oil (30.52 ± 10.34 vs. 32.74 ± 21.26 μg/mL, P = 0.702, Fig. 2B).

PowerPoint プレゼンテーション

Figure 2. Levels of α-linolenic acid before and after 1 week of intake of perilla oil (A) or olive oil (B). Values are presented as mean ± standard deviation; n = 10.

The levels of EPA also increased significantly after perilla oil but not after olive oil (perilla oil: 46.88 ± 16.40 vs. 64.43 ± 31.32 μg/mL, P = 0.023, Fig. 3A; olive oil: 60.44 ± 44.62 vs. 53.90 ± 28.36 μg/mL, P = 0.598, Fig. 3B).

PowerPoint プレゼンテーション

Figure 3. Levels of Eicosapentaenoic acid before and after 1 week of intake of perilla oil (A) or olive oil (B). Values are presented as mean ± standard deviation; n = 10.

Table 4. Biochemical and hematology markers before and after ingesting perilla oil or olive oil for 1 week

Group

Before

After

P

Aspartate aminotransferase (IU/L)

Perilla oil

22.0 ± 6.5

24.0 ± 7.2

0.219

Olive oil

21.6 ± 4.9

22.5 ± 6.2

0.235

Alanine aminotransferase (IU/L)

Perilla oil

26.2 ± 15.4

27.8 ± 15.8

0.437

Olive oil

26.4 ± 15.8

26.5 ± 17.6

0.968

Total protein (g/dL)

Perilla oil

7.0 ± 0.3

7.0 ± 0.4

0.763

Olive oil

7.1 ± 0.3

7.0 ± 0. 3

0.273

γ- glutamyl transferase (IU/L)

Perilla oil

42.8 ± 31.1

42.6 ± 30.6

0.937

Olive oil

48.0 ± 38.5

47.1 ± 38.2

0.780

Uric acid (mg/dL)

Perilla oil

5.6 ± 1.7

5.6 ± 1.6

0.825

Olive oil

5.8 ± 1.6

5.9 ± 1.5

0.672

Blood urea nitrogen (mg/dL)

Perilla oil

13.3 ± 2.6

12.0 ± 1.6

0.229

Olive oil

12.6 ± 2.9

13.7 ± 3.6

0.390

Triglyceride (mg/dL)

Perilla oil

129.2 ± 71.8

137.3 ± 70.0

0.585

Olive oil

122.6 ±59.0

150.9 ± 108.7

0.306

High density lipoprotein cholesterol (HDL-C) (mg/dL)

Perilla oil

64.4 ± 12.8

65.6 ± 14.7

0.549

Olive oil

64.1 ± 14.0

62.8 ± 12.2

0.593

Low-density lipoprotein cholesterol (LDL-C) (mg/dL)

Perilla oil

171.0 ± 31.5

165.0 ± 30.5

0.400

Olive oil

174.4 ± 27.7

168.3 ± 32.8

0.147

C-reactive protein (mg/dL)

Perilla oil

0.2 ± 0.2

0.3 ± 0.6

0.569

Olive oil

0.1 ± 0.1

0.1 ± 0.1

0.835

White blood cell count (10^2/μL)

Perilla oil

55.2 ± 8.3

54.4 ± 10.8

0.741

Olive oil

53.3 ± 9.7

59.2 ± 6.8

0.050

Red blood cell count (104/μL)

Perilla oil

445.5 ± 44.9

444.4 ± 40.0

0.828

Olive oil

448.4 ± 42.1

446.7 ± 37.6

0.564

Platelet count (104/μL)

Perilla oil

26.0 ± 9.8

26.1 ± 10.1

0.628

Olive oil

27.5 ±10.7

26.3 ± 11.0

0.008*

Blood sugar (mg/dL)

Perilla oil

100.5 ± 10.5

98.5 ± 5.5

0.363

Olive oil

99.8 ± 9.3

101.1 ± 11.0

0.537

Hemoglobin A1c (%)

Perilla oil

5.4 ± 0.4

5.3 ± 0.4

0.394

Olive oil

5.3 ± 0.4

5.4 ± 0.4

0.096

Values are presented as mean ± standard deviation; n = 10.
*Significant difference in values analyzed with a paired t-test.

None of the other fatty acids differed significantly before and after intake of either oil (Table 5).

