Xenobiotic Metabolism: Nutritional Effects - American Chemical Society

9 Antioxidants and Malonaldehyde in Cancer

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RAYMOND J. SHAMBERGER Department of Biochemistry, Cleveland Clinic Foundation, Cleveland, OH 44106 Selenium, vitamin C, vitamin E, BHT (butylated hydroxytoluene), BHA (butylated hydroxyanisole) and several compounds with antioxidant properties have been shown to inhibit chemically induced carcinogenesis and mutagenesis. Of the natural antioxidants selenium has been shown to be the most effective against chemically induced carcinogenesis in a large number of animal test systems. In two epidemiological studies selenium in blood bank and forage crop selenium has been inversely correlated with human cancer mortality. Large amounts of vitamins E and C also inhibit chemically induced carcinogenesis in some test systems. Antioxidants may interfere with the formation of a product of peroxidative fat metabolism, malonaldehyde which has been shown to be mutagenic and carcinogenic. In addition, antioxidants may also reduce the interaction of DNA with mutagens and carcinogens from pyrolyzed food. The objective of this report is to summarize some of the evidence relating antoxidants, dietary fat, malonaldehyde and pyrolyzed food. SELENIUM Even though selenium itself is not an antioxidant, selenium is an important cofactor for the enzyme, glutathione peroxidase, which has been shown to break down hydrogen peroxide (1_) as well as organic hydroperoxides {2). The reactions may well be important in removing peroxides which might interact with and damage DNA. 2GSH + H202

->

GSSG + 2H20

(1)

2GSH + R00H

->

GSSG + ROH

(2)

0097-6156/ 85/0277-0111$06.00/0 © 1985 American Chemical Society

Finley and Schwass; Xenobiotic Metabolism: Nutritional Effects ACS Symposium Series; American Chemical Society: Washington, DC, 1985.


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XENOBIOTIC M E T A B O L I S M : NUTRITIONAL EFFECTS

Selenium has been shown to be an unusually important dietary chemopreventative. In general, the dietary chemopreventative e f f e c t s have been demonstrated between 0.5 and 1.0 ppm. However, most animals have a dietary requirement of 0.1 to 0.2 ppm of selenium. The dietary requirement seems to be lower than the amount needed for the optimal chemopreventative effect and therefore may not be related to a minimal n u t r i t i o n a l requirement. On the other hand, one could also postulate that cancer i s a n u t r i t i o n a l l y related disease and that the real requirement i s around 0.5 ppm. In f i v e of s i x nondietary tumor-promotion experiments, sodium selenide s i g n i f i c a n t l y reduced the number of mice with tumors i n duced by 7,12-dimethyl-benzanthracene (DMBA)-croton o i l ( 1 ) . In these experiments, sodium selenide was applied concomitantly along with croton o i l to female Swiss albino mice i n i t i a t e d with DMBA. Riley has also observed a reduction in DMBA-phorbol ester c a r c i n o genesis by sodium selenide ( 2 ) . The effect of selenium-deficient and selenium-adequate diets on DMBA-croton o i l and benzopyrene skin carcinogenesis has also been studied. Supplemental dietary selenium i n h i b i t e d both types of carcinogenesis. Dietary selenium has also reduced carcinogen induced l i v e r carcinogenesis. Clayton and Baumann have reported that the i n c l u sion of 5 ppm of dietary selenium reduced the incidence of l i v e r tumors in rats induced by 3-methyl-4-dimethylaminoazobenzene (DAB) {3). S i m i l a r results were observed by G r i f f i n and Jacobs ( 4 J . Dzhioev has observed a marked reduction of l i v e r tumors induced by diethylnitrosamine (DEN) in the animals fed selenium diets ( 5 ) . Marked reduction of l i v e r tumors induced by acetyaminoflourene have been observed in rats fed dietary selenium {6) or given selenium in the drinking water {]_). Dietary selenium has also been shown to reduce the development of L-azaserine-induced preneoplastic abnormal acinar c e l l modules in male Wistar rats (8), the formation of a f l a t o x i n B induced gamma-glutamyltransferase~[GGTP) p o s i t i v e f o c i i n rat l i v e r (9) and the formation of GGTP p o s i t i v e f o c i induced by DEN (10). Fven though dietary selenium has an effect on skin and l i v e r carcinogenesis, even greater dietary effects have been observed on carcinogen and v i r a l l y induced breast cancer and carcinogen-induced colon cancer in animals. It may be of interest that breast and colon cancer have been shown to be enhanced by dietary fat in both man and animals. Perhaps t h i s enhancement i s due to an increase of fat peroxidation which can be reduced by antioxidants. Schrauzer and Ishmael have fed 2 ppm of selenium in the form of SeO^ in the drinking water for 15 months to v i r g i n C3H female mice wnich are e s p e c i a l l y susceptible to v i r a l l y induced spontaneous mammary t u mors induced by the B i t t n e r milk virus (lj_). The incidence of spontaneous mammary tumors was 82% in the untreated controls and 10% in the selenium treated mice. Thompson and Tagliaferro have observed that selenium supplemented diets have reduced the numbers of DMBA-induced mammary tumors per rat (12J. The fact that s e l e nium-supplemented diets have reduced both v i r a l l y and chemically induced cancer in animals indicates that both the v i r a l l y and chemi c a l l y induced carcinogenesis may have the same mechanism of induct i o n . Ip has studied the effect of selenium supplementation i n the 1



