Prospective study of grapefruit intake and risk of breast cancer in postmenopausal women: the Multiethnic Cohort Study

Abstract

In vitro and in vivo studies have shown that cytochrome P450 3A4 (CYP3A4) is involved in the metabolism of oestrogens. There is evidence that grapefruit, an inhibitor of CYP3A4, increases plasma oestrogen concentrations. Since it is well established that oestrogen is associated with breast cancer risk, it is plausible that regular intake of grapefruit would increase a woman's risk of breast cancer. We investigated the association of grapefruit intake with breast cancer risk in the Hawaii -Los Angeles Multiethnic Cohort Study, a prospective cohort that includes over 50 000 postmenopausal women from five racial/ethnic groups. A total of 1657 incident breast cancer cases were available for analysis. Grapefruit intake was significantly associated with an increased risk of breast cancer (relative risk ¼ 1.30, 95% confidence interval 1.06 -1.58) for subjects in the highest category of intake, that is, one-quarter grapefruit or more per day, compared to non-consumers (P trend ¼ 0.015). An increased risk of similar magnitude was seen in users of oestrogen therapy, users of oestrogen þ progestin therapy, and among never users of hormone therapy. Grapefruit intake may increase the risk of breast cancer among postmenopausal women. The inhibitory effect of grapefruit juice 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 (Bailey et al, 1989(Bailey et al, , 1991. Grapefruit juice was given to subjects to mask the taste of ethanol. Subsequent investigations found that through the inhibition of the CYP3A4 enzyme system, primarily in the liver and small intestine (Guengerich, 1999;Veronese et al, 2003), grapefruit juice interacts with more than 60% of orally administered drugs leading to elevation of their serum concentrations (Maskalyk, 2002;Bailey and Dresser, 2004). Consumption of a single glass (six ounces) can produce the maximal acute pharmacokinetic effect (Edgar et al, 1992;Lundahl et al, 1995Lundahl et al, , 1997Dahan and Altman, 2004) with enhanced oral drug bioavailability occurring up to 24 h after juice consumption (Bailey and Dresser, 2004).Since 1989, the list of drug interactions with grapefruit juice has expanded to include oral 17b-oestradiol and progesterone (Guengerich, 1999;Maskalyk, 2002; Medical Letter, 2005). The US Food and Drug Administration (FDA) mandated labelling for hormone products for postmenopausal women now contains warnings that grapefruit juice may increase plasma concentrations of oestrogen (US Food and Drug Administration, 2006). Schubert et al (1994) found that grapefruit juice increased the area under the curve of oestradiol approximately 20% in ovariectomised women. Recently, we reported that endogenous oestrogen levels were about 30% higher in postmenopausal women in whom periods had stopped naturally and who were consuming the equivalent of 1 4 grapefruit or more per day (Monroe et al, 2007).It is well established that oestrogen is associated with breast cancer r...

Validating genetic risk associations for ovarian cancer through the international Ovarian Cancer Association Consortium

“…CYP3A4 encodes an enzyme critical for oxidation of oestrogens (Keshava et al, 2004) and its inhibition results in higher circulating oestrogen levels (Monroe et al, 2007). Given that exposure to oestrogen is associated with the risk of ovarian cancer (Beral et al, 2007) it is plausible that the CYP3A4 rs2740574 variant might influence ovarian cancer development through decreased expression of the gene and thus reduced metabolism of oestrogen.…”

Complementary and alternative medicines use by Scottish women with breast cancer. What, why and the potential for drug interactions?

“…The reasons for these differences are not clear but may reflect local culture, CAM practice and fads. Given the lack of evidence of benefit and the potential for harm with some therapies [41][42][43], this high level use of CAM may reflect a widespread patientperceived need for supportive therapy and help.…”

Intake of fruit, vegetables, and carotenoids in relation to risk of uterine leiomyomata

“…Other flavonoids (baicalein, galangin, hesperetin, naringenin, and quercetin) also appeared to exert their antiproliferative activity via some other mechanism (77). Epidemiologic studies investigating the relation of grapefruit or grapefruit juice intake to risk of other neoplasms, such as breast cancer, have been mixed, with some showing positive associations (78) and others finding inverse (79) or null (80,81) associations.…”