Grapefruit, Hormones, and Postmenopausal Breast Cancer Risk

Institution: University of Southern California
Investigator(s): Kristine Monroe, Ph.D. -
Award Cycle: 2008 (Cycle 14) Grant #: 14IB-0019 Award: $243,717
Award Type: IDEA
Research Priorities
Etiology and Prevention>Etiology: the role of environment and lifestyle

Initial Award Abstract (2008)

Grapefruit juice is known to interact with many prescription drugs. The inhibitory effect of grapefruit on the intestinal cytochrome P450 3A4 (CYP3A4) system was discovered accidentally in 1989 during a study designed to test the effect of ethanol on a calcium-channel blocker. Grapefruit juice was given to study subjects to mask the taste of the alcohol. Subsequent investigations found that grapefruit juice interacts with more than 60% of orally administered drugs leading to elevation of their serum concentrations. Consumption of a single glass can produce the maximal acute effect with enhanced drug bioavailability occurring up to 24 hours after juice consumption. Importantly, the magnitude of interaction between drugs and grapefruit juice is markedly variable among individuals.

Since 1989, the list of drug interactions with grapefruit juice has expanded to include estrogen and progesterone. In fact, U.S. FDA mandated labeling for hormone products for postmenopausal women now contains a warning that grapefruit juice may increase blood concentrations of estrogen. In addition to its effect on administered hormones, scientists have shown that levels of estrogen produced naturally by the body are also elevated in postmenopausal women who consume very modest amounts of grapefruit. Recently, we reported a 30% increased risk of breast cancer among postmenopausal women who consume the equivalent of ˝ grapefruit or more every other day.

Researchers have identified furanocoumarins as the active ingredient in grapefruit responsible for enhancing the systemic exposure of CYP3A4 substrates. Furanocoumarins are a class of organic chemical compounds produced by a variety of plants and occur at higher concentrations than aflatoxins. Many furanocoumarins are toxic and are produced by plants as a defense mechanism against various types of predators ranging from insects to mammals.

We will characterize the acute and chronic effects of consumption of different grapefruit products on hormone levels using a dietary intervention study. Under strictly controlled conditions, we will measure serum hormones in healthy, postmenopausal female volunteers, both before and after administration of grapefruit (whole fruit and juice).

We will recruit approximately 60 postmenopausal women, all of whom will meet specific recruitment criteria. From each volunteer we will collect two baseline blood samples before grapefruit administration. Participants will then be randomly assigned to one of the following groups: (1) ˝ of whole grapefruit; (2) one glass of fresh processed juice “not from concentrate” (refrigerated section of grocery store); or (3) one glass of juice from concentrate. From blood samples taken over several weeks we will measure estrone (E1), estradiol (E2), the conjugate E1 sulphate, and sex-hormone-binding globulin (SHBG).

If the dietary intervention study proposed by this grant application produces results supporting the grapefruit-estrogen hypothesis, it has the potential of having a significant clinical impact of reducing breast cancer incidence.

Final Report (2010)

Based upon extensive pharmacological research, scientists have established that grapefruit contains natural substances which can inhibit the activity of an enzyme system responsible for the metabolism of estrogen. If the normal metabolism process is affected, the result may be an increase in estrogen circulating in a woman’s body. Since estrogen is a well established risk factor for breast cancer, it is biologically plausible that regular intake of grapefruit can increase a woman’s risk of breast cancer.

The aim of the project was to characterize the acute and chronic effects of consumption of different grapefruit products on endogenous hormone levels. Under strictly controlled conditions, we planned to measure serum hormones in 60 healthy, postmenopausal female volunteers, both before and after administration of grapefruit. Initially, recruitment was difficult as we couldn't find volunteers among friends, colleagues, and neighbors who met our strict study criteria. We, therefore, applied to partner with the Love/Avon Army of Women (AOW) foundation to use their database of volunteers for recruitment. A recruitment email was sent to ~277,000 women beginning the week of May 4, 2009 and by May 7, 2009 we had 200 study volunteers.

The aims of the project have been met. We have 62 study participants who successfully completed the 6-week study. Subjects were randomly assigned to one of four grapefruit product groups: (1) one 6-oz glass of fresh processed juice "Not from Concentrate;" (2) one 6-oz glass of juice from concentrate; (3) 1/2 fresh grapefruit; (4) one 12-oz can of grapefruit soda. After an initial 3-week washout period, subjects consumed their assigned grapefruit product every day for 14 days. This was followed by a 1-week washout period in which subjects discontinued grapefruit intake. We collected 8 blood specimens during the 6-week study: 2 at baseline, 4 during the first 7 days of grapefruit intake, 1 at 14 days of intake, and 1 at the end of the final washout. We measured estrone (E1), estradiol (E2), estrone sulphate (E1S), and sex hormone binding globulin (SHBG) in all blood specimens for all 62 participants. The correlation between blinded duplicate samples was excellent.

We found considerable inter-individual variability between baseline hormone values and hormone values while consuming grapefruit. In comparing results for E1S, the change in hormone values after 24 hours of grapefruit intake ranges from -23% to +74% among study participants. In comparing results for E2, the change in hormone values after 24 hours of grapefruit intake ranges from -30% to +18% among study participants. We still have many analyses to do: to stratify by grapefruit product and to include adjustment factors in the model.

The funding for this project received partial support from the California Community Foundation.