Blocking Nitrosation Reactions In Vivo - ACS Symposium Series (ACS

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Blocking Nitrosation Reactions In Vivo

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WILLIAM J. MERGENS and HAROLD L. NEWMARK Hoffmann-La Roche Incorporated, 340 Kingsland Street, Nutley, ΝJ 07110

N-Nitroso compounds, once formed and present in vivo, generally do not easily or readily revert back to precursors. Instead, in vivo, they metabolize to, or are converted to alkylating agents as terminal or proximate carcinogens. Control of N-nitroso com pounds, as carcinogenic agents, so far has rested on agents that can block their formation. In order to control carcinogenesis due to N-nitroso compounds, i t is necessary to consider their chemical proper ties and methods of formation within the body. The in vivo formation of N-nitroso compounds is directly dependent on the source of nitrosating agent, and recent studies would indicate that they are, indeed, numerous ranging from atmospheric exposure to oxides of nitrogen through bacterial reduction of nitrate in the gastrointestinal tract. The generally accepted mechanism of blocking these reactions is one of competitive kinetics between the susceptible amine and potential blocking agent for the nitrosating agent. The ultimate effectiveness of any given blocking agent then depends on being able to deliver i t in sufficient concentration to the organ and phase where the nitrosation takes place. Ascorbic acid and dl-alpha-tocopherol are water-soluble and lipid-soluble vitamins, respectively, that have been found to be extremely efficient inhibitors of nitro sation reactions in vivo. These mechanism will be presented along with the influence of normal dietary components on nitrosation reactions. The class of N-nitroso compounds (i.e., nitrosamines and nitrosamides) is currently considered a unique group that includes members with remarkable carcinogenic properties. Because of their potency and almost ubiquitous presence in

0097-6156/81 /0174-0193$05.00/0 © 1981 American Chemical Society Scanlan and Tannenbaum; N-Nitroso Compounds ACS Symposium Series; American Chemical Society: Washington, DC, 1981.

194

N-NITROSO COMPOUNDS

certain foods, beverages, and elsewhere i n our environment (jL, 2_ 3), the N-nitroso compounds could represent a significant carcinogenic input i n the gastrointestinal system. The carcinogenic and mutagenic properties of the N-nitroso compounds have been reviewed extensively elsewhere (4). N-nitroso compounds, once formed and present i n vivo, generally do not revert easily or readily back to precursors. Instead, i n vivo, they are metabolized or otherwise converted to alkylating agents as terminal or proximal carcinogens. Control of N-nitroso compounds as carcinogenic agents so far has rested on agents that can block their formation. I t i s the intent of this paper to b r i e f l y review some of the studies which have been performed on the use of blocking agents to prevent N-nitroso compound formation and describe some recent observations on the mechanism by which these agents function. 9

Formation of N-Nitroso Compounds In order to understand how to control carcinogenesis caused by N-nitroso compounds, i t i s necessary to consider t h e i r chemical properties and methods of formation. The nitrosamines are generally very stable compounds i n neutral, alkaline, and weakly acidic solutions. They are uncharged, very soluble, and can readily diffuse through many media and "barriers", including rubber gloves (3, 5^, 6). Nnitroso compounds can be decomposed by heating i n strong acid or by exposure to u l t r a v i o l e t l i g h t . Their comparatively good s t a b i l i t y has permitted development of r e l i a b l e methods for the ready i s o l a t i o n of nitrosamines i n complex analytical schemes (7)· Nitrosamides, however, are generally far less stable, and t h i s has complicated development of r e l i a b l e analytical methods for measuring their presence i n low levels i n tissues, foods, etc. However, the reactions caused by their i n s t a b i l i t y do not result i n their reversion back to precursors but to re active intermediates leading to alkylating agents. Thus, i n the case of both nitrosamines and nitrosamides, once formed, there i s a r i s k of carcinogenesis by their conversion to an alkylating agent i n vivo. I t i s , therefore, interesting to determine i f (1) forma t i o n of these N-nitroso compounds can be prevented or blocked and (2) whether the terminal active alkylating agent can be prevented from attacking the c e l l u l a r DNA. A large body of reports has appeared i n recent years on the successful use of blocking agents, including ascorbic acid (vitamin C) i n aqueous media and alpha-tocopherol (vitamin E) i n l i p i d phase, to prevent N-nitroso compound formation (8-29).