9.

SHAMBERGER

Antioxidants and Malonaldehyde in Cancer

113

i n i t i a t i o n and promotion phase of DMBA-induced mammary carcinogenes i s in rats fed a high-fat diet (13). In t h i s experiment, rats were fed 5 ppm of sodium s e l e n i t e for various periods of time before and a f t e r treatment with DMBA. From t h i s experiment the f o l lowing conclusions were made: (1) both the i n i t i a t i o n and promotion phase of carcinogenesis can be i n h i b i t e d by selenium; (2) in order to achieve maximal i n h i b i t i o n of tumorigenesis, a continuous intake of selenium i s necessary; (3) the i n h i b i t o r y e f f e c t of selenium i n the early promotion phase i s probably r e v e r s i b l e ; (4) the u s e f u l ness of selenium i s decreased when i t i s given long a f t e r carcinogenic i n j u r y . Two types of epidemiological relationships have been found in two d i f f e r e n t populations. Both relationships were inverse to s e lenium b i o a v a i l a b i l i t y and p a r a l l e l e d the results from animal s t u d i e s . In one type of study, selenium b i o a v a i l a b i l i t y has been i n versely related to human cancer mortality in American c i t i e s and states (14-15). Schrauzer e t . a l . correlated the age-adjusted morta l i t y from cancer at 17 major body s i t e s with the apparent dietary selenium intakes estimated from food consumption data in 27 count r i e s (16). S i g n i f i c a n t inverse correlations were observed for cancers of the large i n t e s t i n e , rectum, prostate, breast, ovary, lung, and leukemia. In a d d i t i o n , weaker inverse associations were found for cancers of the pancreas, s k i n , and bladder. Vitamin E_ Vitamin E may prevent mouse skin tumorigenesis through i t s known antioxidant effect (1). Rats fed a diet containing large amounts of vitamin E had fewer mammary tumors induced by DMBA than did the controls {17). Shklar has observed that Syrian golden hamsters given oral vitamin E had fewer smaller buccal pouch cancers induced by DMBA (181. Konings and T r i e l i n g have observed an enhanced i n h i b i t i o n of~T H] thymidine incorporation into the DNA of vitamin Edepleted lymphosarcoma c e l l s (19). Weisburger e t . a l . have observed a greater incidence of stomach cancer in populations consuming low levels of vitamin E and other selected micronutrients. Vitamin C_ Vitamin C may prevent tumorigenesis through i t s antioxidant a c t i o n . Vitamin C i s water soluble and complements the antioxidant action of vitamin E which i s l i p i d s o l u b l e . When vitamin C was applied concomitantly with croton o i l to mouse skin previously treated with DMBA, the t o t a l number of mouse skin papillomas was reduced (20). S i m i l a r l y , Slaga and Bracken observed a decrease in the number of skin tumors induced by DMBA-phorbol carcinogenesis in mice treated with vitamin C (21). Tumor i n h i b i t i o n by ascorbic acid has also been observed on toad skin treated with DMBA (22). Schlegel e t . a l . have observed that vitamin C reduces u r o e p i t h e l i a l carcinoma i n mice and also suggested a s i m i l a r mechanism in humans (23). The tryptophan metabolite 3-hydroxyanthranilic acid (3-HOA) i s thought to be s t a b i l i z e d by ascorbic a c i d , thereby preventing carcinogenic i t y when 3-HOA i s implanted in the bladder. Vitamin C i s also known to prevent tumorigenesis through i t s a b i l i t y to block the 2IL


