Herb-Drug Interactions: Soya

Glycine max (L.Merr.) (Fabaceae)

Synonym(s) and related species

Soy.

Glycine soja Siebold and Zucc.

Pharmacopoeias

Hydrogenated Soya Oil (British Ph 2009); Hydrogenated Soybean Oil (European Ph, 6th ed., 2008 and Supplements 6.1, 6.2, 6.3 and 6.4, The United States Ph 32); Powdered Soy Isoflavones Extract (US Ph 32); Refined Soya Oil (British Ph 2009); Soybean Oil (US Ph 32); Soybean Oil, Refined (European Ph, 6th ed., 2008 and Supplements 6.1, 6.2, 6.3 and 6.4).

Constituents

The isoflavones in soya beans consist mainly of genistein and daidzein, with smaller amounts of isoformononetin, ononin, glycetein, desmethyltexasin and others. They are present mainly as glycosides, and the amount varies between the different soya products. Soya beans also contain coumestans (mainly in the sprouts) and phytosterols. The fixed oil from soya beans contains linoleic and linolenic acids.

Fermented soya products contain variable amounts of tyramine.

Use and indications

Soya is a widely used food, particularly in Japanese and Chinese cuisine. Flour and protein from the beans are used as tofu and as a substitute for meat. Fermented products include soy sauce, natto and miso, and these can contain high concentrations of the isoflavones. Soya milk is used as a substitute for individuals who are allergic to cows’ milk, including in infant formula. Edamame beans are soya beans eaten while still green.

There are numerous purported benefits of soya protein, the most well studied being possible reductions in hyperlipid-aemia, menopausal symptoms and osteoporosis, and prevention of some cancers. Epidemiological studies suggest that a diet with a high intake of soya might protect against breast cancer. Numerous randomised clinical studies show a small benefit for soya protein on blood lipids (which is probably independent of isoflavone content), and there is also evidence of a modest benefit in patients with diabetes. Soya protein and the isoflavone fraction have also shown some benefits for menopausal symptoms and postmenopausal osteoporosis in some studies. One paper notes that many of the demonstrable actions of isoflavones in soya are attributed to the aglycones genistein and daidzein; however, these occur in negligible amounts unless the product has been fermented.For further information on the individual isoflavones present in soya, see isoflavones. Despite numerous studies and meta-analyses, the health benefits of soya have not been conclusively proven and remain controversial. In a 2006 analysis, the American Heart Advisory Committee concluded that the main benefit of a soya-based diet probably relates to its high content of polyunsaturated fats and fibre and low content of saturated fat.

Pharmacokinetics

In healthy subjects, a soya extract did not induce the cytochrome P450 isoenzyme CYP3A4. In vitro, soya bean products and a hydrolysed soya extract, as well as the soya isoflavones daidzein and genistein, inhibited CYP3A4 and CYP2C9. However, in one of these studies, St John’s wort also inhibited CYP3A4, but clinically this herb is known to be an inducer of CYP3A4. This highlights the problems of extrapolating the findings of in vitro studies to clinical situations. Soya-based infant formulas (as well as cow-milk infant formulas) induced CYP1A2 in vitro see caffeine).

The pharmacokinetics of the isoflavone constituents of soya are further discussed under isoflavones.

Interactions overview

Soya products may increase the metabolism of caffeine and reduce the absorption of levothyroxine. Fermented soya bean products contain high levels of tyramine and vitamin K and may therefore cause hypertensive reactions with MAOIs, and decrease the activity of warfarin and related anticoagulants.

Potential interactions of isoflavone constituents of soya are covered under isoflavones; see antibacterials, nicotine, paclitaxel, tamoxifen, and theophylline.

Soya + Antibacterials

No data for soya found. For the theoretical possibility that broad-spectrum antibacterials might reduce the metabolism of the isoflavone constituents of soya, such as daidzein, by colonic bacteria, and so alter their efficacy, see Isoflavones + Antibacterials.

Soya + Caffeine

Soya products may increase the metabolism of caffeine.

