Prostatic response to supranutritional selenium supplementation: comparison of the target tissue potency of selenomethionine vs. selenium-yeast on markers of prostatic homeostasis

Abstract

Prostate cancer is the product of dysregulated homeostasis within the aging prostate. Supplementation with selenium in the form of selenized yeast (Se-yeast) significantly reduced prostate cancer incidence in the Nutritional Prevention of Cancer Trial. Conversely, the Selenium and Vitamin E Cancer Prevention Trial (SELECT) showed no such cancer-protective advantage using selenomethionine (SeMet). The possibility that SeMet and Se-yeast are not equipotent in promoting homeostasis and cancer risk reduction in the aging prostate has not been adequately investigated; no direct comparison has ever been reported in man or animals. Here, we analyzed data on prostatic responses to SeMet or Se-yeast from a controlled feeding trial of 49 elderly beagle dogs-the only non-human species to frequently develop prostate cancer during aging-randomized to one of five groups: control; low-dose SeMet, low-dose Se-yeast (3 μg/kg); high-dose SeMet, high-dose Se-yeast (6 μg/kg). After seven months of supplementation, we found no significant selenium form-dependent differences in toenail or intraprostatic selenium concentration. Next, we determined whether SeMet or Se-yeast acts with different potency on six markers of prostatic homeostasis that likely contribute to prostate cancer risk reduction-intraprostatic dihydrotestosterone (DHT), testosterone (T), DHT:T, and epithelial cell DNA damage, proliferation, and apoptosis. By analyzing dogs supplemented with SeMet or Se-yeast that achieved equivalent intraprostatic selenium concentration after supplementation, we showed no significant differences in potency of either selenium form on any of the six parameters over three different ranges of target tissue selenium concentration. Our findings, which represent the first direct comparison of SeMet and Se-yeast on a suite of readouts in the aging prostate that reflect flux through multiple gene networks, do not further support the notion that the null results of SELECT are attributable to differences in prostatic consequences achievable through daily supplementation with SeMet, rather than Se-yeast.

Figure 1

Attempting to explain the disappointing results of selenomethionine supplementation in SELECT: Does selenium-yeast have superior activity in prostatic tissue? Strong prostate cancer risk reduction with selenized yeast (Se-yeast) was reported in men in the Nutritional Prevention of Cancer (NPC) Trial. In contrast, men in SELECT received no such cancer protective advantage from supplementation with selenomethionine (SeMet). In an attempt to explain these disparate results and the apparent superiority of Se-yeast, researchers are wondering whether these two forms of selenium are equally capable of promoting prostatic homeostasis and lowering cancer risk. In the randomized dietary supplementation paradigm in dogs reported here, Se-yeast was not superior to SeMet in boosting systemic or target tissue selenium concentrations; equal oral dosing with Se-yeast or SeMet yielded comparable post-supplementation selenium concentrations measured in toenails and within prostatic tissue (See Results section of this manuscript). Thus, the idea that form-dependent differences in resultant intraprostatic selenium concentration might explain the disappointing results of SELECT is not supported here. In this paper, we sought to validate an alternative explanation: Could the remarkable prostate cancer risk reduction seen in the NPC Trial with Se-yeast, but not seen with SeMet in SELECT, reflect that supplementation with Se-yeast works better within the prostate to promote homeostasis and reduce prostate cancer risk (Se-yeast depicted in this cartoon as stars throughout the prostate), whereas SeMet supplementation is less active within the prostate in terms of homeostasis and cancer risk reduction (SeMet depicted in this cartoon as biologically sequestered, possessing a limited working effect within the prostate)? The particular molecular target for selenium’s anticancer effect within the prostate has not been elucidated. Further, the effects of these two forms of selenium on this target may be dose-dependent. Conceding then that the optimal concentration within the prostate to activate the key molecular pathway is unknown, we probed the biological consequences of reaching three different ranges of intraprostatic selenium concentration. Specifically, we determined whether individuals receiving Se-yeast or SeMet that achieve a particular level of intraprostatic selenium post-supplementation would show significant differences in six measures of homeostasis within the prostate. The readouts we measured—DNA damage, cell proliferation, apoptosis, testosterone (T), dihydrotestosterone (DHT) and DHT:T—capture flux through multiple signaling pathways and reflect processes that likely influence cancer risk within the prostate. The cartoon predicts that when Se-yeast supplemented and SeMet supplemented individuals that reach equivalent intraprostatic selenium concentrations are compared, the prostates of individuals receiving Se-yeast will have significantly different readouts of DNA damage, proliferation, apoptosis, or hormonal milieu compared to SeMet supplemented prostates. Alternatively, if no differences are found in the readouts between the two forms across three different ranges of intraprostatic selenium concentration, these observations would lend no further support for the scenario set forth in the cartoon—that Se-yeast has superior activity in prostatic tissue (See text for Results and Discussion).

Figure 2

Form-dependent effects of selenium supplementation on selenium status as measured by toenail and intraprostatic selenium concentration. Each bar presents median ± inter-quartile range. Interquartile range indicates the difference between the first and third quartiles. P values represent Mann-Whitney U test comparing low-dose selenomethionine (SeMet) with low-dose selenized yeast (Se-yeast), and comparing high-dose SeMet with high-dose Se-yeast. The dashed line indicates the median value of toenail or intraprostatic selenium concentration in unsupplemented dogs, which differs significantly from the median toenail and intraprostatic selenium concentration of each of the four selenium supplemented groups (Mann-Whitney U Test, p < 0.05). ppm: parts per million.

Figure 3

Correlation between toenail and intraprostatic selenium concentration after seven months of supplementation with selenomethionine (SeMet) or selenized yeast (Se-yeast).