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Apples

Scientific Name(s): Malus pumila Mill.
Common Name(s): Apple

Clinical Overview

Use

Traditional uses of apples include treatment for cancer, diabetes, dysentery, constipation, fever, heart ailments, scurvy, and warts. However, there are no clinical trials to support the use of apple for these conditions. There is increasing evidence suggesting apple consumption may be protective against cancer, particularly colorectal, lung, and possibly other types; may prevent cardiovascular disease by virtue of its beneficial effects on cardiovascular risk factors (eg, atherosclerosis, hypercholesterolemia, obesity, diabetes); and may have beneficial effects on pulmonary function, including preventing asthma. In addition, there is preliminary evidence that the antioxidant and anti-inflammatory effects of apples may provide benefits in a range of other conditions.

Dosing

From epidemiological observations, regular consumption of 1 or more apples per day may contribute to the prevention of certain types of cancer.

Contraindications

Severe allergy to apples.

Pregnancy/Lactation

Generally recognized as safe (GRAS) when used as food. Avoid ingestion above that found in food, because safety and efficacy are unproven.

Interactions

Apple juice can potentially decrease the absorption of some drugs by inhibiting drug uptake from the gut. This effect has been demonstrated with fexofenadine. Separating administration times might not prevent this interaction; it would be prudent for patients taking fexofenadine to avoid apple juice and to take the medication with water.

Adverse Reactions

Research reveals little data regarding adverse reactions, except for reports of allergy including oral allergy syndrome, a case report of contact urticaria, and 2 cases of apple-dependent, exercise-induced asthma.

Toxicology

Apple fruit is considered safe. The seeds, which can liberate hydrogen cyanide, should not be consumed in large quantities.

Botany

The apple tree is deciduous with simple clusters of flowers. The fruit is termed a "pome." Apple trees are cultivated throughout the temperate climates of the world, and the fruit is widely available in commercial markets. About 2,500 known varieties (cultivars) of apples are grown in the United States and more than 7,500 varieties are grown in the world.1 Most apples are grown from grafted scions and rootstocks because apples do not reproduce consistently from seed. The cultivated apple is thought to have originated in central Asia from the wild species Malus sieversii (Ledeb.) M. Roem.

History

American settlers brought apple trees and seeds from England in the 1600s.1 The apple has been recognized as a valuable food; it is the second most popular fresh fruit consumed by Americans.1 Its uses in traditional medicine have been varied, including treatment of cancer, diabetes, dysentery, constipation, fever, heart ailments, scurvy, and warts.2 Apples are also said to be effective in cleaning the teeth. The fruit juice is drunk fresh, fermented as cider, or distilled into apple brandy. The wood of the apple tree is valued as a firewood.

Chemistry

Apples contain high levels of polyphenols (up to 2 g/kg fresh weight) and other phytochemicals, many of which are strong antioxidants.3 When compared with many other commonly consumed fruits in the United States, apples had the second highest level of antioxidant activity4 were ranked second for total phenolic compounds, and had the highest portion of free phenolics.5

Polyphenols represent 0.01% to 1% of the fresh fruit weight. In particular, apples contain large amounts of flavonoids.1, 3, 6 Chromatographic analysis reveals that flava-3-nols (eg, catechin, procyanidins) are the major class of apple polyphenols (71% to 90%; 50 to 393 mg/L in juice/cider and 116 to 411 mg/kg fresh fruit weight), followed by hydroxycinnamates (eg, chlorogenic acid, caffeic acid, cumaroylquinic acid; 4% to 18%; 57 to 593 mg/L in juice/cider, 45 to 384 mg/kg fresh fruit weight), flavonols (eg, quercetin conjugates; 1% to 11%; 0.4 to 27 mg/L in juice/cider, 34 to 83 mg/kg fresh fruit weight), dihydrochalcones (eg, phloretins, phloridzins; 2% to 6%; 10 to 171 mg/L in juice/cider, 20 to 144 mg/kg fresh fruit weight), and anthrocyanins in red apples (1% to 3%; 0 to 37 mg/kg fresh fruit weight).6, 7, 8