XENOBIOTIC M E T A B O L I S M : NUTRITIONAL E F F E C T S

114

v i t r o formation of N-nitroso compounds by the reaction between n i trous acid and oxytetracycline, morpholine, piperazine, N-methyla n i l i n e , methyl urea, and dimethyl amine. The amount of blocking depends on the compounds nitrosated and the experimental conditions (24). The species formed from nitrous acid responsible for the oxidation of ascorbic acid i s the same species a f f e c t i n g n i t r o s a t i o n of secondary amines (25). Between pH 1.5 and 5 . 0 , the n i t r o sation of secondary amines in the presence of ascorbic acid and the absence of oxygen can be summarized by the following two competit i v e p a r a l l e l second-order reactions:

Amine + N 0 Downloaded by UNIV OF ARIZONA on March 11, 2017 | http://pubs.acs.org Publication Date: May 6, 1985 | doi: 10.1021/bk-1985-0277.ch009

2

^

3

Ascorbate + N 0 2

3

k

2

->

nitrosamine + N0 " + H

->

dehydroascorbate + 2N0 + 2H 0

2

(3)

+

?

(4)

If k » k p then reaction (4) i s mostly complete before (3) starts. Large doses of vitamin C have been observed to protect rats from l i v e r tumors induced by aminopyrine and sodium n i t r i t e (26). This i n h i b i t i o n i s thought to r e s u l t , in p a r t , from blockage of in vivo n i t r o s a t i o n , which forms dimethylnitrosamine. There have been several epidemiological and several case r e ports inversely r e l a t i n g ascorbic acid intake from food to human cancer m o r t a l i t y . These studies are i n t e r e s t i n g , but may be confounded with the fact that the same ascorbic acid containing foods, namely f r u i t s and vegetables, also contain large amounts of vitamin A and f i b e r . Both vitamin A and f i b e r have been inversely related to human cancer mortality and have been shown to i n h i b i t several types of chemically-induced carcinogenesis in animals. Therefore, the possible anticancer effect of ascorbic acid may be due to other factors. 2

BHA and BHT Even though BHA (butylated hydroxyanisole) and BHT (butylated hydroxytoluene) are not naturally occurring antioxidants, various amounts of these compounds are added to food as food preservatives in order to reduce oxidative r a n c i d i t y . Both BHA and BHT are i n cluded in the FDA l i s t of substances generally accepted as safe (GRAS) and many acute and chronic tests have been done. Based on the evidence from these s t u d i e s , the FDA in 1977 recommended that BHT be removed from the GRAS l i s t and proposed interim s t u d i e s . BHA has been demonstrated to be an important i n h i b i t o r of carcinogenesis and has been extensively studied for i t s a b i l i t y to i n h i b i t carcinogen-induced neoplasia. Table I l i s t s several e x p e r i ments i n which BHA was administered before or during carcinogen exposure (27).


9.

SHAMBERGER


Table I .


Inhibition of Carcinogen-Induced Neoplasia by BHA

Carcinogen i n h i b i t e d

Species

S i t e of Neoplasm

Benzo(a)pyrene Benzo(a)pyrene Benzo(a)pyrene-7,8-dehydrodiol

Mouse Mouse Mouse

7,12-Dimethylbenz(a)anthracene 7,12-Dimethylbenz(a)anthracene 7,12-Dimethylbenz(a)anthracene 7,12-Di methylbenz(a)anth racene 7-Hydroxymethyl-12-methylbenz(a)anthracene Dibenz(a)anthracene Ni trosodi ethyl ami ne 4-Ni troqui noli ne-N-oxi de Uracil mustard Urethan Methylazoxymethanol acetate trans-5-Amino-3[2-(5-nitro-2furyl)vinyl]-l,2,4-oxadiazole

Mouse Mouse Mouse Rat

Lung Forestomach Forestomach, lung and lymphoid ti< Lung Forestomach Skin Breast

Mouse Mouse Mouse Mouse Mouse Mouse Mouse

Lung Lung Lung Lung Lung Lung Large i n t e s t i n e

Mouse

Forestomach, lung and lymphoid t i s s u e

It i s believed that BHA i n h i b i t s chemically induced carcinogenesis by producing a coordinated enzyme response that may be interpreted as causing a greater rate of d e t o x i f i c a t i o n (28). In a d d i t i o n , i n creased glutathione s-transferase and glutathione levels have been observed i n mice that have been fed BHA f o r 1-2 weeks i n carcinogen i n h i b i t i o n experiments (29). Glutathione s-transferase i s known t o be an important enzyme f o r detoxifying chemical carcinogens (2829). The anticarcinogenicity of BHA and BHT i n many experiments seems t o depend on the relationship of the time of administration of the carcinogen and BHA or BHT administration. If BHT was given before carcinogen administration, then i n h i b i t i o n of carcinogenesis occurs. However, i f BHT was given after the carcinogen, then enhancement of carcinogenesis occurs. Three groups of A/J mice were injected with urethan, 3-methylcholanthrene, or nitrosodimethylamine and then repeated doses of BHT. With a l l three carcinogens BHT treatment a f t e r carcinogen treatment s i g n i f i c a n t l y increased the numbers of lung tumors (30). Malonaldehyde Malonaldehyde, a three-carbon dialdehyde (0HC-CH -CH0), i s produced during l i p i d peroxidation by the oxidative decomposition of arachi donic and other unsaturated f a t t y a c i d s . Malonaldehyde i s present in a number of food products and i t s concentration i s increased by i r r a d i a t i o n of c e l l u l a r amino a c i d s , carbohydrates, deoxyribose, and DNA. Recent surveys (31-32) have confirmed the presence of malonaldehyde i n supermarket samples of meat, p o u l t r y , and f i s h , 2


