Curcumin and letrozole (femara)
Jacob Schor ND, FABNO
DenverNaturopathicOncology.com
DenverNaturopathicClinic.com
September 12, 2018

We have had several patients contact our clinic this summer in distress because their medical doctors have told them that curcumin will cancel out the anti-cancer action of the aromatase inhibitor letrozole (Femara), which they are taking to reduce their risk of breast cancer recurrence.
Their doctors have gotten this idea from their hospital pharmacists who have read it on online. The message they have copied from their online source and pasted in emails to the MDs who then forwarded it to their patients, and who in turn eventually shared them with our office goes like this:
“Specifically, the Meriva (curcumin) is associated with drug interactions involving CYP 3A4 substrates. Femara is metabolized in the liver via the CYP3A4 pathway and the supplement likely to affect metabolism leading to either increased risk of side effects or less efficacy.”

This could be a serious concern if it were true. As one patient wrote me, “… I do not want to mess with the effect of the hormone blocking medication if I have to take it, at least I want to think it is working!”

After careful study, it is our conclusion that their worry can safely be ignored.
Let’s look at it carefully. Unfortunately, none of the pharmacists who have made these pronouncements have referenced where they sourced this information. Thus, we have tried to track down and confirm it as best we can.

Femara is metabolized in the liver via the CYP3A4 pathway; this is true. Letrozole is broken down by two possible pathways, CYP3a4 or CYP3a5 (or possibly CYP2a6 depending on which study you read [1] ). Currently we do believe that CYP 3a4 plays the largest role. A 2009 in vitro study (test-tubes) suggested that “… P450 2A6 and 3A4 catalyze the conversion of letrozole to its carbinol metabolite in vitro at low and high concentrations of letrozole” [2]

According to a 2011 paper, the amount of CYP3a4 circulating in the body varies greatly depending on an individual’s genetics, their weight (BMI) and their age. By ‘greatly,’ we are talking about a ten-fold variation in levels. Levels of CYP3a4 in the body have been suggested as a possible predictor of letrozole effectiveness or of adverse effects from the drug. [3] Yet it is not common practice to measure circulating CYP3a4 or adjust the letrozole dose to compensate for high or low levels of CYP3a4. The more CYP3a4 present the faster the drug is broken down and the less enzyme present, the longer the drug lingers in the body, sonthe more effect it will have and the greater the potential for side effect.

One would think that doses of letrozole would need to be adjusted in order to compensate for these varying levels of CYP3a4 activity to keep letrozole levels in an effective treatment range but “… dose adjustment is not necessary, because of the wide therapeutic range.” [4] It doesn’t appear to matter how much CYP3a4 is present. Any level of letrozole that gets into the system is enough to do the job and block estrogen production. An interesting side note is to consider that patients who have adverse reactions may be able to lower their doses.
CYP3a4 is the same enzyme that makes drinking grapefruit juice problematic with certain drugs. Grapefruit juice inhibits this CYP3a4 enzyme to the extreme, it stops it from working. Statin drugs are broken down by CYP3a4 and so levels of these drugs will skyrocket in the body, increasing more than ten-fold, if taken with grapefruit juice or still double if taken the day after drinking a glass of grapefruit juice. [5] Although pharmacists are supposed to warn patients taking letrozole to avoid grapefruit juice, we have yet to see adverse effects reported from ignoring this advice. Letrozole does not pose the same threat other drugs do when levels increase above the target range.

Does taking curcumin change levels of CYP3a4? The answer to this question still isn’t clear, various studies have reported contradictory findings. In 2014, Hsieh suggested that curcumin changes CYP3a4 action, activating it dramatically, based on data obtained from rats who were given the human dose equivalent of 4 to 8 grams/day. [6] In a 2013 human study, Volak et al were unable to confirm that curcumin increases CYP3a: they found no significant changes in the pharmacokinetics of drugs that should have been sensitive to CYP3a action. [7]

It should be noted that the curcumin Volak’s study participants took was a mixture of curcumin and piperine, a formula that we now rarely suggest. That combination has been replaced by newer more effective liposomal products, which are much better absorbed. Does this make them more or less likely to affect CYP3a? At this point, no data is available. Piperine itself may affect cyp3a enzymes. A 2002 report suggests that piperine inhibits CYP 3a4. [8] Thus, Volak’s study is even more interesting. Volak’s study used human subjects, a better predictor of what chemicals do in human bodies than in vitro or rat studies.

An earlier human trial published back in 2010 reported that curcumin affected the elimination of caffeine from the human body by modifying action of CYP1A2 activity (decreased by 28.6%) and CYP2A6 (increased by 50%) but did not provide data on any of the CYP3a enzymes that we are maybe concerned about. [9]

If curcumin does inhibit CYP 3a4 as the in vitro study suggested it will increase letrozole’s effects because it slows the drug’s elimination to whatever degree, the enzyme is inhibited.

If this warning from the pharmacists were true, that curcumin inhibited CYP3a4 we would expect curcumin to increase letrozole effectiveness. That would seem to be a moot point as we assume letrozole works over a wide range of serum concentration and it unlikely to change effect We have not seen any increase in side effects, specifically joint pain when taken with curcumin. If anything, we expect to see the opposite but that’s probably secondary to curcumin’s significant anti-inflammatory effect.

There is another 2015 paper, this one by Kim et al, testing curcumin in rats, which strongly suggests that curcumin does nothing to inhibit cyp3a activity. The authors write “…CUR[cumin] cannot function as an inhibitor for CYP3A-mediated drug metabolism in vivo.” [10]

Seah et al in another 2015 paper, not animal but employing lab assays, suggested that curcumin had no effect specifically on cyp3a4. They do mention though that omeprazole, the proton pump inhibitor Prilosec, does induce CYP3a4 enzymes. Inducing or increasing enzyme levels will break down letrozole faster so it will have less effect. [11]

If this concern is not making much sense to you, well, welcome to the club.

