Japanese Journal of Clinical Oncology 32:296-300 (2002)
© 2002 Foundation for Promotion of Cancer Research
Is Daidzein Non-metabolizer a High Risk for Prostate Cancer? A Case-controlled Study of Serum Soybean Isoflavone Concentration
1 Department of Urology, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Ibaraki, 2 Department of Urology, Faculty of Medicine, University of Kyushu, Fukuoka, 3 Department of Urology, Nara Medical School, Kashihara, Nara and Departments of 4 Urology and 5 Epidemiology, Sapporo Medical University School of Medicine, Sapporo, Japan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONAcknowledgmentREFERENCES |
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Background: It has been postulated that soybean isoflavones act as inhibitory factors in prostate cancer. However, to date there have been no case-controlled clinical studies carried out to compare the circulating concentrations of isoflavones in prostate cancer patients and control subjects.
Methods: The serum levels of genistein, daidzein and equol were determined and compared in 253 experimental subjects (141 prostate cancer patients and 112 cancer-free controls).
Results: The serum concentrations of isoflavones were compared in hospitalized and non-hospitalized subjects and for both the prostate cancer patients and the controls the concentrations were lower in the hospitalized subjects. The serum concentrations of genistein and daidzein were compared in subjects <70 years of age and subjects 
70 years old and the levels were significantly lower in the younger group. Contrary to our expectation, comparison of the patient group and the control group revealed the serum concentrations of isoflavones to be higher in the patient group. Daidzein non-metabolizers were compared in the hospitalized experimental subjects of the patient group and the control group and they were significantly more common in the patient group. The poorly differentiated cancer patient group included a significantly lower percentage of daidzein metabolizers.
Conclusions: The above findings revealed that equol itself or some unknown factor regulating the metabolism of daidzein is deeply involved in the biology of prostate cancer. Future studies are urgently needed to compare the incidence of daidzein metabolizers among various countries.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONAcknowledgmentREFERENCES |
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Epidemiological studies have shown that the incidences of malignancies such as breast cancer, prostate cancer and colon cancer, which are common in the populations of Western Europe and the USA, are low in Asian populations, who consume large amounts of soybean-derived foods (1). It has been argued for many years that these lower incidences are due to the inhibitory effects on carcinogenesis of isoflavones contained in soybeans (2,3). In recent years, various in vitro and in vivo experimental studies have demonstrated that these isoflavones indeed inhibit prostate cancer (4,5). However, there remains a large gap in the interpretation of the epidemiological data compiled to date. That is, it is true that the incidence of prostate cancer in Europe and the USA is high, and the diets of their populations include few foods that contain isoflavones (6). However, the difference in the prostate cancer incidences between Westerners and Asians cannot be logically explained merely on the basis of these facts. It is at least necessary to compare the consumption of isoflavone-containing foods by prostate cancer patients and control subjects within the populations of each geographical area and also compare the serum isoflavone concentrations between those two groups. In this paper, we report a case-controlled study of prostate cancer in which the serum concentrations of isoflavones were compared in prostate cancer patients and control subjects.
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SUBJECTS AND METHODS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONAcknowledgmentREFERENCES |
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The experimental subjects had been examined at the collaborating urology departments (University of Tsukuba, University of Kyushu, Nara Medical School and Sapporo Medical University School of Medicine). This study was approved by the Institutional Review Board of each University and informed consent was obtained from all subjects. Subjects were divided into two groups: one group consisted of patients with histologically proven prostate cancer, and the second group consisted of age- and geographically matched cancer-free and urological disease-free male subjects who served as the controls. The prostate cancer patients had to have been diagnosed for the first time no longer than 3 years earlier, but no conditions were attached regarding the content of their therapy or their disease stage. For both inpatients and outpatients blood samples were drawn before breakfast and the separated sera were stored at –10°C or lower. The sample size of the cases and controls for detecting serum isoflavone concentration was not calculated, but it was regulated by the feasibility for each investigator.