Scanlan and Tannenbaum; N-Nitroso Compounds ACS Symposium Series; American Chemical Society: Washington, DC, 1981.

14.

MERGENS AND

NEWMARK

Blocking

Nitrosation

Reactions

In V i t r o and In Vivo Studies Matty i n v i t r o and i n vivo studies have demonstrated their effectiveness i n i n h i b i t i n g nitrosamine formation i n a gastric f l u i d environment (11, 12, 13, 28). When large single doses of dimethylamine or aminopyrine were gavaged to rats or mice together with a larger NaNO- dose, acute l i v e r t o x i c i t y de veloped after a few days (3u). With both dimethylamine and aminopyrine, the effect i s attributed to intragastric forma t i o n of dimethylnitrosamine (DMN), which i s an acute hepatotoxic agent. When similar experiments were performed with aminopyrine, but with sodium ascorbate added to the amine solution before gavage, hepatotoxicity was completely pre vented. In studies where rats received single doses of 1500 mg dimethylamine hydrochloride and 125 mg NaNO^ per kg body weight, sodium ascorbate doses down to 90 mg/kg completely protected the rats from l i v e r necrosis by preventing formation of DMN (19). Sander and Burkle (31) were the f i r s t to induce tumors by feeding n i t r i t e and amines or amides. The tumors were at tributed to i n vivo formation of the N-nitroso compounds, probably i n the stomach. When pregnant rats were gavaged with ethylurea and n i t r i t e , hydrocephalus and nervous system tumors were induced i n the offspring. Both these effects were pre vented when sodium ascorbate was gavaged together with the ethylurea (2JL, 32). Using a piperazine and n i t r i t e system, lung adenoma induction was approximately proportional to piperazine dose and to the square of n i t r i t e dose, when precursor concen trations were varied (33). When sodium ascorbate was added to the food together with the amine or urea and NaNO^ was added to drinking water, the number of lung adenomas was reduced, compared to the group without sodium ascorbate (9). The incidence of l i v e r tumors due to morpholine and n i t r i t e was reduced from 65% i n the absence of to 49% i n the presence of sodium ascorbate, and the latent period was nearly doubled, from 54 to 93 weeks, indicating i n vivo nitrosomorpholine (NMOR) production was probably about 50% inhibited (10). Sources of Amines and Nitrosating Agents In c l a s s i c a l organic chemistry, nitrosamines were con sidered only as the reaction products of secondary amines with an a c i d i f i e d solution of a n i t r i t e s a l t or ester. Today, i t i s recognized that nitrosamines can be produced from primary, secondary, and t e r t i a r y amines, and nitrosamides from second ary amides. Douglass et a l . (34) have published a good review of nitrosamine formation. For the purposes of this presenta t i o n , i t w i l l suffice to say that amine and amide precursors for nitrosation reactions to form N-nitroso compounds are indeed ubiquitous i n our food supply, environment, and par-


195

196

N-NITROSO COMPOUNDS

t i c u l a r l y i n vivo. These precursors of nitrosamines and nitrosamides compose a large part of our l i v i n g organic world. Therefore, to study means of blocking N-nitroso com pound formation, i t i s necessary to look at the nature of the nitrosating agents and the chemistry of formation of Nnitroso compounds. There have been some preliminary reports of nitrosamines being found i n normal humans, i n blood (.2, 35), and i n urine (36). The precise o r i g i n of these substances, i f their pres ence i s confirmed, i s not f u l l y understood at this time. An attempt to estimate human daily impact of N-nitroso compounds i s shown i n Table I. The apparent intake from food of preformed nitrosamines i s comparatively low, at least i n these surveys of a Western diet i n England (3). The intake d i r e c t l y to the respiratory tract from smoking could be somewhat larger. However, i f the blood levels reported are confirmed as correct, then inputs of up to 700 meg per day of at least N-nitrosodimethylamine (NDMA) may be calculated, based on pharmacokinetic considerations of data obtained i n animals and extrapolated to man. I t should be emphasized that no informa t i o n i s available at present on nitrosamide intake or i n vivo formation, largely because of a n a l y t i c a l limitations. Intake of n i t r i t e or nitrosating gases (N0 , N 0o, or generally N0 given as NaN0 equivalent) i s potentially much higher than preformed nitrosamines. We wish to point particu l a r l y to the potential input into the respiratory tract of nitrosating gases, 2-3 mg of N0 equivalent from smoking a pack of cigarettes, or up to 100 mg of N0 equivalent per day from normal breathing of polluted a i r with 1 ppm of Ν0 content. This l e v e l of Ν0 i s often achieved i n c i t i e s , and some, l i k e Los Angeles, occasionally reach 2.5 ppm (37). Tests have demonstrated that inhaled N0 i s largely absent i n expired a i r , suggesting that i t i s absorbed rapidly or consumed i n reactions i n the lung (38). I f an individual breathes 1.5 l i t e r s per breath, 12 breathes per minute (normal resting breathing f o r an adult), i n an atmosphere of 1 ppm of N0 , over 1 mmole per day i s absorbed. 2

