[CANCER RESEARCH 44, 2803-2806, July 1984] Effect of an Inorganic and Organic Form of Dietary Selenium on the Promotional Stage of Mammary Carcinogenesis in the Rat1 Henry J. Thompson,2 L. David Meeker, and Stephen Kokoska Departments of Animal and Nutritional Sciences [H. J. T.] and Mathematics [L. D. M., S. K.], University of New Hampshire, Durham, New Hampshire 03824 ABSTRACT The relative effectiveness of either sodium selenite or seleno- methionine in the inhibition of mammary carcinogenesis was studied in virgin female Sprague-Dawley rats. In one experiment, rats were given 50 mg of 1-methyl-1-nitrosourea per kg of body weight s.c. at 50 days of age. Beginning 7 days post-1 -methyl- 1-nitrosourea, they were assigned to a basal diet containing 0.1 ppm of selenium or basal diet supplemented to contain either 4, 5, or 6 ppm of selenium as sodium selenite or 5 or 6 ppm of selenium as selenomethionine. Selenium treatment was contin ued until termination of the study 135 days after 1-methyl-1- nitrosourea treatment. Sodium selenite, at the 5-ppm level, was the most effective chemopreventive agent. The highest level of selenomethionine (6 ppm) caused grossly apparent liver damage. No liver damage was noted in sodium selenite-treated rats. In a second experiment, rats were given 5 mg of 7,12-dimethyl- benz(a)anthracene at 50 days of age. Beginning 7 days after 7,12-dimethylbenz(a)anthracene treatment, rats were assigned randomly to the control group or to one of two selenium treat ment groups receiving either 3.4 ppm of selenium as sodium selenite or 3.4 ppm as selenomethionine in their drinking water. Selenium supplementation was continued throughout the study until its termination at 111 days postcarcinogen. Sodium selenite significantly reduced cancer incidence and the average number of cancers per rat. Treatment with selenomethionine was less effective and caused severe liver damage. Although both sodium selenite and selenomethionine can inhibit some aspect of the postinitiation stage(s) of mammary carcinogenesis, selenium pro vided as sodium selenite was the more effective and less toxic of the two chemicals. Increasing the dose of sodium selenite above 5 ppm did not enhance the inhibitory activity of selenium. INTRODUCTION Experimental evidence continues to accumulate supporting the hypothesis that selenium can inhibit one or more stages of the carcinogenic process in several target tissues, including the mammary gland (7, 13, 16, 20, 25, 28). The anticancer effect(s) of selenium has been found to be exerted against chemically induced cancers in the rat and mouse and against virally induced lesions in the mouse (7, 13, 20, 25). In certain mouse tumor systems, selenium has been reported to exert its greatest pro tective effect on early stages of the disease process, and contin uous selenium treatment has been observed to be necessary to sustain anticancer activity (13, 14). At the levels of dietary 1 Supported by USPHS Grant CA 28109 from the National Cancer Institute. Scientific Contribution 1228 from the New Hampshire Agricultural Experiment Station. 2 To whom requests for reprints should be addressed, at the Human Nutrition Center, Colovos Road, University of New Hampshire, Durham, NH 03824. Received March 10,1983; accepted March 29, 1984. selenium reported to inhibit mammary carcinogenesis, no alter ations in the circulating levels of estrogen and progesterone have been observed, and inhibition of mammary carcinogenesis by selenium has been reported in the presence or absence of the ovaries (7). These data taken collectively have resulted in con siderable interest in the potential of selenium as an anticarcino- gen. Very little work has been conducted to determine the effect(s) of feeding organic forms of selenium on chemically induced neoplasia. That which has been reported has been done primarily with high-selenium yeast in which the forms in which selenium exists are not defined completely (20). It was therefore decided to determine the anticarcinogenic efficacy of selenomethionine in the MNU3- and DMBA-induced mammary carcinogenesis sys tems. This choice was made since selenomethionine has been reported to be one of the predominant organic forms of selenium in cereals, vegetables, and grains and, hence, is a form of selenium that is ingested commonly (10, 31). Furthermore, it has been shown that the selenium in selenite and selenomethionine is absorbed to a similar degree and enters the same metabolic pool in the body (24). In addition, despite the fact that the forni of selenium at the active site of glutathione peroxidase appears to be 1-selenocysteine, sodium selenite and selenomethionine have about equal potency for maintaining and restoring glutathi one peroxidase in rats, and equal selenium retention in the body results from feeding either compound (2, 15, 19). It was antici pated that this study would also provide mechanistic insights into the mode of action of selenium as an antipromoter, since the initial steps in the metabolism of the 2 compounds differ. MATERIALS AND METHODS All experiments were conducted with virgin female Sprague-Dawley rats obtained from Taconic Farms, Inc., Germantown, NY. Animals were fed a torula yeast diet, the composition of which is shown in Table 1. A 20% fat diet was selected because such high fat diets have been reported to promote mammary carcinogenesis (3). Given that the antipromotional activity of selenium was being investigated, diet conditions were chosen to amplify the promotion phase of carcinogenesis. The diet was also formulated to contain 0.5% DL-methionine, the most limiting amino acid in torula yeast (5). It is important to note that this is far below the 2.0% level of dietary methionine known to be toxic to the rat (6, 17). We also felt it to be extremely important to provide sulfur-containing amino acids sufficiently above requirement levels so that the selenomethionine would be available for metabolic utilization as selenium and would not be used to satisfy the requirement for methionine (22). Furthermore, increasing the concentration of dietary methionine has been reported to reduce selenium toxicity (11). Dt-Selenomethionine was used since it has been reported to be as equally well utilized as sodium selenite for regeneration of glutathione peroxidase activity in the rat (29). Experiment 1. The purpose of this study was to confirm and extend 3 The abbreviations used are: MNU, 1-methyl-1-nitrosourea; DMBA, 7,12-di- methylbenz(a)anthracene. JULY 1984 2803 Research. on January 20, 2016. © 1984 American Association for Cancer cancerres.aacrjournals.org Downloaded from