115


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XENOBIOTIC METABOLISM: NUTRITIONAL EFFECTS

which constitute the main sources of malonaldehyde in the North American diet. Fruits and vegetables, in general, do not contain detectable amounts of malonaldehyde. There is also evidence that malonaldehyde is produced in vivo when there is an inadequate intake of vitamine E (33), which serves as a lipid antioxidant. Evidence has been reported on the formation of malonaldehyde in vivo during prostaglandin synthesis. Malonaldehyde is also formed on cellular exposure to ozone, carbon tetrachloride, ethanol and hydrocarbon compounds. Malonaldehyde (34-36) and the sodium form (37-38) have been shown to be mutagenic in the Salmonella test system, in L 5178 lymphoma cells (39), in rat skin fibroblasts (40), Drosophilia (41), and the Muller-5 sex-linked recessive lethaT mutation system"T41). Malonaldehyde also has some weak carcinogenic activity under some circumstances. Shamberger et. al. have found malonaldehyde to be an initiator in a malonaldehyde-croton oil test system (42). However, Fischer et. al. have found the sodium form of malonaldehyde to have neither initiating nor promoting activity (43). The sodium form of malonaldehyde also has been shown to increase the number of liver lesions in mice (44). Whether or not malonaldehyde is an important factor in the cancer process is not known. However, malonaldehyde is known to cross-link both protein and DNA. In general, unsaturated fat has more tumor-enhancing properties in many systems. However, there is no certain mechanism by which the breakdown of cell membrane unsaturated fatty acids might damage genetic material. In humans, about 50-60% of the ingested malonaldehyde from meat is excreted in the urine (45). It is not known how the remainder of the malonaldehyde is metabolized. The relative importance of the mutagenicity of malonaldehyde in human food is unknown. Certainly pyrolyzed food contains complete carcinogens such as benzopyrene and mutagenic substances such as tryptophan pyrolysates (Trp-P-1 and Trp-P-2), glutamic acid pyrolysates (Glu-P-1 and Glu-P-2), lysine pyrolysate (Lys-P-1), phenylalanine pyrolysate (Phe-P-1), and protein pyrolysates from broiled sardines (IQ and MelQ) and from broiled beef (MelQx). It is likely that antioxidants such as selenium and vitamins C and E also reduce the carcinogenic and mutagenic effect of these substances formed from pyrolyzed food in the same way that these antioxidants reduce the mutagenicity of malonaldehyde (46). Certainly more research is needed in this area. Literature Cited 1. 2. 3. 4. 5.

Shamberger, R.J., J. Nat. Cancer Inst. 1970, 44, 931-936. Riley, J.F., Experientia 1968, 15, 1237-1238. Clayton, C.C. and Baumann, C.A., Cancer Res. 1949, 9, 575-582. Griffin, A.C. and Jacobs, M.M., Cancer Lett. 1977, 3, 177-181. Dzhoiev, F.D., In Kantserog N-Nitrozosoedm: Deistvie, Obraz., Mater Simp., 3rd Tallinn, USSR, 1978; pp 51-53. 6. Harr, J.R., Exon, J.H., Weswig, P.H., and Whanger, P.P. Clin. Toxicol. 1973, 8, 487-495. 7. Marshall, M.V., Arnott, M.S., Jacobs, M.M., and Griffin, A.C., Cancer Lett. 1979, 7, 331-338. 8. O'Conner, T.P., Youngman, L.D., and Campbell, T.C., Fed. Proc. 1983, 42, 670.