X

2

2

2

2

χ

χ

2

2

1500 ml

—————

12 breaths

»

χ

60 minutes

3ζ _—-———.

breath minute 1 yl* 1 mM** _ 10& μΐ 24.45 ml *1 ppm N0 i n a i r **NI0SH Expression for NO 24.45 liters/mole x

24 hours χ

hour 1.06 mMoles day

________

χ

day

2

at 77°F (Ideal Gas

Law),

Depending on the amount of NO absorbed simultaneously, a n i t r o s a t i o n capacity equivalent to 70-140 mg of NaN0£ can be taken d i r e c t l y into the lungs each day.


14.

MERGENS AND

NEWMARK

Blocking

Nitrosation

197

Reactions

Table I N-Nitroso Compounds and Precursors (Human Daily Impact - Estimate) Preformed Nitrosamines (pg/day)

Preformed Nitrosamides

Nitrosating Sources (mg/day) (NaN0 equiv.) 2

Food (1, 3)

Saliva Smoking (57, 58)

NDMA (0.5-1.0) NPYR (0.1-0.2) NDMA (0.1-1.3) NNN (0.8-5.0) Others (0.1-0.9) NDMA (up to 700) NDMA ( D

3 (2-5)

(60)

9 (7-11) (61) 2-3 (1 pack/day)(38)

C

In Vivo Synthesis Air Pollution

approx. 10 (62) at 0.1-1.0 ppm NO i n a i r 10-100 mg

Based on blood levels of 0.1-1.5 ppb, t, - 30-40 minutes i n Jl f 1_ * .man and animals. NPYR - N-nitrosopyrrolidine °NNN « N'-nitrosonornicotine


198

N-NITROSO COMPOUNDS

It i s conceivable that nitrosamines can be synthesized i n the intestine, since the precursors are present. While the conditions f o r aqueous nitrosation reactions are not optimum at pH values encountered i n the lower gastrointestinal t r a c t , several studies have shown that these reactions can be cata lyzed (39, 40, 41). It has been suggested that the intestine might be a s i t e f o r the formation of nitrosamines by bacterial action (42). Sander (43) has demonstrated the formation of nitrosamines by b a c t e r i a l action from precursor amines and n i t r a t e at neutral pH and Klubes and coworkers have reported the formation of NDMA upon incubation of l^C-dimethylamine and sodium n i t r i t e with rat f e c a l contents (44, 45). Chemistry of Blocking Reactions Aqueous Systems: In aqueous solution, the optimum con d i t i o n for nitrosation (46) i s usually found to be about pH 34 and r e f l e c t s the mutual optimization of two conditions, (1) the formation of the nitrosating intermediate Ν °3 * ^ concentration of the more reactive unprotonated form of the amine which i s governed by the following equations: an(

