N05010: Biochemical and molecular markers of functional selenium status in man

Study Duration: April 1998 to February 2002

Contractor: Rowett Research Institute

Foodstuffs in Great Britain contain less of a very minor component named selenium when compared with other parts of the world. Although the proportion of selenium in food is a less than one part in a million it is essential for normal health and wellbeing. For example, inadequate intake of selenium in China has been associated with a form of heart disease which can result in heart failure. Additionally, supplementation of cancer patients in the United States with selenium has resulted in decreased death rates and decreased incidence of lung, prostate and colon cancers when compared with rates in subjects consuming a placebo tablet. As well as the scientific evidence for the importance of small amounts of selenium in the diet research has also shown selenium’s involvement in several aspects of the chemical mechanisms which contribute to normal functioning of the human body. These so called 'metabolic' functions have associated selenium with thyroid hormone metabolism, reproduction, protection against damage caused by active oxygen from the air we breathe and also the control of the expression of genes. Selenium is involved in all these essential processes through proteins in the body that require the selenium for their structure or activity.

In the context of the above background it was important to investigate the relatively low selenium intake of the UK population. As well as being lower than in many other parts of the world, the selenium intake in the UK has also fallen by over 50% in the last 15 to 20 years. Thus the range of chemical reactions within the body that are dependent on selenium-containing proteins may be compromised in the UK population and thus lead to suboptimal and impaired health. The disorders such as heart disease and cancers that may be impacted on by lower selenium status can, however, take many years to develop. Thus 'markers' need to be determined to assess the health impact of changing selenium status to avoid waiting for beneficial or other effects on diseases. The objectives of the current research project were therefore to increase selenium intake of volunteers in a highly controlled manner and to determine the effect of this on measurements in blood samples which may be related to both selenium status and overall health. This project was run in parallel with another study at the University of Liverpool (N05012) that used a similar selenium supplementation protocol. Combination of the results of both studies is intended to give a more powerful insight into potential beneficial or other effects of selenium supplementation. The outcome of the research as well as giving information on the effects of selenium supplementation was intended to contribute to the debate as to whether selenium status should be increased in the UK in order to promote optimal health. Excessive amounts of selenium can be toxic and it is therefore important to have robust data that will contribute to the setting of selenium requirements and how these may be achieved by dietary means.

Sixty-nine healthy adult human volunteers (3 extra per group) were allocated to 3 groups, one of which took 50 micrograms selenium per day as sodium selenite. A second group consumed 100 micrograms selenium per day as sodium selenite and a third group, which acted as control, took a visually identical placebo. Over a period of 6 weeks blood samples were taken from the volunteers at regular intervals. The liquid and cell portions of the blood were separated and tests performed to determine the overall effects of selenium supplementation. These tests included measurements of different proteins that have selenium as an essential component for their activity and measurements that reflect the health effects of the selenium proteins on the body.

The supplementation trial was successfully completed with 69 volunteers participating giving 3 extra volunteers in each of the 3 groups. This was to allow for people who could not complete the trial due to illness or other circumstances. At the start each volunteer was given 7 extra tablets than needed for the period of the study and in all cases the extra tablets were returned at the end of the study. Thus it was assumed that all subjects had complied with the instructions to supplementation. This was confirmed by measurements of total blood plasma selenium which increased approximately 25% in the 50 micrograms selenium per day group and 35% in the 100 micrograms selenium per day group. In addition, the selenium-containing proteins in plasma also increased by approximately similar amounts. The greater increases caused by 100 micrograms selenium were very surprising, so much so, that American colleagues at the University of Nashville redesigned a supplementation trial they were carrying out in China to include higher doses of selenium. A major outcome of this study and the parallel study from Liverpool is that greater increases in selenium are required in the UK population to saturate selenium-containing protein levels than was previously thought. Determination of selenium-containing proteins in blood continues to be the best way of assessing the selenium status of the human population. We have developed methods for the determination of the genetic message for the selenoproteins in blood cells. These measurements are much less sensitive to selenium supplementation than the protein measurements. Therefore, although the genetic measurements provide no advantage over selenoproteins in terms of determining selenium intake they show great potential for identifying individuals within the population who may particularly benefit from selenium supplementation.

In addition to the above primary aims of the project we also discovered that 100 micrograms per day of selenium decreased plasma triglycerides, increased high-density lipoprotein cholesterol and stimulated lipoxygenase (an essential enzyme in the inflammatory response) in plasma and blood cells. All these changes could be argued as being beneficial and consistent with selenium contributing to long-term good health in the UK population. As part of the project we also investigated whether measurements of plasma isoprostanes would provide a measure of antioxidant potential. We showed that these measurements would be much too variable to be useful in any other selenium trials. (All these findings are considered in more detail in the technical report).

This work will be of particular importance in helping decisions to be made as to whether selenium intake within the UK is adequate. This conclusion is strengthened when the work is considered in conjunction with project N05012. It shows the agency that current selenium intakes within the UK are inadequate to allow the full (i.e. maximum) expression of selenium-containing proteins within the body. Doses of selenium (50 micrograms per day) which take total intake to that which occurred 15 to 20 years ago was still inadequate to maximise selenoprotein expression. Although diseases that are potentially associated with low selenium intake may take many years to develop the biochemical changes determined in this study that are

Villette S, Kyle JAM, Brown KA, Pickard K, Milne JS, Nicol F, Arthur JR, Hesketh JE. A novel single nucleotide polymorphism in the 3¿untranslated region of human glutathione peroxidase 4 influences lipoxygenase metabolism. Blood Cell, Molecules and Diseases 2002; 29(2):174-178.

Contact: Dr Alison Tedstone
Tel: 020 7276 8929
Email: alison.tedstone@foodstandards.gsi.gov.uk