Table 5. Levels of Fatty acid before and after ingestion of perilla oil or olive oil for 1 week

Group

Before

After

P

Lauric acid (μg/mL)

Perilla oil

1.96 ± 1.21

2.37 ± 1.19

0.156

Olive oil

2.83 ± 2.18

2.80 ± 1.56

0.974

Myristic acid (μg/mL)

Perilla oil

25.65 ± 11.17

29.55 ± 14.12

0.160

Olive oil

28.21 ± 10.11

31.96 ± 18.92

0.504

Myristoleic acid (μg/mL)

Perilla oil

1.45 ± 0.68

2.04 ± 1.59

0.147

Olive oil

1.50 ± 0.62

2.48 ± 2.32

0.223

Myristoleic acid (%)

Perilla oil

0.04 ± 0.02

0.05 ± 0.04

0.153

Olive oil

0.04 ± 0.01

0.06 ± 0.06

0.283

Palmitic acid (μg/mL)

Perilla oil

806.65 ± 179.01

840.05 ± 199.55

0.271

Olive oil

817.21 ± 168.76

862.76 ± 261.01

0.522

Palmitoleic acid (μg/mL)

Perilla oil

64.77 ± 25.50

73.94 ± 39.24

0.247

Olive oil

65.75 ± 37.47

73.91 ± 33.71

0.445

Stearic acid (μg/mL)

Perilla oil

260.59 ± 41.50

274.05 ± 45.73

0.106

Olive oil

262.54 ± 43.77

276.61 ± 57.94

0.346

Oleic acid (μg/mL)

Perilla oil

740.99 ± 233.84

776.63 ± 258.10

0.503

Olive oil

718.07 ± 198.32

831.36 ± 306.45

0.219

Linoleic acid (μg/mL)

Perilla oil

1166.83 ± 146.40

1155.99 ± 115.14

0.654

Olive oil

1154.53±119.03

1169.50 ± 216.89

0.799

γ-linolenic acid (μg/mL)

Perilla oil

13.84 ± 5.74

12.25 ± 3.03

0.394

Olive oil

14.07 ± 3.57

14.31 ± 3.87

0.891

Arachidic acid (μg/mL)

Perilla oil

9.37 ± 1.53

9.59 ± 1.57

0.340

Olive oil

9.38±1.54

9.55 ± 1.57

0.623

Eicosenoic acid (μg/mL)

Perilla oil

5.35 ± 2.05

5.17±1.88

0.515

Olive oil

4.76 ± 1.32

5.78 ± 3.33

0.276

Eicosadienoic acid (μg/mL)

Perilla oil

8.89 ± 2.30

8.63 ± 2.43

0.562

Olive oil

8.48 ± 1.85

8.94±3.35

0.604

5–8–11 eicosatrienoic acid (μg/mL)

Perilla oil

3.18±0.82

2.9 ± 1.31

0.410

Olive oil

2.96 ± 1.04

3.26 ± 1.18

0.387

Dihomo-γ-linolenic acid (μg/mL)

Perilla oil

47.76 ± 9.52

44.83 ± 13.35

0.242

Olive oil

51.63 ± 21.62

51.38 ± 16.84

0.945

Arachidonic acid (μg/mL)

Perilla oil

261.62 ± 42.74

253.67 ± 50.44

0.261

Olive oil

267.28 ± 45.99

258.96 ± 44.81

0.226

Behenic acid (μg/mL)

Perilla oil

25.2 ± 5.21

25.59 ± 5.14

0.607

Olive oil

25.83 ± 4.67

25.64 ± 5.00

0.785

Erucic acid (μg/mL)

Perilla oil

1.04 ± 0.07

1.12±0.14

0.121

Olive oil

1.09 ± 0.12

1.14 ± 0.21

0.475

Docosatetraenoic acid (μg/mL)

Perilla oil

6.82 ± 1.36

6.67 ± 1.80

0.726

Olive oil

6.77 ± 1.53

7.04 ± 2.02

0.666

Docosapentaenoic acid (μg/mL)

Perilla oil

19.82 ± 5.39

22.67 ± 8.14

0.126

Olive oil

20.24 ± 5.70

19.5 ± 6.72

0.505

Lignoceric acid (μg/mL)

Perilla oil

22.14 ± 3.74

22.57 ± 4.06

0.580

Olive oil

22.68 ± 2.91

22.52 ± 3.93

0.778

Docosahexaenoic acid (μg/mL)

Perilla oil

139.94 ± 42.19

142.82 ± 48.54

0.644

Olive oil

152 ± 51.35

140.64 ± 42.32

0.134

Nervonic acid (μg/mL)

Perilla oil

42.39 ± 7.28

41.71 ± 5.64

0.641

Olive oil

43.76 ± 6.12

42.04 ± 5.86

0.197

Values are presented as mean ± standard deviation; n = 10.