t n e

2

+

•>H0N0

N0~ + H 2H0N0 ^ = R NH + H

N

+

> R NH

2

2

R NH + N 0 2

2

+ H

- 2 ° 3 2°

3

2

^ R NN0 + HONO 9

The mechanism, then, by which ascorbic acid functions to block these reactions i s one of competitive kinetics with the susceptible amine for the nitrosating agent. Hence, the r e a c t i v i t y of any given amine w i l l be an important parameter. These above equations suggest that amines with pKa i n the range of 4-6 w i l l be more rapidly nitrosated than those with pKa values i n the range of 9-11. This has been borne out i n practice many times. Amines such as N-methylaniline with a pKa value of 4.84, piperazine (pKa value 5.9, 9.8), and amino pyrine (pKa value 5.04) are much more rapidly nitrosated than piperdine (pKa value 11.2), dimethylamine (pKa value 10.72), and pyrrolidine (pKa value 11.27). Under many of the condi tions studied, i t has been shown that the r e a c t i v i t y of ascor bic acid i s s u f f i c i e n t l y rapid that i t can successfully com pete with most a l l amines when present i n approximately 2 mole r a t i o excess of the nitrosating agent. In alkaline aqueous solution, on the other hand, one would expect that nitrosations would not occur at a l l because of the absence of an active nitrosating intermediate, and no


14.

MERGENS AND NEWMARK

Blocking

Nitrosation

Reactions

199

blocking agent would be necessary. However, Challis et a l . (47) have shown that N-nitrosamines and N-nitramines are readily formed i n aqueous solution between pH 7 and 14 when the nitrosation agents are the gases N 0~ and N °A* Inter estingly, amines not only compete effectively witn the ex pected OH" hydrolysis reaction, but the nucleophilic reactivity of various amines becomes v i r t u a l l y independent of pKa value. In this case, the alkaline pH of the aqueous solvent exhibits a "leveling" effect on dissolved amines i n that a l l the amines are unprotonated and become equivalent i n reactivity. Challis also noted that under their experimental conditions 2 χ 10_ M amines competed effectively with 55.5 M H 0 and 0.1 M 0H~ for the nitrosating agent and suggested that possibly more reactive isomers of ^ 0 ^ and N«0, are generated by the gaseous NO and N0 components. Here, N-nitrosamines result from reaction of the unsymmetrical tautomer (ON-NO^), whereas the symmetrical tautomer (0 N-N0 ) produces an N-nitramine pos s i b l y v i a a four-center transition state. The results for 2°3 n*aybeexplained similarly i n terms of the corresponding 0 Ν - Ν 0 M — — — 0Ν-0Ν0 tautomers. This conclusion has a prece dent T48) i n the case of N ^ but not for N ^ . In moderately acidic aqueous n i t r i t e solution, the n i t r o sating agent i s essentially nitrous acid anhydride, NJ)^, formed from nitrous acid, Η0Ν0 (pKa = 3.14 at 25°C), which i s in turn formed from a c i d i f i c a t i o n of n i t r i t e ions. Stronger a c i d i f i c a t i o n can yield a very reactive nitrosating agent, H-ONO*. Of even greater interest i n nitrosation i n vivo i s tne catalytic effect of certain anions that form more reactive nitrosating agents (39, 49, 50, 51). Thiocyanate i s thejnost__ active such catalyst, followed by halides i n the order I , Br , CI . This effect i s often strong at low pH. 2

2

2

2

2

2

N

Nonaqueous Systems: In nonaqueous (nonpolar) solvent systems, nitrosation also proceeds. In these solvents, alphatocopherol acts as a l i p i d soluble blocking agent i n much the same fashion as ascorbic acid functions i n the aqueous phase. Alpha-tocopherol reacts with a nitrosating agent and reduces i t to n i t r i c oxide. At the same time, alpha-tocopherol i s oxidized to tocoquinone, which i s the f i r s t oxidation product of vitamin Ε and also a normal metabolite i n vivo. Once the conditions are set for a nitrosating agent and susceptible amine to enter a l i p i d nonpolar phase, the re action i s generally extremely rapid. Free amines readily dissolve i n aprotic l i p i d solvent systems as the unprotonated base, yielding a high proportion ( i f not a l l ) of the more reactive free base form of the molecule for nitrosation. The active intermediates of the nitrosating agents Νο°3 or even N0 are gases with appreciable s o l u b i l i t y i n l i p i d nonpolar solvent systems. This i s i n marked contrast to the poor l i p i d s o l u b i l i t y of n i t r i t e ion N0~. The existence of a nitrosating 2


