Se-enriched vegetables and cancer reduction

1. Se-enriched vegetables and cancer reduction P. D. WHANGER, PhD. Department of Environmental & Molecular Toxicology Oregon State University Corvallis, OR. 97330

3. Low Variable Adequate Accumulators SELENIUM LEVELS

4. Epidemiological Studies Shamberger and Frost Can. Med. Assoc. J. 104:82 (1969)—reported inverse relationship of selenium intake with cancer Shamberger and Willis CRC Crit. Rev. Clin. Lab. Sci. 2: 211 (1971)—more detailed study showing this same inverse relationship Schrauzer et al Bioinorganic Chem. 7:23 (1977)--27-country comparison revealed certain cancers varied inversely with estimated per capita selenium intake

5. Selenium and Tumors with Small Animals There have been over 100 experiments conducted (Combs and Gray, Pharmacol. Ther. 79: 179 (1998) • Two-thirds of animal studies showed • statistically significant reductions of tumors by selenium • One-half showed reductions of 50% or more by selenium

6. Effects of Selenium on Cancer in Humans Modified From J. Amer. Med. Assoc. 276: 1957 (1996)

7. GSSeH GSSG H2Se GSSeSG Acetylserine GSH -glutamyl Selenocystathionine Acetate SeO3 Selenocysteine ADP Succinyl homocysteine ATP glutamine SeO4 Proteins Se-methylselenocysteine Succinate Selenocystathionine Se-methylSeCysSe-oxide -glutamyl –Se methyl Selenocysteine Selenohomocysteine Dimethyldiselenide Se-methylselenomethionine adenosine Selenomethionine -keto--methyl selenobutyrate ATP Se-adenosyl selenocysteine ADP dimethylselenopropionate Se-adenosylselenomethionine dimethyl selenide

8. General body proteins SeO4 Selenoproteins (as selenocysteine) SeO3 selenomethionine GS-Se-SG selenocystathionine selenophosphate selenocysteine GS-SeH H2Se -keto--methyl selenobutyrate CH3SeH methyl seleno propionate (CH3)2Se Se-methyl selenocysteine (CH3)3Se+ -glutamyl-Se-methyl selenocysteine

9. Anticarcinogenic Efficacy of Different Selenium Compounds for Reduction of Mammary Tumors in Rats

10. Mammary Tumors in Rats Fed Various Diets Nutr. Cancer 17:279 (1992)

11. Effect of Selenium on the Incidence of Tumors in Rats Injected with Methylnitrosourea

12. Mammary Cancer Prevention in Rats Fed Different Sources of Selenium

13. Effect of Dietary Form of Selenium on Tissue Selenium Concentrations in Rats J. Agric Food Chem. 49: 2681 (2001)

14. Tissue Selenium Levels in Rats Fed Different Sources of Selenium Carcinogenesis 15: 573 (1994)

15. Mammary cancer prevention by selenium enriched garlic or selenium enriched yeast in the DMBA and MNU models

16. Percent Composition of Identified Selenium Species of Selenized Garlic and Yeast J. Agric Chemistry, 48:2065 (2000)

17. NH-CO-CH2-CH2-CH(NH2)-COOH | CH3-Se-CH2-CH-COOH (-glutamyl-Se-methylselenocysteine) CH3-Se-CH2-CH(NH2)-COOH (Se-methylselenocysteine) CH3-Se-CH2-CH2-CH(NH2)-COOH (Selenomethionine) Figure 6. Structures of -glutamyl-Se-methylselenocysteine, Se-methylselenocysteine, and selenomethionine. J. Agric. Food Chem., Vol: 48, No. 6, 2000

18. Percentages of Total Selenium as SeMCYS in Selenium Enriched Plants % Se as SeMCYS Plants Summarized in J. American College of Nutrition 21: 223 (2002)

19. Effect of Dietary Form of Selenium on Total Number of Aberrant Crypt Foci in Rats J. Agric Food Chem. 49: 2681 (2001)

20. Effect of Dietary Form and Amount of Selenium on Colon Tumors in Rats J. Nutr. 130:2384 (2000)

21. Wheat and Broccoli • High Selenium wheat reduced colon tumors in rats but selenomethionine was not very effective in this reduction. Biofactors 14: 191 (2001). • High selenium broccoli reduced colon tumors in rats, but will SEMCYS be effective (Finley, personal communication)

22. SELENOMETHIONINE • - Primary form of Se in enriched yeast, wheat, corn, rice and • soybeans • Se-METHYLSELENOCYSTEINE • - Primary form of Se in Astragalus, enriched garlic, broccoli (florets and sprouts), onions and ramps

23. Uptake of Selenium from Soil versus Leaves 400 300 Se in broccoli µg/gm 200 100 0 Addition to soil Sprayed on Leaves

24. Effects of Sticker on the Uptake of Selenium by Broccoli

37. Conclusions • Selenium enriched garlic, broccoli florets, onions and ramps significantly reduced mammary tumors in rats. • 2. Selenium enriched broccoli (florets and sprouts) and wheat reduced colon tumors in rats. • These selenium enriched vegetables did not result in excessive tissue accumulation of selenium and thus are safe for human consumption. • SeMCYS is the most effective selenocompound in plants for reduction of mammary tumors in rats. Methylselenol appears to be the specific selenocompound that is effective against mammary tumors.

40. Accumulation of Selenium in blood, kidney, and liver from rats fed a selenium-enriched diet

41. Control = basal diet SEL = selenate SeM = selenomethionine SeR = Se-enriched ramps Accumulation of Selenium in muscle and testes from rats fed a selenium-enriched diet Control SEL SeM SeR SeR+SeM

43. Schematic flow chart showing the main sites where selenobetaine, Se-methyselenocysteine, selenobetaine methyl ester, and dimethyl- selenoxide enter the selenium metabolic pathway. Selenium in Biology and Human Health, p 173, Springer Verlag, New York

44. Wheat and Broccoli • High selenium wheat reduced colon tumors

45. AcknowledgmentMy collegues: C. Ip (Roswell Park Cancer Institute, Buffalo, NY; C. Polan and G. Welbaum, Virginia Technical University; and P. Uden, University of Massachusetts.

46. Acknowledgment • We are grateful to Judy Butler and Yu Sun for doing the selenium analyses and the bioavailability study • Thanks to R. Hafez and M. Kotrebai for the selenium speciation. • Thanks to Wendy Werks, John Chandler; Johnny, Ruby, Harvey and Debbie Whanger; Jeannie, Keith, Zemry and Margaret Lou Crookshanks; Wayne and Beverly Hinkle; and Bill Definbaugh who worked on various aspects of this project.