The determinations of the concentrations of isoflavones in the serum samples were performed by reversed-phase high-performance liquid chromatography–multiple reaction ion monitoring mass spectrometry (HPLC–MS (7). The isoflavones assayed were genistein, daidzein and equol. Equol is a metabolite of daidzein and it is known that some humans are able to metabolize daidzein into equol whereas others are not (8,9). Therefore, in addition to comparing the serum concentrations of these three isoflavones in the two experimental subject groups, we also carried out a comparison of the subjects on the basis of their being metabolizers or non-metabolizers. Non-metabolizers were defined as having a serum equol concentration below the limit of detection of the present assay system, i.e. 0.5 ng/ml. Statistical analyses were performed using Wilcoxon’s test (non-parametric), the Kruskal–Wallis test and the chi-squared test. A P value of <0.05 was defined as representing a statistically significant difference.
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RESULTS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONAcknowledgmentREFERENCES |
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Samples were assayed for a total of 253 experimental subjects, consisting of 141 cancer patients (66 inpatients and 75 outpatients) and 112 control subjects (103 inpatients and nine outpatients). There was no significant institutional difference in the comparison of serum isoflavone concentration. The mean age of the cases and controls was 69.2 years (SD 7.3 years) and 67.0 years (SD 9.2 years), respectively. Tables 1, 2, 3 present comparisons of the data for the serum concentrations of the isoflavones between the patient group and the control group on the basis of inpatients, outpatients and overall. The data for equol are for the positive subjects (i.e. daidzein metabolizers) only. Contrary to expectation, the concentration of each of the three isoflavones was higher in the patient group than in the control group. Comparison of the inpatients and outpatients revealed that the outpatients showed higher serum concentrations of genistein and daidzein in both the patient group and the control group, i.e. 80.1 vs 119.6 ng/ml of genistein for inpatients and outpatients, respectively (P = 0.04) and 22.7 ng/ml vs 54.5 ng/ml of daidzein for inpatients and outpatients, respectively (P = 0.0004). Table 4 compares the ratio of daidzein metabolizers and non-metabolizers. The data showed that, for the hospitalized experimental subjects, the percentage of metabolizers was significantly smaller in the patient group than in the control group (30.3% vs 49.5%; P = 0.013), although when the percentages of daidzein metabolizers in the total experimental subjects in each of the patient and control groups were compared, the P value increased to the not significant range (39.7% vs 50.0%; P = 0.102).
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Table 5 presents a comparison of the serum genistein and daidzein concentrations in the experimental subjects stratified by age, i.e. <70 years of age versus
70 years. Those isoflavone concentrations in the younger stratum of the experimental group (consisting of both patient group and control group subjects) showed a tendency to be lower than the levels in the older stratum. Especially the concentration of daidzein of the younger stratum of the patient group was significantly lower than the level in the older stratum of the patient group (31.4 vs 49.3 ng/ml; P = 0.034). In Tables 6, 7, 8, the experimental subjects are classified on the basis of their PSA value, disease stage and degree of histological atypia at the time of diagnosis and they are then compared in terms of the concentration of each isoflavone and the ability to metabolize daidzein into equol. Interestingly, the data show that the percentage of daidzein metabolizer was significantly lower in the histologically poorly differentiated group compared with the other atypia ratings. We compared the findings as a function of the treatment of the patients at the time of serum sampling, but no significant differences were found among no therapy, surgery (i.e. total prostatectomy) and endocrine therapy. In addition, we compared the serum genistein and daidzein concentrations as a function of daidzein metabolizer and non-metabolizer, but no significant differences were found between them.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONAcknowledgmentREFERENCES |
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The one-point serum sampling that we performed in our present study does not represent the general trend of the serum isoflavone concentration, especially not at the time of diagnosis of prostate cancer in the case group. However, the following are reasonably concluded. (i) Comparison of the serum concentrations of isoflavones in hospitalized and non-hospitalized subjects revealed that, for both the prostate cancer patients and the controls, the concentrations were lower in the hospitalized subjects. This finding suggests the possibility that the meals provided in the hospitals contain less soybean isoflavones than the regular diets consumed by the experimental subjects at their homes. (ii) The serum concentrations of daidzein differed significantly between the patients who were <70 years of age and those who were