200

N-NITROSO COMPOUNDS

agent i n aprotic solvents has been known for a long time and was demonstrated by Mirvish et a l . (52) who recorded the UV spectra of "dried HN0 " i n methylene chloride. The formation of nitrosamines i n aprotic solvents has a p p l i c a b i l i t y to many p r a c t i c a l l i p o p h i l i c systems including foods (particularly bacon), cigarette smoke, cosmetics, and some drugs. The very rapid kinetics of nitrosation reactions i n l i p i d solution indicates that the l i p i d phase of emulsions or analogous multiphase systems can act as "catalyst" to f a c i l i t a t e nitrosation reactions that may be far slower i n purely aqueous media (41, 53, 54). This i s apparently true i n some cosmetic emulsion systems and may have important a p p l i c a b i l i t y to nitrosation reactions i n vivo, p a r t i c u l a r l y i n the GI t r a c t . In these multiphase systems, the pH of the aqueous phase may be poor for nitrosation i n aqueous media (e.g., neutral or alkaline pH) because of the very small concentra t i o n of Η0Ν0 or N 0 that can exist at these pH ranges. However, the small amount of N °3 readily enters the l i p i d where the nitrosation reaction i s very rapid. The nitrosation reaction i s almost completely unidirectional towards the formation of N-nitroso compounds. The net result i s that the presence of the l i p i d i n such an emulsion brings together low concentrations of free base (which increases i n the l i p i d as the pH goes up towards a l k a l i n i t y ) and nitrosating agent (N 0g) which react rapidly and probably completely to form Nnitroso compounds. In physiological l i p i d s , especially i n the GI t r a c t , the free hydroxyl groups of substances such as monoglycerides, some phosphatides, cholesterol, b i l e acids, and s a l t s , etc. may contribute by functioning as transnitrosating agents. Generally, i t can be seen that nitrosamine formation can take place i n both the aqueous and l i p o p h i l i c phases. Hence, i t becomes extremely important when investigating i n vivo blocking of nitrosamine formation that i t i s understood where nitrosamine formation i s taking place (e.g., stomach, lung, intestine) and, additionally, i n what phase the reaction proceeds. Lacking such an understanding of an i n vivo sys tem, i t would appear prudent to employ blocking agents which protect both phases of the potential reaction medium. Indeed, given an improperly designed or understood sys tem, a blocking agent, l i k e ascorbic acid, could be c a t a l y t i c toward nitrosamine formation. For example, i f the source of nitrosating agent i s n i t r i t e ion and the susceptible amine i s i n the l i p i d phase, conceivably ascorbic acid could cause the rapid reduction of n i t r i t e ion to n i t r i c oxide which could migrate to the l i p i d phase. Subsequent oxidation of NO to N0 i n the l i p i d phase could cause nitrosation. Aside from ascorbic acid and alpha-tocopherol, which have been shown to be effective blocking agents, there are other factors which appear important i n blocking nitrosamine formation 2

2

3

2

2

2


14.

MERGENS AND NEWMARK

Blocking

Nitrosation

Reactions

201

under i n vivo conditions. These are the normal constituents of food which can be referred to as "reductones". In studies per formed using the aminopyrine-nitrite system i n the presence of semisynthetic or conventional animal chow diets, differences were observed i n the degree of nitrosation which occurred, as can be seen i n Table I I and I I I . These results indicate that i n the presence of conventional animal chow (55) the potential for dimethylnitrosamine formation i s considerably reduced over that which was formed i n the semisynethetic diet (56). These are not t o t a l l y accountable by the change i n pH of the medium brought about by the buffering effect of conventional chow on the simu lated gastric f l u i d medium. Additionally, we have observed that these differences are not accountable based on the t o t a l vitamin C and Ε present i n the chow but rather indicate the presence of other reducing compounds which can divert the nitrosating agent from attacking the susceptible amine. These results would i n d i cate that the design of any i n vivo experiment should include consideration of not only the amine substrate and i t s possible mechanism of nitrosation ( i . e . , stomach v i a N0 ion or lung v i a N0 gas) but, for studies of gastrointestinal nitrosation, the influence of normal dietary components as well. 2