Letrozole levels vary a great deal between women, by a 1000% and this doesn’t seem to make much difference in drug action. It still seems to work. Taking curcumin may increase the levels of letrozole if it lowers enzyme action, but whether it does so isn’t clear. Letrozole isn’t toxic. The adverse effects it causes are due to it lowering estrogen levels and apparently almost any dose does this. We find no cases of women poisoned by too much of this drug.

On the other hand, there are a great many reasons why women with a breast cancer history and being treated with letrozole should take curcumin. Curcumin may increase bone density in women with osteopenia. [12] This could be a useful benefit because letrozole is associated with increased bone loss. Curcumin is one of a short list of chemicals known to target cancer stem cells and this may prove to be advantageous in the long term by reducing recurrence. [13] There is evidence that in some cancers curcumin in combination with letrozole has a synergistic anti-cancer action. [14] Curcumin inhibits the stimulation of estrogen sensitive breast cancer cells in experimental settings, something that we would very much like to happen in the human body as well. [15] Curcumin inhibits invasive capabilities of breast cancer cells. [16] In cancer cells that have learned become insensitive to the hormone blockade from tamoxifen, curcumin restores that drug sensitivity. [17]

In searching the peer reviewed medical literature, we have yet to come across any words of caution about combining letrozole with curcumin.

 
References:

1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2774495/

2. Murai K, Yamazaki H, Nakagawa K, Kawai R, Kamataki T. Deactivation of anti-cancer drug letrozole to a carbinol metabolite by polymorphic cytochrome P450 2A6 in human liver microsomes. Xenobiotica. 2009 Nov;39(11):795-802

3. Desta Z, Kreutz Y, Nguyen AT,et al. Plasma letrozole concentrations in postmenopausal women with breast cancer are associated with CYP2A6 genetic variants, body mass index, and age. Clin Pharmacol Ther. 2011 Nov;90(5):693-700. doi: 10.1038/c
lpt.2011.174.

4. Tanii H, Shitara Y, Horie T. Population pharmacokinetic analysis of letrozole in Japanese postmenopausal women. Eur J Clin Pharmacol. 2011 Oct;67(10):1017-25.

5. Lilja JJ, Kivistö KT, Neuvonen PJ. Duration of effect of grapefruit juice on the pharmacokinetics of the CYP3A4 substrate simvastatin. Clin Pharmacol Ther. 2000 Oct;68(4):384-90.

6. Hsieh YW, Huang CY, Yang SY, et al. Oral intake of curcumin markedly activated CYP 3A4: in vivo and ex-vivo studies. Sci Rep. 2014 Oct 10;4:6587.

7. Volak L1, Hanley MJ, Masse G, et al. Effect of a herbal extract containing curcumin and piperine on midazolam, flurbiprofen and paracetamol (acetaminophen) pharmacokinetics in healthy volunteers. Br J Clin Pharmacol. 2013 Feb;75(2):450-
62.

8. Bhardwaj RK, Glaeser H, Becquemont L, et al. Piperine, a major constituent of black pepper, inhibits human P-glycoprotein and CYP3A4. J Pharmacol Exp Ther. 2002 Aug;302(2):645-50.

9. Chen Y, Liu WH, Chen BL, et al. Plant polyphenol curcumin significantly affects CYP1A2 and CYP2A6 activity in healthy, male Chinese volunteers. Ann Pharmacother. 2010 Jun;44(6):1038-45.

10. Kim SB, Cho SS, Cho HJ, Yoon IS. Modulation of Hepatic Cytochrome P450 Enzymes by Curcumin and its Pharmacokinetic Consequences in Sprague-dawley Rats. Pharmacogn Mag. 2015 Oct;11(Suppl 4):S580-4. doi: 10.4103/0973-1296.172965.

11. Seah TC, Tay YL, Tan HK, et al. Determination of CYP3A4 Inducing Properties of Compounds Using a Laboratory-Developed Cell-Based Assay. Int J Toxicol. 2015 Sep-Oct;34(5):454-68.

12. Riva A, Togni S, Giacomelli L, et al. Effects of a curcumin-based supplementation in asymptomatic subjects with low bone density: a preliminary 24-week supplement study.
Eur Rev Med Pharmacol Sci. 2017 Apr;21(7):1684-1689.

13. Dandawate PR, Subramaniam D, Jensen RA, Anant S. Targeting cancer stem cells and signaling pathways by phytochemicals: Novel approach for breast cancer therapy. Semin Cancer Biol. 2016 Oct;40-41:192-208.

14. Liang YJ, Zhang HM, Wu YZ, Hao Q, Wang JD, Hu YL. [Inhibiting effect of letrozole combined with curcumin on xenografted endometrial carcinoma growth in nude mice]. Chin J Cancer. 2010 Jan;29(1):9-14. [Article in Chinese]

15. Ediriweera MK, Tennekoon KH, Samarakoon SR, Thabrew I, de Silva ED. Protective Effects of Six Selected Dietary Compounds against Leptin-Induced Proliferation of Oestrogen Receptor Positive (MCF-7) Breast Cancer Cells. Medicines (Basel). 2017 Jul 26;4(3). pii: E56.

16. Gallardo M, Calaf GM. Curcumin inhibits invasive capabilities through epithelial mesenchymal transition in breast cancer cell lines. Int J Oncol. 2016 Sep;49(3):1019-27.

17. Geng C, Li J, Ding F, et al. Curcumin suppresses 4-hydroxytamoxifen resistance in breast cancer cells by targeting SLUG/Hexokinase 2 pathway. Biochem Biophys Res Commun. 2016 Apr 22;473(1):147-153.

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