Clinical evidence

Caffeine elimination is low in neonates, but increases faster in those receiving formula feeds (type not specified), than in breast-fed infants. In another study of caffeine for apnoea, formula-fed (type not specified) infants required higher caffeine doses than breast-fed infants (4.4mg/kg compared with 8.3mg/kg), but still had lower trough caffeine levels.

Experimental evidence

Both soya-based and cow milk-based infant formulas induced the cytochrome P450 isoenzyme CYP1A2 in in vitro studies, whereas breast milk samples from 29 women did not. Conversely, note that high doses of the soya isoflavone daidzein modestly inhibit CYP1A2, see Isoflavones + Theophylline.

Mechanism

Neonates are less able to metabolise caffeine than adults: hepatic metabolism matures in the first year of life. Infant formula appears to induce the cytochrome P450 isoenzyme CYP1A2, by which caffeine is metabolised. This property is common to both cows’ milk and soya, so must be due to a common constituent of both, or the lack of a constituent present in breast milk. The fact that soya isoflavones have some CYP1A2 inhibitory activity does not appear to counteract this effect.

Importance and management

Clinical evidence in support of an interaction between soya and caffeine is limited, because the two studies do not state the formula feeds used, although it seems likely that soya feeds are implicated; this suggestion is supported by experimental evidence. In infants, caffeine is dosed individually, but be aware that required doses are likely to increase in those receiving formula feeds, including soya-based formula.

Note that, conversely, in high doses, soya isoflavone supplements might reduce the required dose of CYP1A2 substrates such as Isoflavones + Theophylline.

Soya + Food

No interactions found.

Soya + Herbal medicines

No interactions found.

Soya + Levothyroxine and related drugs

Soya products or soya isoflavones might increase the dose required of thyroid hormone replacement therapy.

Clinical evidence

A 45-year-old woman who had hypothyroidism after a near-total thyroidectomy and radioactive iodine ablative therapy for papillary carcinoma of the thyroid required unusually high oral doses of levothyroxine (300 micrograms daily) to achieve clinically effective levels of free thyroxine (T4); suppression of thyroid-stimulating hormone (TSH) was unsatisfactory, even at this dose. She had routinely been taking a ‘soya cocktail’ protein supplement immediately after her levothyroxine. Taking the soya protein cocktail in the morning and the levothyroxine in the evening avoided this effect.

A newborn infant with primary hypothyroidism failed to respond to a usual dose of levothyroxine until his soya formula was replaced with cows’ milk formula. In another report, three infants with primary hypothyroidism fed soya formula required 18 to 25% decreases in their levothyroxine dose after soya formula was discontinued. In a retrospective study of primary hypothyroidism, TSH values took longer to normalise in 8 infants fed soya formula than in 70 other infants not given soya.

Historical data (from before the 1960s) show that soya formula without iodine supplementation caused goitre, which could be reversed by iodine supplementation.

Experimental evidence

Soya isoflavones inhibited the activity of thyroid peroxidase, an enzyme required for thyroid hormone synthesis, in cell culture and animal studies (this has been the subject of a review). However, soya isoflavones do not appear to cause thyroid hormone abnormalities in euthyroid individuals (also reviewed).

Mechanism

Soya isoflavones clearly inhibit thyroid peroxidase; however, hypothyroidism does not usually occur unless iodine deficiency is also present. Soya formula or other similar products might decrease levothyroxine absorption in some individuals.

Importance and management

There is a good body of evidence, which suggests that soya products or soya isoflavones might increase the dose required of thyroid hormone replacement therapy. It would seem prudent to closely monitor the resolution of primary hypothyroidism in infants receiving soya formula, and expect to use higher dose of levothyroxine than anticipated in these individuals. Monitor thyroxine levels, and either discontinue the soya formula or further increase the dose if necessary. Similar precautions would seem prudent if patients receiving levothyroxine wish to take soya supplements; however, remember that the intake of soya supplementation will need to remain relatively constant.

Soya + MAOIs or RIMAs

A potentially fatal hypertensive reaction can occur between the non-selective MAOIs and tyramine-rich foods. Significant amounts of tyramine may be present in fermented or preserved soya products such as soy sauce and tofu, and it may be prudent to avoid these while taking an MAOI. Effects may last for up to two weeks after discontinuation of the MAOI. However, other soya products such as dried textured soya protein and fresh soya beans are unlikely to contain important amounts of tyramine. The risk of a serious hypertensive reaction with moclobemide (or other RIMAs) is very much reduced. Most patients therefore do not need to follow the special dietary restrictions required with the non-selective MAOIs.