2

Summary The N-nitroso compounds are a potential source of carcino genesis i n humans. N-nitroso compounds appear to be ubiquitous i n our environment, being present i n low levels i n foods, cos metics, drugs, atmosphere, etc., and also appear to be formed endogenously i n vivo. Once formed, N-nitroso compounds are converted i n vivo to reactive e l e c t r o p h i l i c ultimate carcinogens. Therefore, the most p r a c t i c a l method of eliminating carcinogenesis by nitrosamine i s to prevent their formation by diverting potential nitrosating agents to nonnitrosating substances (e.g., by reduction to NO) by the use of appropriate blocking agents. Ascorbic acid and alpha-tocopherol are effective blocking agents against N-nitroso compound formation. Ascorbic acid i s effective p a r t i c u l a r l y i n aqueous media, and tocopherol effective p a r t i c u l a r l y i n l i p i d phases. They should be used i n conjunction due to the mutually complementary actions of the two vitamins i n blocking nitrosamine formation i n both aqueous and l i p i d media. As safe nutrient ingredients i n many food systems, as well as available from commercial synthesis, the combination of vitamins C and Ε represents very useful compounds for the n u t r i t i o n a l i n h i b i t i o n of formation of tumorigenic N-nitroso compounds. In addition to vitamin C and vitamin Ε as effective blocking agents, there are other substances which also are capable of preventing nitrosamine formation which are present i n normal foods. The influence of this factor on the design of experi mental studies should not be overlooked.


202

N-NITROSO COMPOUNDS

Table I I Nitrosation of Aminopyrine

Gastric F l u i d Aminopyrine Chow (control) Synthetic (control) NaN0 PH o

2

A

Β

C*

50 ml 35 mg

50 ml 35 mg

50 ml 35 mg 10 g

—

— —

—

10 g 10 mg 1.1

10 mg 1.1

10 mg 1.1

After 1 hour at 37°C DMN (mg) DMN % Theory DMN % Std

3.89 35 100**

3.29 29 85

1.03 9 26

*Normal pH of t h i s sample was 3.2; pH adjusted from 3.2 to 1.1 f o r experimental comparison. **By d e f i n i t i o n

Table I I I Nitrosation of Aminopyrine D* Gastric F l u i d Aminopyrine Chow (control) Synthetic (control) NaN0~ pH 1

50 ml 35 mg 10 g — 10 mg 3.2

Ε 50 ml 35 mg 10 g 10 mg 3.2

After 1 hour at 37°C DMN (mg) DMN % Theory DMN % Std

1.45 13 37

3.44 31 88

*Normal pH of t h i s sample was 1.1; pH adjusted from 1.1 to 3.2 f o r experimental comparison.


14.

MERGENS AND NEWMARK

Blocking

Nitrosation

Reactions

Literature Cited 1. 2. 3. 4. 5. 6.

7.

8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18.

19. 20.