Triterpenoids and quercetin conjugates are found exclusively in the peel, along with much higher concentrations of procyanidins, catechin, epicatechin, and phloridzin. Anywhere from 2 to 6 times more phenolics and 2 to 3 times more flavonoids are found in the peel than in the flesh.9 However, higher amounts of chlorogenic acid are in the flesh than in the peel.9 Consequently, apple peels have much greater antioxidant activity10, 11 and antiproliferative activity5, 12 than the flesh.

Vitamin C in apples contributes less than 0.4% of the total antioxidant activity.4

Notably, there are differences in the polyphenol content between apple cultivars.4, 7, 13, 14, 15 Harvest, storage, and processing also have an effect.4

The fruit contains up to 17% pectin and pectic acids.2

Hydrogen cyanide, liberated from the cyanogenic glycoside amygdalin, is found in the seeds. In addition, the seeds contain a yellow semi-drying oil (glucoside phlorizin) with the odor of bitter almonds.2, 16

Apple leaves, bark, and root contain phloretin, an antibacterial substance that is active in vitro in low concentrations.2

Uses and Pharmacology

Besides supplying key nutrients, several lines of evidence suggest that apples and apple products possess a wide range of biological activities that may contribute to beneficial health effects.4, 7, 17 Increasing evidence from in vitro, in vivo, and epidemiological studies suggest that flavonoids found in apples may be protective against cancer, cardiovascular disease, diabetes, asthma, obesity, and other chronic diseases.1, 4

It has been reported that of all the flavonoid sources, apple intake was inversely associated with the occurrence of all cancers combined (especially lung cancer), asthma, type 2 diabetes, thrombotic stroke, total mortality, and ischemic heart disease. In addition, flavonoid intake was associated with a lower mortality; apples were one of the main dietary sources that showed the strongest association with decreased mortality.18

Mechanism of action

Beneficial health effects can be attributed to the phytochemicals and dietary fiber found in apples.4 Apples are low in calories, fat, and sodium, which are all positive contributors to cardiovascular health.1

Raw apples are a good source of dietary fiber. Apples contain soluble and insoluble fiber, two-thirds of which are found in the peel.1, 19 Soluble fiber, such as pectin, helps lower cholesterol levels and normalize blood glucose and insulin levels.20, 21 Pectin has also been used to treat diarrhea. (For further information, see the Pectin monograph.) Insoluble fiber promotes bowel regularity and helps move food quickly through the digestive tract; it is therefore effective in the treatment of constipation, diverticulosis, and some types of cancer.20

The phytochemicals in apples possess strong antioxidant activity. It is this antioxidant activity, along with the effects of the fiber content, that influence multiple mechanisms relevant for cancer prevention and cardiovascular protection.4 In cancer prevention, these include antimutagenic activity6, 22, 23, 24 modulation of carcinogen metabolism6 antioxidant activity6, 25, 26, 27 anti-inflammatory mechanisms6, 26, 27, 28, 29 modulation of signal transduction pathways6 antiproliferative activity5, 10, 25, 30, 31, 32, 33 and apotosis-inducing activity.32, 34, 35 In cardiovascular protection, it is likely that the relevant mechanisms include decreasing lipid oxidation6, 36, 37 lowering cholesterol38, 39, 40, 41, 42, 43 improving blood glucose and lipid profiles, reducing risk of type 2 diabetes, and beneficial effects on obesity.4

One study compared 8,029 patients with incidences of oral, pharyngeal, esophageal, laryngeal, colorectal, breast, ovarian, and prostate cancer to 6,629 patients without cancer. Consumption of 1 or more apples per day was inversely associated with the risk of cancer when compared with less than 1 apple per day.44 Similarly, an inverse relationship between apple consumption and the risk of cardiovascular disease has been illustrated in various human studies.4

Allergic disorders

Apple extract and procyaniin extract inhibited histamine release in in vitro allergic models.91 It is postulated that this effect is mediated by inhibition of calcium influx reducing histamine degranulation.