Clinical evidence

A 33-year-old woman taking tranylcypromine 10 mg four times daily presented to an emergency department with global headache and stiffness of the neck and was found to have a blood pressure of 230/140 mm Hg and bradycardia of 55 bpm. Twenty minutes earlier she had eaten chicken teriyaki containing aged soy sauce. She was successfully treated with intravenous labetolol.

Experimental evidence

The tyramine content of a variety of soya products showed marked variability, including clinically significant tyramine levels in tofu when stored for one week and high tyramine content in one of 5 soy sauces (a tyramine level of 6 mg or less was considered safe). In another analysis, high tyramine levels were found in two soy sauces, fermented soya beans, fermented soya bean paste and a soya bean curd condiment. Other non-fermented soya products (tofu, soya bean soup, bean flour, dried bean curd, soya bean drink) had low levels of tyramine, as did one fermented soya bean soup product (miso soup).

Mechanism

Potentiation of the pressor effect of tyramine. Tyramine is formed in foods by the bacterial degradation of proteins, firstly to tyrosine and other amino acids, and the subsequent decarboxylation of the tyrosine to tyramine. This interaction is therefore not associated with fresh foods, but with those that have been allowed to over-ripen or ‘mature’ in some way, or if spoilage occurs. Tyramine is an indirectly acting sympathomimetic amine, one of its actions being to release noradrenaline (norepinephrine) from the adrenergic neurones associated with blood vessels, which causes a rise in blood pressure by stimulating their constriction.

Normally any ingested tyramine is rapidly metabolised by the enzyme monoamine oxidase in the gut wall and liver before it reaches the general circulation. However, if the activity of the enzyme at these sites is inhibited (by the presence of an MAOI), any tyramine passes freely into the circulation, causing not just a rise in blood pressure, but a highly exaggerated rise due to the release from the adrenergic neurones of the large amounts of noradrenaline that accumulate there during inhibition of MAO.

RIMAs such as moclobemide and toloxatone selectively inhibit MAO-A, which leaves MAO-B still available to metabolise tyramine. This means that they have less effect on the tyramine pressor response than non-selective MAOIs.

Importance and management

A potentially fatal hypertensive reaction can occur between the non-selective MAOIs and tyramine-rich foods. Significant amounts of tyramine may be present in fermented or preserved soya products such as soy sauce and tofu, and it may be prudent to avoid these while taking an MAOI. Effects may last for up to two weeks after discontinuation of the MAOI. However, other soya products such as dried textured soya protein and fresh soya beans are unlikely to contain important amounts of tyramine.

Moclobemide is safer (in the context of interactions with tyramine-rich foods and drinks) than the non-selective MAOIs, because it is more readily reversible and selective. Therefore the risk of a serious hypertensive reaction with moclobemide (or other RIMAs) is very much reduced. Most patients therefore do not need to follow the special dietary restrictions required with the non-selective MAOIs.

Soya + Nicotine

For discussion of a study showing that soya isoflavones (daidzein and genistein) caused a minor decrease in the metabolism of nicotine, see Isoflavones + Nicotine.

Soya + Paclitaxel

No data for soya found. For the possibility that genistein, an isoflavone present in soya, might markedly increase paclitaxel levels, see Isoflavones + Paclitaxel.

The data relating to the use of soya products and isoflavone supplements (containing the isoflavones daidzein and genistein, among others) with tamoxifen are covered under Isoflavones + Tamoxifen.

Soya + Theophylline

No data for soya found. For the possibility that high doses of daidzein present in soya might modestly increase theophylline levels, see Isoflavones + Theophylline.

Soya + Warfarin and related drugs

Natto, a Japanese food made from fermented soya bean, can markedly reduce the effects of warfarin and acenocoumarol, because of the high levels of vitamin K2 substance produced in the fermentation process. In one study, soya bean protein also modestly reduced the effects of warfarin, and a similar case has been reported with soy milk. Two cases of ‘warfarin resistance’ have been seen in patients given intravenous soya oil emulsions.