Preussmann, R.; Eisenbrand, G.; Spiegelhalder, B. "En vironmental Carcinogenesis," Elsevier/North-Holland Biomedical Press, Amsterdam, 1979, pp. 51-71. Fine, D. H.; Ross, D.; Rounbehler, D.; S i l v e r g l e i d , Α.; Song, L. Nature 1977, 263, 753-755. Gough, Τ. Α.; Webb, K. S.; Coleman, R. F. Nature 1978, 272, 161-163. Druckrey, H.; Preussmann, R.; Ivankovic, S.; Schmahl, D. Krebsforsch 1967, 69, 103. Sansone, Ε. B.; Tenari, Y. B. "Environmental Aspects of N-Nitroso Compounds," International Agency f o r Research on Cancer, Lyon, 1978, pp. 517-529. Walker, Ε. Α.; Castegnaro, M.; Garren, L.; Pignatelli, B. "Environmental Aspects of N-Nitroso Compounds," Inter national Agency for Research on Cancer, Lyon, 1978, pp. 535-543. Fan, S. T.; Krull, I. S.; Ross, R. D.; Wolff, M. H.; Fine, D. H. "Environmental Aspects of N-Nitroso Com pounds," International Agency for Research on Cancer, Lyon, 1978, pp. 3-17. Mirvish, S. S.; Wallcave, L.; Eagen, M.; Shubik, P. Science 1972, 177, 65-68. Mirvish, S. S.; Cardesa, Α.; Wallcave, I . ; Shubik, P. J. Nat. Cancer Inst. 1975, 55, 633-636. Mirvish, S. S.; Pelfrene, A. F.; Garcia, H.; Shubik, P. Cancer Letters 1976, 2, 101-108. Mirvish, S. S. Ann. N.Y. Acad. S c i . 1975, 258, 175-180. Greenblatt, M. J . Nat. Cancer Inst. 1973, 50, 1055-1056. Kamm, J . J.; Dashman, T.; Conney, A. H.; Burns, J . J . Proc. Nat. Acad. S c i . 1973, 70, 747-749. Kamm, J . J.; Dashman, T.; Conney, A. H.; Burns, J . J . "N-Nitroso Compounds in the Environment," International Agency f o r Research on Cancer, Lyon, 1974, pp. 200-204. Kamm, J . J.; Dashman, T.; Newmark, H. L.; Mergens, W. J . Toxicol.and Appl. Pharmacol. 1977, 41, 575-583. Fong, Y. Y.; Chan, W. C. "Environmental N-Nitroso Com pounds: Analysis and Formation," International Agency for Research on Cancer, Lyon, 1976, pp. 461-464. Kinawi, V. Α.; Doring, D.; Witte, I. Arzutim. -Forsch. 1977, 27, 747. Preda, N.; Popa, L.; Galea, V.; Simo, G. "Environmental N-Nitroso Compounds: Analysis and Formation," Inter national Agency for Research on Cancer, Lyon, 1976, pp. 301-304. Cardesa, Α.; Mirvish, S. S.; Haven, G. T.; Shubik, P. Proc. Soc. Exp. Biol. Med. 1974, 145, 124-128. Kawabata, T.; Shazuki, H.; Ishibashi, T. Nippon Suisan Gakkaishi 1974, 40, 1251.


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204

21. 22. 23. 24. 25. 26. 27. 28. 29.

30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44.

N-NITROSO COMPOUNDS

Ivankovic, S.; Preussmann, R.; Schmahl, D.; Z e l l e r , J . W. "N-Nitroso Compounds in the Environment," International Agency f o r Research on Cancer, Lyon, 1974, pp. 101-102. Archer, M. C.; Tannenbaum, S. R.; Fan, T.-Y.; Weisman, M. J. Nat. Cancer Inst. 1975, 54, 1203-1205. Fan, T. Y.; Tannenbaum, S. R. J . Food Sci. 1973, 38, 1067-1069. Sen, N. P.; Donaldson, B. "N-Nitroso Compounds in the Environment," International Agency for Research on Cancer, Lyon, 1974, pp. 103-106. Sen, N. P.; Donaldson, B.; Charbonneau, C.; Miles, W. F. J. Agric. Food Chem. 1974, 22, 1125-1130. Sen, N. P.; Donaldson, B.; Seaman, S.; Iyengar, J . R.; Miles, W. F. J . Agric. Food Chem. 1976, 24, 397-401. Gray, J . I.; Dugan, L. R. J . Food Sci. 1975, 40, 981-984. Ziebarth, D.; Scheunig, G. "Environmental N-Nitroso Compounds: Analysis and Formation," International Agency for Research on Cancer, Lyon, 1976, pp. 279-290. Mergens, W. J . ; Kamm, J . J . ; Newmark, H. L.; Fiddler, W.; Pensabene, J . "Environmental Aspects of N-Nitroso Com pounds," International Agency f o r Research on Cancer, Lyon, 1978, pp. 199-212. L i j i n s k y , W.; Greenblatt, M. Nature 1972, 236, 177. Sander, J.; Burkle, G. Z. Krebsforsch. 1969, 73, 54. Ivankovic, S.; Preussmann, R.; Schmahl, D.; Z e l l e r , J . Z. Krebsforsch. 1973, 79, 145-147. Greenblatt, M.; Mirvish, S. S. J . Nat. Cancer Inst. 1973, 50, 119-124. Douglass, M. L.; Kabacoff, B. L.; Anderson, G. Α.; Cheng, M. C. J . Soc. Cosmet. Chem. 1978, 29, 581-606. L a k r i t z , L.; Simenhoff, M. L.; Dunn, S. R.; Fiddler, W. Food Cosmet. Toxicol. 1980, 18, 77-79. Kakizoe, T.; Wang, T. T.; Eng, V. W. S.; Furrer, R.; Dion, P.; Bruce, W. R. Cancer Res. 1979, 39, 829-832. Wayne, L. G. "Technical Progress Report Vol. III," Los Angeles County A i r Pollution Control District, Los Angeles, 1962. Bokhoven, C.; Niessen, H. J . Nature 1961, 192, 458-459. Boyland, E.; Nice, E.; Williams, K. Food Cosmet. Toxicol. 1971, 9, 639-643. Keffer, L. K.; R o l l e r , P. P. Science 1973, 18, 1245-1247. Okun, J . D.; Archer, M. C. J . Nat. Cancer Inst. 1977, 58, 409-411. Magee, P. N.; Montesano, R.; Preussmann, R. "Chemical Carcinogens," American Chemical Society, 1976, pp. 491625. Sander, J . Hoppe-Seyler's Ζ. Physiol. Chem. 1968, 349, 429-432. Klubes, P.; Jondurf, W. R. Chem. Pathol. Pharmacol. 1971, 2, 24-34.