Animal data

An in vivo study in mice suggested that apple polyphenol extract administered orally has an antiallergic effect on type 1 allergy symptoms.92

Clinical data

In a double-blind clinical trial using apple polyphenol extract 500 mg twice daily (produced commercially from unripe apples) in pediatric patients with atopic dermatitis, the itching score decreased compared with placebo.93

In another study, 33 patients 15 to 65 years of age with moderate or severe persistent allergic rhinitis were treated with no, low-, or high-dose apple polyphenols. Improvements were observed in sneezing attacks and nasal discharge in the high-dose group and in sneezing attacks in the low-dose group. In addition the percentage of patients who showed improvement in swelling in the nasal turbinates was higher in the polyphenol-treated groups. It was concluded that apple polyphenols are effective in alleviating symptoms of persistent allergic rhinitis.94

Asthma and pulmonary function

Apple consumption has been inversely linked with asthma and has also been positively associated with general pulmonary health.4

Clinical data

Asthma

A study from the United Kingdom surveying nearly 600 asthmatics and 900 nonasthmatics about diet and lifestyle showed total fruit and vegetable intake was weakly inversely associated with asthma, while apple intake showed a stronger inverse relationship with asthma80 particularly in those who consumed at least 2 apples per week. Other foods high in flavonoids, such as tea, red wine, and onion were not related to asthma incidence.

In a large study in Finland involving 10,000 men and women, apple and orange intake were associated with a reduced incidence of asthma, whereas other fruits and vegetables, such as onions, grapefruit, cabbage, and juices, were not associated with a decreased risk in asthma.75 Similarly, a study in Australia involving 1,600 adults showed apple and pear intake was associated with a decreased risk of asthma and a decrease in bronchial hypersensitivity, whereas total fruit and vegetable intake was not associated with asthma risk or severity.81

Pulmonary function

Two studies have demonstrated a beneficial effect of apple consumption on lung function.82, 83 One study of 13,000 adults in the Netherlands associated apple and pear intake positively with pulmonary function and negatively with chronic obstructive pulmonary disease.82 In the other study of 2,500 Welsh men, consumption of apples was positively correlated with forced expiratory volume in 1 second (FEV1) even after adjustment for possible confounding factors such as smoking, BMI, social class, and exercise. Participants who consumed 5 apples or more each week had a greater FEV1 compared with those who did not consume apples.83

Cancer

Animal data

Numerous in vivo studies in animal cancer models have shown that apple products may inhibit the growth of chemically induced mouse skin papillomas45; chemically induced rat mammary carcinogenesis46; liver, lung, and lymphatic metastases induced by hepatoma cell inoculation in rats47; and melanoma cells in host mice transplanted with B16 cells.48 Studies have shown the potentially important role of oligomeric procyanidins in colon cancer prevention.49 Similarly, numerous studies have shown a beneficial effect of apple-derived dietary fiber in reducing the ratio of secondary bile acids formed by the bacterial metabolism from primary bile acids synthesized in the liver (regarded as a risk index for colorectal cancer).50, 51, 52 It has been reported that the combined ingestion of apple pectin and polyphenol-rich fraction was more effective on large intestine fermentations and lipid metabolism than if they were fed separately, suggesting interactions between fiber and polyphenols of apple.42

