These data represent a first examination of methyl selenocysteine (MSC) as administered to humans. There was no evidence of toxicity.
A substantial body of preclinical data indicates that selenium is important to protection against oxidative stress.14-21, 29, 32-34
Selenium deficiency is also associated with increased cancer risk;22-23, 35-36
whether supplementation of those who are selenium deficient might decrease vulnerability to oxidative stress is not well known; whether an agent that protects against oxidative stress would protect against carcinogenesis is not known. SELECT suggests that, among men who are selenium replete, selenium offers no such protection 12
Preclinical toxicology studies of MSC—long and short term—have been performed by the National Cancer Institute, through the Division of Cancer Prevention (DCP) Rapid Access to Preventive Intervention Development (RAPID) Program.37-38
The studies, conducted on rats and dogs, showed dogs to be the most sensitive species. The no adverse effect level after 28 and after 90 days of dosing in dogs based on histopathologic and hematologic findings was 0.3 mg MSC/kg-bw/day (0.13 mg Se/kg-bw/day); an equivalent value extrapolated to humans for a 70 kg person is 21,000 mcg MSC/day, or 9,100 mcg Se/day. Single, bolus doses of MSC were largely converted to excretory metabolites in breath and urine; even chronic, high doses of MSC may lead to very modest tissue accumulations of Se.34,36
NCI, DCP-sponsored genotoxicity studies with MSC were negative.38
Selenium is a natural dietary constituent, so that varying baseline concentrations were present in the plasma of subjects. In order to accurately gauge the pharmacokinetic parameters, we took these baseline values into consideration. It will be important to take a similar approach in future investigations. This factor, along with the single-dose nature of the study design and the relatively low doses investigated, limits the conclusions that can be drawn. However, these are inherent to the study of a first-time-in-human chemopreventive agent, and represent safeguards purposefully built into the design of the study. These factors notwithstanding, this study provides some important initial findings.
There was little difference in the pharmacokinetic parameters of the 400 and 800 mcg doses. The values observed were clearly above those observed in the placebo cohort. There are important differences when the 1200 mcg cohort is compared to the other two MSC cohorts. Together, they are consistent with the possibility of saturation in metabolism and/or excretion. This is supported by the finding of a shorter time of maximum concentration in the 1200 mcg cohort; that time trends downward as dose increases, and it is coupled with a delay in the peak urinary excretion time. The time of maximum concentration for the 1200 mcg dose of MSC appears to be shorter than for SeMet,23
although it needs to be evaluated in a direct pharmacokinetic comparison.
The Cmax and AUC for the 1200 mcg cohort are proportionally greater than the respective values for the 800 mcg cohort. There are several potential implications to this for design of multi-dose studies. Specifically, given the possibility for accumulation, multi-dose studies should not exceed the 1200 mcg dose until additional information becomes available. This value is approximately one eighth the value extrapolated from tests on the most sensitive non-human mammal. Second, this finding is not consistent with MSC moving into a large storage reservoir. This contrasts sharply with SeMet; as SeMet accumulates within essentially all proteins, the body provides a vast storage reservoir. This may explain why selenium concentration increases so directly with multiple doses of SeMet.
Preclinical research indicates MSC provides a more efficient route than SeMet to the formation of methyl selenol, a metabolite that may impart a chemopreventive effect.24-25, 35, 39
It will be important in the future to accurately speciate methyl selenol and related plasma selenium metabolites. This represents an evolving field, and work is actively progressing.30, 36
Once the technology is in place, it can be applied to stored samples. The major downstream protein products of selenium supplementation, selenoprotein P and glutathione peroxidase, which are the key and most abundant selenoproteins in plasma, can be readily evaluated. Indeed, in that the function of selenium resides primarily in the proteins to which it gives rise, a focus on these key selenoproteins may be highly informative.27
Analysis of these is under way.
Work by Ip and others suggests that methyl selenocysteine (MSC) might prove more physiologically relevant than SeMet or S. It has efficacy in preclinical prevention models, and it may therefore represent an important potential chemopreventive agent, if only for those who are selenium deficient.14, 21, 24-26, 28, 39
MSC is a close derivative of selenocysteine (SeCys). SeCys is referred to in the literature as the physiologic form of selenium30
; it is necessary for the synthesis of selenoproteins, and these proteins appear to be responsible for selenium's physiological effects in humans.
The SELECT results leave little room for hope that selenium as SeMet will prove of chemopreventive efficacy for selenium-replete subjects 12
. Whether supplementation will be of benefit to those who are not selenium replete is less clear. Moreover, the form of selenium administered in SELECT, SeMet, may have important limitations. It is important not to extrapolate without adequate evidence the findings of SELECT (i.e. SeMet) to all Se compounds and all populations. Preclinical findings, as well as findings in humans now available through the current study, demonstrate in a corroborative fashion that there may be important differences between MSC and SeMet.21, 24-27
Taken together, prior studies and findings from the current study support continued investigation of the role of MSC in cancer risk among humans.