70 years. Is this due to a change in dietary habits as people age in Japan? Or does it reflect a general change in the eating habits of Japanese of different generations? This is an interesting finding that warrants further study, because in Japan as well as among other Asian people, the incidence and mortality rates of prostate cancer are rapidly increasing (10). (iii) The serum concentrations of isoflavones were higher in the patient group than in the controls. Generally, serum isoflavones may have suppressive effects on the prostate cancer carcinogenesis and some papers have reported that a low dietary intake of isoflavones may contribute to a high incidence of prostate cancer (1–5). Hence our result is difficult to explain, but it may be related to recent findings regarding dietary habits, which indicate that prostate cancer patients increase their consumption of soybean-based foods after having been diagnosed with this malignancy. Future epidemiological studies will probably be able to shed further light on the above three findings. (iv) Daidzein metabolizers significantly decreased in the hospitalized experimental subjects of the patient group than in the hospitalized control group subjects. The significance of the ability to metabolize daidzein remains unclear. In Japanese women, the percentage of daidzein metabolizers is about 50% (11), whereas it has been reported to be about 35% in American men (12). All reported data have been for healthy subjects and to date there have been no reports concerning this parameter in prostate cancer patients. As for breast cancer, Ingram et al. (13) pointed out the significance of equol in reducing the risk of the disease, but they did not recognize the metabolizers/non-metabolizers of daidzein. In the present study, the percentage of metabolizers was significantly lower in the prostate cancer patients compared with the control subjects among hospitalized subjects who were considered to have the same diets during their hospital stays. This finding is interesting in view of the fact that equol, a metabolite of daidzein, is considered to be the most potent phytoestrogen among the soybean isoflavones (12). (v) The subgroup consisting of poorly differentiated cancer patients included a significantly lower percentage of daidzein metabolizers. In prostate cancer, the incidence of latent cancer is the same in all geographical areas in the world but the incidence of clinically diagnosed cancer shows great differences (14). This means that geographical differences arise during the stage of cancer progression and that the environment and diet are causative factors of the large geographical differences observed in the incidence of prostate cancer (15). In addition, it is thought that the direction of progression of the prostate cancer is from a highly differentiated cancer to a poorly differentiated cancer (16). In this context, the finding that the percentage of daidzein metabolizers was lower in the poorly differentiated prostate cancer patients suggests that equol might be playing an inhibitory role in the progression of prostate cancer. Fritz et al. reported that dietary genistein downregulates sex hormone receptor expression (17). We analyzed our data in relation to the type of treatment in the case group. However, there was no significant difference in the serum isoflavone concentration and daidzein metabolizer/non-metabolizer between patients with and without hormonal treatment.
The five findings discussed above are novel results never before reported with respect to the prostate cancer. This study yielded results which indicate that there is some sort of correlation between daidzein non-metabolizers and prostate cancer patients. The mechanisms of metabolism of daidzein remain unclear, but it has been reported that the intestinal bacterial flora is involved (18–20). Urgent studies need to be carried out to identify the bacterial groups involved and their growth requirements. In addition, it will be necessary to investigate the biological activity of equol in the inhibition of the carcinogenesis and progression of prostate cancer. Finally, it will be especially important to carry out an international comparison of the incidence of daidzein non-metabolizers and use those findings to attempt to elucidate the reasons for geographical differences in the incidence of prostate cancer.
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Acknowledgment |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONAcknowledgmentREFERENCES |
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This study was supported by a Grant-in-Aid for Scientific Research on Priority Areas; Cancer A03-720, Ministry of Education, Science, Sports and Culture, Japan.
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FOOTNOTES |
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+ For reprints and all correspondence: Hideyuki Akaza, Department of Urology, Institute of Clinical Medicine, University of Tsukuba, 1–1–1, Tennoudai, Tsukuba, Ibaraki, Japan. E-mail: akazah@md.tsukuba.ac.jp
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Received February 27, 2002; accepted May 14, 2002
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