9. SHAMBERGER


9. Baldwin, S., Parker, R.S., and Misslbeck., Fed. Proc. 1983, 42, 1312. 10. LeBoeuf, R.A., Laishes, B.A., and Hoekstra, W.G., Fed. Proc. 1983, 42, 669. 11. Schrauzer, G.N., and Ishmael, D., Ann. Clin. Lab. Sci. 1974, 4, 411-467. 12. Thompson, H.J., and Tagliaferro, A.R., Fed. Proc. 1980, 39, 1117. 13. Ip, C., Cancer Res. 1981, 41, 4386-4390. 14. Shamberger, R.J. and Willis, C.E. CRC Crit. Rev. Clin. Lab. Sci. 1971, 2, 211-221. 15. Shamberger, R.J., Tytko, S.A., and Willis, C.E., Arch. Environ. Health 1976, 31, 231-235. 16. Schrauzer, G.N., White, D.A., and Schneider, C.J., Bioinorg. Chem. 1977, 7, 23-24. 17. Ip, C., Carcinogenesis 1982, 3, 1453-1456. 18. Shklar, G.J., Natl. Cancer Inst. 1982, 68, 791-797. 19. Konings, A.W.T. and Trieling, W.B., Int. J. Radiat. Biol. 1977, 31, 397-400. 20. Shamberger, R.J., J. Natl. Cancer Inst. 1972, 48, 1491-1497. 21. Slaga, T.J. and Bracken, W.M., Cancer Res. 1977, 37, 1631-1635. 22. Sadek, I.A. and Abdelmegid, N., Oncology 1982, 39, 399-400. 23. Schlegel, J.U., Pipkin, G.E., Nishumura, R., and Schultz, G.N., Trans. Am. Assoc. Genitourinary Surg. 1969, 61, 85-89. 24. Mirvish, S.S., Wallace, L., Eagen, M. and Shubik, P., Science 1972, 177, 65-68. 25. Archer, M.C., Tannenbaum, S.R., Tan, T., and Weisman, M., J. Natl. Cancer Inst. 1975, 54, 1203-1205. 26. Chan, W.C. and Fong, Y.Y., Int. J. Cancer 1970, 20, 268-270. 27. Wattenberg, L.W. "In Environmental Carcinogenesis", Emmelot, P. and Kriek, E. Elsevier/North Holland Biomedical Press, Amsterdam, 1979, pp. 241-263. 28. Wattenberg, L.W., "In Cancer: Achievements, Challenges, and Prospects for the 1980's", Burchenol, J.H. and Oettgen Eds. Vol 1. Grune and Stratton, New York, 1981, pp. 517-539. 29. Benson, S.M., Cha, Y.N., Bueding, E., Heine, H.S., and Talalay, P., Cancer Res. 1979, 39, 2971-2977. 30. National Cancer Institute. Technical Report Series number 150. NIH Publ. No. 79-1706, Bethesda, Maryland: Carcinogenesis Testing Program, National Cancer Institute. 31. Shamberger, R.J., Shamberger, B.A., and Willis, C.E., J. Nutr. 1977, 107, 1404-1409. 32. Siu, G.M., and Draper, H.H., J. Food Sci. 1978, 43, 1147-1149. 33. Trostler, N., Brady, P.S., Romsos, D.R., and Leveille, G.A., J. Nutr. 1979, 109, 345-352. 34. Mukai, F.H. and Goldstein, B.D., Science, 1976, 191, 868-869. 35. Muchielli, A., 1975, Thesis, Univ. of Lille, CNRS, AO 11792. 36. Lawrence, M.J. and Tuttle, M.R., Cancer Res. 1980, 40, 276-282. 37. Marnett, L.J. and Tuttle, M.A., Cancer Res. 1980, 40, 276-282. 38. Basu, A.K. and Marnett, L.J., Carcinogenesis, 1983, 4, 331-334. 39. Yau, T.M., Mech Aging Dev., 1979, 11, 137-144. 40. Bird, R.P. and Draper, H.H., J. Toxicol. Environ. Hlth, 1980, 6, 811-823.


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41. Szabad, J., Soos, I., Polgar, G., Heijja, G., Mutation Research 1983, 113, 117-133. 42. Shamberger, R.J., Andreone, T.L., and Willis, C.E., J. Nat. Cancer Inst. 1974, 53, 1771-1773. 43. Fischer, S.M., Cancer Letters, 1983, 19, 61-66. 44. Bird, R.P., Draper, H.H., and Valli, V.E.O., J. Toxicol. and Environ. Hlth, 1982, 10, 897-905. 45. Jacobson, E.A., Newmark, H.L., Bird, R.P., and Bruce, W.R., Nutr. Rep. Int., 1983, 28, 509-517. 46. Shamberger, R.J., Corlett, C.L., Beaman, K.D. and Kasten, B.L., Mutat. Res. 1979, 66, 349-356.


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Xenobiotic Metabolism: Nutritional Effects - American Chemical Society

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