Clinical data

Interventional studies

Short-term human intervention studies providing some insight into the potential cancer preventive activity have focused on the modulation of antioxidant status and markers of oxidative stress by consumption of apple and apple juice.36, 53, 54 However, these studies suggest that apple or apple juice consumption results in only a brief transient increase in antioxidant capacity 0.5 to 3 hours after consumption. In a series of in vitro, ex vivo, and in vivo studies, it was demonstrated that the increase in human plasma antioxidant capacity after apple consumption is not caused by apple-derived antioxidants, but is most likely due to a metabolic effect of fructose contained in apples on urate, an important endogenous antioxidant in plasma.55, 56, 57

Epidemiological studies

Colorectal cancer

Evidence indicates that regular consumption of 1 or more apples each day may reduce the risk of colon cancer.44, 58, 59, 60, 61, 62 In the US Nurses' Health Study, the cohort of women who ate the most apples had a reduced risk of developing colorectal adenomas when compared with those with the lowest apple intake.58 A case-control study in Uruguay showed apple consumption was associated with a dose-dependent reduction in colorectal cancer risk in men and women.59 In a case-control study in Korea, fruit consumption, including apples, lowered the risk for colon cancer in men, but not in women.60 A recent case-control study from Scotland did not find a statistically significant association between apple consumption and colon cancer risk.61 In a study from Italy, including 1,953 patients with colorectal cancer, consumption of 1 or more apples per day when compared with less than 1 apple per day significantly reduced the odds ratio (OR) for colorectal cancer (OR = 0.8 [95%, confidence interval (CI) 0.71 to 0.9]).44 A more recent study showed that adjusted risk of colorectal cancer was reduced by consumption of at least 1 apple per day (OR = 0.65 [95%, CI 0.39 to 1.09]), and that the intake of more than 1 apple per day reduced the risk by approximately 50% (OR = 0.53 [95%, CI 0.35 to 0.79]).62 Reanalysis of several case-control studies illustrated an inverse relationship between risk of colorectal cancer and the daily number of apple servings; the most significant reductions were observed for an intake of 1 or more apple servings daily (OR = 0.37 [CI 95%, 0.15 to 0.91]).63

Lung cancer

A 21% reduction in risk of lung cancer among women was observed in the large prospective Nurses' Health cohort study64 but no effect was seen among men in the Health Professionals' Follow-up study.64 In a large cohort study from Finland, the risk of lung cancer was reduced by 60% in men who ate the most apples (more than 47 g/day) compared with those who did not eat apples at all.18 The Zutphen study in elderly men showed apple intake was not associated with reduced lung cancer risk.65 In a case-control study conducted in Hawaii, a statistically significant inverse relationship between lung cancer and apple consumption was found.66

Renal cancer

High apple consumption (more than 94 g/day) was associated with a reduced renal cancer risk. The reduction was particularly strong for those people who ate the most apples and for nonsmokers, whereas no effect was seen in smokers.67

Other cancers

In a study from Italy, meta-analysis revealed consumption of 1 or more apples per day compared with less than 1 apple per day reduced the odds ratio for cancers of the oral cavity, larynx, breast, and ovary.44

Cardiovascular disease

The effects of apple have been studied in various conditions that are related to cardiovascular disease and its risk factors, (eg, atherosclerosis, hypercholesterolemia, obesity, type 2 diabetes).

Atherosclerosis

Animal data

A study compared the effects of apples, purple grapes, and their juices on hamsters fed an atherogenic diet for 12 weeks. Plasma cholesterol, non–high-density lipoprotein cholesterol, liver superoxide dismutase and glutathione peroxidase activities, and thiobarbuturic acid reactive substances were efficiently reduced by the fruits and their juices compared with controls. Plasma antioxidant capacity was also increased and aortic fatty streak area was decreased. It was concluded that apples, grapes, and their juices prevent the development of atherosclerosis in hamsters and the underlying mechanism is mainly related to increased antioxidant status and improved serum lipid profile.68