Clinical evidence

(a) Fermented soya bean products (natto)

In a controlled study in 12 healthy subjects stabilised on acenocoumarol, a single meal containing 100 g of natto decreased the mean INR from 2.1 to 1.5 after 24 hours, and the INR had still not returned to the original level after 7 days (INR 1.75 one week later). The effect was considered clinically important in 6 of the 12 subjects. Similarly, in an earlier retrospective study of 10 patients taking warfarin, eating natto caused the thrombotest values to rise from a range of 12 to 29% up to a range of 33 to 100%. The extent of the rise appeared to be related to the amount of natto eaten. The thrombotest values fell again when the natto was stopped. A healthy subject taking warfarin, with a thrombotest value of 40%, ate 100 g of natto. Five hours later the thrombotest value was unchanged, but 24 hours later it was 86%, and after 48 hours it was 90% (suggesting that the anticoagulant effect was decreased).

(b) Soya milk

In a 70-year-old man stabilised on warfarin 3 mg daily, consumption of soya milk 480 mL daily (240 mL of both Sun Soy and 8th Continent mixed together) decreased the INR from 2.5 to 1.6 after about 4 weeks. One week after stopping the soya milk, his INR was 1.9, and 4 weeks after it was 2.5.

(c) Soya oil

Soya oil is an important source of dietary vitamin K. Two cases of ‘warfarin resistance’ have been seen in patients given intravenous soya oil emulsions.

(d) Soya protein

In a study in 10 patients with hypercholesterolaemia who were stabilised on warfarin, substitution of all animal protein for textured soya protein for 4 weeks caused a marked reduction (Quick value approximately doubled) in the anticoagulant effects of warfarin by the second week.

Experimental evidence

Experiments in animals to investigate the clinical observations for natto found that natto strongly antagonised the effects of warfarin.In one in vitro metabolism study in human liver microsomes,hydrolysed soya extract inhibited all of the cytochrome P450 isoenzymes tested, particularly CYP2C9 and CYP3A4 (which are responsible for the metabolism of warfarin). This suggests that an increased warfarin effect might have been expected, but the authors point out there is a lack of concordance between in vitro and in vivo findings.

Mechanism

Soya beans are a moderate source of vitamin K1 (19 micrograms per 100 g), and soya oil and products derived from it are an important dietary source of vitamin K. However, the soya milk brand taken in the case report did not contain vitamin K, and another reference source lists soya milk as containing just 7.5 micrograms vitamin K per 250 mL, which would not be expected to cause an interaction. Why this product decreased the effect of warfarin is therefore open to speculation.

The vitamin K content of textured soya protein is unknown. Note that soy sauce made from soya and wheat is reported to contain no vitamin K, and soft tofu made from the curds by coagulating soya milk contains only low levels (2 micrograms per 100 g).

In contrast, fermented soya bean products such as natto contain very high levels of a particular vitamin K2 substance (MK-7), because of the fermentation process with Bacillus natto. In addition, the bacteria might continue to act in the gut to increase the synthesis and subsequent absorption of vitamin K2. Although the role of vitamin K2 in anticoagulation is less well established than vitamin K1, it appears that this also opposes the actions of coumarins and indanediones, which are vitamin K antagonists.

Importance and management

The interaction between warfarin and fermented soya bean products is established, marked and likely to be clinically relevant in all patients. Patients taking coumarin and probably indanedione anticoagulants should be advised to avoid natto, unless they want to consume a regular, constant amount.

Although information is limited, it appears that soya protein might also modestly reduce the effect of warfarin. In particular, complete substitution of animal protein for soya protein appears to reduce the effect of warfarin. Case reports suggest that soya milk and soya oil may also interact, and therefore some caution would be prudent with these products. On the basis of known vitamin K content, whole soya beans could potentially reduce the effect of warfarin, whereas soy sauce should not. Note that patients taking coumarins and indanediones are advised to have their INR checked if they markedly change their diet. This would seem particularly important if they decide to change their intake of soya-related products.