Safety. There were no serious adverse events related to the intervention. There were also no significant changes in WBC, RBC, and platelet counts after ingestion of perilla oil.

Discussion

Prevention of arteriosclerosis which leads to cardiovascular disease is very important [17]. Given its apparent preventing effects, we focused our experiments on ALA and confirmed that a week’s daily intake of perilla oil significantly increased the plasma levels of ALA and EPA. It has been reported that 11% to 19% of ALA ingested from a meal is converted to EPA or DHA through an in vivo chain extension process [18]. In this study, ALA and EPA increased significantly after intake of perilla oil.. The levels of LDL-C and HDL-C were not changed after intake of perilla oil, while the LDL-C/HDL-C ratio was significantly improve. Recently, the LDL-C/HDL-C ratio has been regarded as an important index of arteriosclerosis. Even in the presence of normal levels of LDL-C, myocardial infarction may occur with low levels of HDL-C. Prevention of arteriosclerosis thus necessitates balancing the levels of LDL-C and HDL-C, which supports the concept of the LDL-C/HDL-C ratio as an important index [19, 20]. Previous study has been reported that Omega – 3 polyunsaturated fatty acids treatments reduced serum total cholesterol and LDL-C and increased HDL-C [21]. Improving of HDL-C / LDL-C ratio is important for prevention of arteriosclerosis [22]. Improving the ratio would be important to reduce arteriosclerosis risk.

No other significant differences except the changes in the LDL-C/HDL-C ratio and levels of ALA and EPA after ingestion of perilla oils were found in any of the variables we measured. There were no changes in blood pressure or BMI. Overdoses of ALA, EPA, and DHA may affect blood coagulation [15]. However, the platelet counts in our subjects did not change significantly before and after ingestion of perilla oil, and no adverse events related to blood clotting were occurred. No adverse events occurred. Therefore, the daily ingestion of perilla oil for 1 week appears to be safe.

RHI evaluates the vasodilator functions of vascular endothelium-derived vasodilators [23]. In this study, RHI was measured as an indicator of vascular endothelial function. Long-term treatment with EPA has been reported to improve impaired endothelium-dependent relaxations of atherosclerotic blood vessels [24]. In this study, we expected that the RHI might improve by perilla oil-induced increases in ALA, but there was no significant difference in the RHI before and after perilla oil.

Because ours was a short-term study with ingestion of perilla oil occurring for only 1 week and involving a small number of subjects, the study may have been underpowered to detect a significant difference in the RHI. Future studies in large numbers of individuals with long-term intake of perilla oil are needed.

Conclusion

We confirmed significant increases in the plasma levels of ALA and improvement in the LDL-C/HDL-C ratio induced by intake of perilla oil. To the extent that improvement of those markers may have a preventive effect against arteriosclerosis, our study suggests that ingestion of perilla oil may be of value in decreasing or preventing arteriosclerosis. Confirming this hypothesis will require long-term administration of perilla oil supplementation and adequate numbers of subjects so that cardiovascular outcomes can be assessed.

Acknowledgments

We are grateful to J. Saito and M. Kamiaraiso and the staff of the Department of Clinical Laboratory, Nanpuh Hospital for their tireless efforts in the carrying out this study. We also thank the study subjects for their participation.

Conflict of Interest

No potential conflicts of interest were disclosed.

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Article Type

Research Article

Publication history

Received: December 05, 2018
Accepted: December 12, 2018
Published: December 19, 2018

Citation

Erena Tokudome, Masakazu Imamura, Sayaka Shiomitsu, Ryoko Miyanohara, Emiko Hori, Hiroto Nishimata, Takuma Yoshinaga (2018) Effect of Perilla Oil on Reducing Arteriosclerosis Risk: A Randomized Controlled Cross-Over Study. J Clin Res Med Volume 1(4): 1–6. DOI: 10.31038/JCRM.2018144

Corresponding author

Takuma Yoshinaga, Ph.D.
Division of Clinical Application,
Nanpuh Hospital, 14–3 Nagata-cho,
Kagoshima-city, Japan 892–8512;
Tel; 81-99-226-9111,
Fax; 81-99-225-8096;
Email: t-yoshinaga@nanpuh.or.jp