Another study designed to assess the effect of apple juice on risk factors of atherosclerosis and on the development of atherosclerosis in rabbits fed a high cholesterol diet found that apple juice decreased the risk factors (total cholesterol, triglycerides, C-reactive protein, fibrinogen, and factor VII levels). In addition, there were fewer atherosclerotic lesions (fatty streak formations) in the right and left coronary artery in the apple-fed rabbits.27 They concluded that apple juice can effectively prevent the progress of atherosclerosis in this model, and it is likely due to its antioxidant and anti-inflammatory effects.27

Hypercholesterolemia

Animal data

Various in vivo animal models have found that apple constituents counteracted the development of hypercholesterolemia and/or exerted beneficial hypocholesterolemic effects.27, 40, 42, 69, 70, 71

Clinical data

Apples have been shown to lower cholesterol in humans.4 In a randomized, double-blind, placebo-controlled study on moderately obese men and women with body mass indices (BMIs) ranging from 23 to 30, the 12-week intake of polyphenols from apples and hop bract (600 mg/day) decreased total cholesterol and low-density lipoprotein cholesterol levels. The effect from the apple-containing capsules was more marked than that from the hop bract, demonstrating that apple polyphenols regulate fat metabolism in healthy subjects with high BMIs.72 Similarly, cultivars of 5 fresh apples were shown to significantly improve lipid parameters in a single-blind, randomized placebo-controlled trial conducted in 250 adults with mild hypercholesterolemia. Patients consumed 200 g of apple (1 or 2 depending on the size) daily for 8 weeks, which led to significant improvements in total cholesterol, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) observed within the first month of the study. Hypocholesterolemic effects were found to be positively correlated to the polyphenol amounts in each cultivar, which were in decreasing order: Annurca, Granny Smith, Red Delicious, Fuji, Golden Delicious. Decreases in total cholesterol ranged from −8.3% to −1.2%, while LDL reductions ranged from −14.5% to −2.6%. Improvements were also observed in HDL ranging from +14.0% to +1.5%. In contrast, plasma glucose and triglycerides increased significantly by an average of +13.1% and +12.7%, respectively.109

Obesity

Animal data

A study in rats compared the effect of apple polyphenol diets containing 5% and 0.5% with a control group. After a 3-week experimental period, adipose tissue weights in the 5% group were lower than those in the control group. Pathological examination suggested the existence of proliferating pre-adipocytes only in the control group. They concluded that dietary apple polyphenol had an antiadipogenic effect.73

Clinical data

Various clinical studies have illustrated that apple polyphenols may regulate fat metabolism.72 In a study from Brazil, hypercholesterolemic nonsmoking women were randomized to apple, pear, or oat cookies consumed 3 times daily for 12 weeks. Participants consuming either fruit had a significant weight loss. However, those on oat cookies did not.74

Diabetes

Clinical data

In a study from Brazil, women consuming apples or pears 3 times daily had a lower blood glucose level when compared with women consuming oat cookies.74 Consumption of apple polyphenol extract alone and in combination with blackcurrant anthocyanins significantly lowered early postprandial plasma glucose, insulin, and C-peptide compared to controls. The combination had a stronger effect than the apple extract alone. The study enrolled 34 healthy men and postmenopausal women who consumed each test drink prior to a high-carbohydrate test meal. In vitro dose-response assays of apple polyphenol concentrations yielded an estimated corresponding physiological dose in humans of 600 mg apple polyphenols (900 mg apple extract).110

Epidemiological studies and cardiovascular disease risk

Clinical data

In the Women's Health study, which surveyed nearly 40,000 women with a 6.9-year follow-up, women ingesting apples had a 13% to 22% decrease in cardiovascular risk.75

In a large study in Finland, apple and onion intake was significantly inversely associated with coronary mortality, especially in women.76 Data collected from the study in Finland also showed that those who had the highest consumption of apples had a lower risk of thrombotic stroke77 and apple consumption was associated with a reduced risk of type 2 diabetes. Onion, orange, grapefruit, and cabbage were not associated with a lower risk of diabetes.18