14.

45. 46. 47.

48. 49. 50. 51. 52.

53.

54.

55. 56. 57. 58. 59. 60. 61. 62.

MERGENS AND NEWMARK

Blocking

Nitrosation

Reactions

205

Klubes, P.; Cerna, I . ; Rabinowitz, A. D.; Jondurf, W. R. Food Cosmet. Toxicol. 1972, 10, 757-767. Mirvish, S. S. Toxicol, and Appl. Pharmacol. 1975, 31, 325-351. C h a l l i s , B. C.; Edwards, Α.; Hunma, R. R.; Kryptopolous, S. Α.; Outram, J . R. "Environmental Aspects of N-Nitroso Compounds," International Agency f o r Research on Cancer, Lyon, 1978, pp. 127-142. Steel, F.; Nogradi, J . ; B r e i t , Η. Z. Anorg. Chem. 1952, 269, 102. Boyland, E.; Walker, S. A. "N-Nitroso Compounds in the Environment," International Agency for Research on Cancer, Lyon, 1974, pp. 132-136. Fan, T.-Y.; Tannenbaum, S. R. J . Agric. Food Chem. 1973, 21, 237-240. Schweinsberg, F. "N-Nitroso Compounds in the Environ ment," International Agency for Research on Cancer, Lyon, 1974, pp. 80-85. Mirvish, S. S.; Karlowski, K.; Sams, J . P.; Arnold, S. D. "Environmental Aspects of N-Nitroso Compounds, Inter national Agency for Research on Cancer, Lyon, 1978, pp. 161-174. Kim, Y.-K.; Tannenbaum, S. R.; Wishnok, J . S. "N-Nitroso Compounds: Analysis, Formation and Occurrence," Inter national Agency for Research on Cancer, Lyon, 1980, pp. 207-214. Mergens, W. J . ; Chau, J . ; Newmark, H. L. "N-Nitroso Compounds: Analysis, Formation and Occurrence," Inter national Agency for Research on Cancer, Lyon, 1980, pp. 259-267. Ralston-Purina Rat Chow Wogan, G. N.; Newberne, P. M. Cancer Res. 1967, 27, 23702376. Brunnemann, K. D.; Yu, L.; Hoffmann, D. Cancer Res. 1977, 37, 3218-3222. Brunnemann, K. D.; Hoffmann, D. "Environmental Aspects of N-Nitroso Compounds," International Agency f o r Research on Cancer, Lyon, 1978, pp. 343-356. Fine, D. H.; Rounbehler, D. P.; Belcher, Ν. M.; Epstein, S. S. Science 1976, 192, 1328-1330. White, J . W., J r . J . Agric. Food Chem. 1975, 23, 886-891. Tannenbaum, S. R.; Weisman, M.; Fett, D. Food Cosmet. Toxicol. 1976, 14, 549-552. Archer, M. C.; Saul, R. L.; Lee, L.-J.; Bruce, W. R. "Gastrointestinal Cancer: Endogenous Factors," Cold Spring Harbor Laboratory, Long Island, 1981, pp. 321-330.

RECEIVED

August

10,

1981.


Blocking Nitrosation Reactions In Vivo - ACS Symposium Series (ACS

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