In a study of nearly 35,000 postmenopausal women in Iowa, apple and wine consumption was also inversely associated with coronary mortality.78

In the Zutphen study in elderly men, apple intake contributed to approximately 10% of the total ingested flavonoids and was associated with a reduced risk of death from coronary heart disease; however, the relationship was not statistically significant.79

Cholera

Studies reported that crude extract of immature apples inhibited the enzymatic activities of, and the fluid accumulation induced by, the cholera toxin in a dose-dependent manner. It is likely that polymerized catechins are responsible for this action.97

Inflammatory bowel disease

A study in mice with chemically induced colitis showed beneficial anti-inflammatory and immunomodulatory effects of apple procyanidins on intestinal epithelial cells and intraepithelial lymphocytes, suggesting that apples may be an effective preventive agent for inflammatory bowel disease.95 Another study showed that administration of apples rich in polyphenols ameloriates colon inflammation in rats developing spontaneous inflammatory bowel disease.96

Neurodegeneration and aging

Animal data

Experimental studies in rat and mouse53, 84, 85, 86, 87, 88, 89 models demonstrated that impairment of brain function during aging could be prevented by an increase in apple consumption.

Clinical data

A study in 15 elderly subjects consuming an apple a day for 1 month revealed lower oxidant levels and higher antioxidant potential after the study period compared with prestudy levels. It was concluded that it is possible that reduced peroxidation processes owing to consumption of apple may play a part in some of the beneficial effects seen in elderly subjects.90

Dosing

While extrapolation from animal studies to humans is difficult, a daily dose equivalent to 800 mL of cloudy apple juice reduced colon cancer98and a dose equivalent to 6 apples7 reduced mammary cancer.

From epidemiological observations, regular consumption of 1 or more apples per day may contribute to the prevention of certain types of cancer.7

Pregnancy / Lactation

Apples have a GRAS status when used as food. Avoid ingestion above that found in food because safety and efficacy are unproven.99

Interactions

Apple juice can potentially decrease the absorption of different drugs by inhibition of the organic anion transporting polypeptide, which is involved in drug uptake in the gut, liver, and kidney.100, 101 The effect of apple juice on the pharmacokinetics of fexofenadine was studied in 10 healthy volunteers. Compared with water, apple juice reduced the fexofenadine area under the plasma concentration-time curve 73%, the peak plasma concentration 72% (from 288 to 81 ng/mL), and the urinary excretion 69%.100 Separating administration times might not prevent this interaction.

Adverse Reactions

Research reveals little or no information regarding adverse reactions with the use of apples, except for allergy. Approximately 2% of the northern and central European population is allergic to apples.102 Oral allergy syndrome is a common presentation103, 104; however, contact urticaria has also been reported.104 Two cases of apple-dependent exercise-induced anaphylaxis were reported.105

There is evidence that the allergenic potential is dependent on the apple cultivar, with some varieties being less allergenic.102 One study has revealed about 100-fold differences in lipid proteins implicated in severe allergic reactions to fruits between cultivars.106 Cross-sensitivity among the apple fruit and other members of the Rosaceae family has been demonstrated.107

Toxicology

Apples are GRAS.

One study in rats addressed toxicology and safety of a polyphenol-rich extract from unripe apples containing high levels of oligomeric procyanidins (64%), flavan-3-ols (12%), flavonoids (7%), and nonflavonoids (18%). At a dose of 2,000 mg/kg bodyweight, no signs of toxicity were observed in acute and subchronic toxicity tests.108

Because of their hydrogen cyanide content, apple seeds should not be ingested in large quantities. A small number of seeds may be ingested without symptoms.16 Large amounts of seeds have the potential for toxicity. One recurring report cites the case of a man dying of cyanide poisoning after ingesting a cupful of apple seeds.2 Because cyanogenic glycoside must be hydrolyzed in the stomach in order to release cyanide, several hours may elapse before symptoms of poisoning occur.16

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