Quantitative Aspects of Exposure and Mechanism ... - ACS Publications

9 Quantitative Aspects of Exposure and Mechanism in N-Nitrosamine Carcinogenesis J O H N S. W I S H N O K

Downloaded by FUDAN UNIV on January 30, 2017 | http://pubs.acs.org Publication Date: June 20, 1979 | doi: 10.1021/bk-1979-0101.ch009

Department of Nutrition and Food Science, Massachusetts Institute of Technology, Cambridge, MA 02138

N-nitrosodialkylamines - nitrosamines - constitute one of the most extensive series of known chemical carcinogens. Most nitrosamines can i n i t i a t e tumors in at least one animal species, and all animal species which have so far been tested are susceptible to nitrosamine carcinogenesis (1, 2). These compounds have received increasing attention as i t has become apparent that some of them are present in the environment (3, 4, 5, 6), and that they can be readily formed under physiological conditions from amines and n i t r i t e (7, 8, 9). In addition to these potentially important epidemiological aspects, the nitrosamines are especially interesting in terms of the biochemistry of chemical carcinogenesis. This i s exemplified most strikingly, perhaps, in the organ specificity of these compounds (10, 11), and in the wide variations in potency within the series (10, 12). We have been particularly interested in these potency variations both in terms of environmental exposure and formation and in the context of the mechanism through which nitrosamines i n i t i a t e cancer. The important review by Druckrey and Preussmann and their coworkers (10) contains quantitative carcinogenicity data for more than 60 N-nitroso compounds acting on a single animal strain - the BD rat. In this study, the animals were administered a small daily dose of each N-nitroso compound, and the mean total carcinogenic dose (D expressed as moles/kg body) required for production of tumors in 50% of the animals was then determined. Increasing values for D represent decreasing carcinogenicity. In our analyses, we usually express carcinogenic potency as 1/D in order to have increased potency represented by increasing numbers ( 1 3 ) . For a series of f a i r l y simple nitrosamines the potency among compounds which were observedly carcinogenic varied over a range of nearly one thousand. Some nitrosamines, e.g., N-nitrosoditert-butylamine, were not carcinogenic under the conditions of the experiments ( 1 0 ) . 50

50

50

0-8412-0503-5/79/47-101-153$05.00/0 ©

1979 A m e r i c a n C h e m i c a l Society

Anselme; N-Nitrosamines ACS Symposium Series; American Chemical Society: Washington, DC, 1979.

154

N-NITROSAMINES


R e l a t i v e Risks o f Nitrosamines. The mere e x i s t e n c e o f r e p r o d u c i b l e v a r i a t i o n s i n c a r c i n o g e n i c i t y from one nitrosamine t o another i s d i r e c t l y r e l e v a n t t o the question o f p o t e n t i a l human h e a l t h hazards from environmental nitrosamines. The problem o f nitrosamines i n cooked bacon i s a simple and s t r a i g h t f o r w a r d example. Several n i t r o s a m i n e s , i n c l u d i n g N - n i t r o s o p y r r o l i d i n e (NP), N-nitrosodimethylamine (NDMA), and N-nitrosodiethylamine (NDEA), have been detected a t v a r i o u s c o n c e n t r a t i o n s i n t h i s food. Table 1 ^ l i s t s some t y p i c a l values f o r the c o n c e n t r a t i o n s o f these com pounds i n cooked bacon and some other prepared meat products (14). N i t r o s o p y r r o l i d i n e has been g e n e r a l l y found, e s p e c i a l l y i n bacon, at much higher l e v e l s than NDMA o r NDEA, and most a t t e n t i o n has consequently been d i r e c t e d toward t h i s compound (15_, 16). Table 1 Concentration o f nitrosamines i n processed meats, i n c l u d i n g bacon T y p i c a l high v a l u e s (14,17) T y p i c a l low values (14,17) Nitrosamine ppb mol X 10 /g food ppb mol X 10 /g food 9

NDMA NDEA NP

25 12 50

9

0.34 0.12 0.50

0.04 0.02 0.05

3 2 5

Table 2_ shows the c a r c i n o g e n i c p o t e n c i e s o f NP, NDMA and NDEA, expressed as I/D50. I n t e r e s t i n g l y , NDMA and NDEA are more potent ( i n BD r a t s , a t l e a s t ) than NP. We have consequently pointed out (17) t h a t the p o t e n c i e s o f environmental carcinogens should be considered along with c o n c e n t r a t i o n s when a s s e s s i n g the p o t e n t i a l hazards o f these compounds. Table 2 Carcinogenic p o t e n c i e s i n the BD r a t (10,13,17) Nitrosamine

D a i l y Dose (mmol/kg)

50 (mol/kg)

1/D50

Relative Potency

NDMA NDEA NP

0.05 0.05 0.05

0.0054 0.0065 0.039

185 154 26

7 6 1

u

These ideas can be expressed q u a n t i t a t i v e l y i n terms o f a relative risk factor: R = PC where C i s the c o n c e n t r a t i o n and Ρ i s the r e l a t i v e potency o f a


9.

wiSHNOK

Ν-Nitrosamine

given compound. and NDEA.

Carcinogenesis

155

Table 3 shows the r e l a t i v e r i s k s o f NP, NDMA Table 3 R e l a t i v e c a r c i n o g e n i c r i s k s (17) R e l a t i v e Risk/g Food High Intake Low Intake

Nitrosamine


NDMA NDEA NP

48 19 10

6 2 1

From these c o n s i d e r a t i o n s , i t appears t h a t NDMA and NDEA both o f which have r e c e i v e d l e s s a t t e n t i o n than NP - may a c t u a l l y pose greater hazards than does NP. T h i s a n a l y s i s , along with some observations concerning the p o s s i b l e absolute hazards a r i s i n g from nitrosamines i n bacon, has been d e t a i l e d i n an e a r l i e r r e p o r t (17). S t r u c t u r e - A c t i v i t y R e l a t i o n s h i p s . More i n t e r e s t i n g , and s c i e n t i f i c a l l y , a t l e a s t - more s i g n i f i c a n t , i s the question o f why one nitrosamine should be more or l e s s c a r c i n o g e n i c than another. In a general sense, the answer i s obvious: d i f f e r e n c e s i n r e a c t i v i t y w i t h i n a s e r i e s are, almost by d e f i n i t i o n , the r e s u l t o f d i f f e r e n c e s i n s t r u c t u r e . T h i s concept i s one o f the cornerstones o f p h y s i c a l organic chemistry and, more r e c e n t l y , has been a p p l i e d e x t e n s i v e l y t o drug systems i n a systematic and q u a n t i t a t i v e way f o l l o w i n g the i n i t i a l and continued successes o f Corwin Hansch and h i s coworkers (18-25). These and other i n v e s t i g a t o r s have shown, f o r many systems where a b i o l o g i c a l response can be measured q u a n t i t a t i v e l y , t h a t r e l a t i v e b i o l o g i c a l response can be expressed as f u n c t i o n s o f v a r i o u s molecular p r o p e r t i e s by using equations o f the same forms as Hammett o r T a f t r e l a t i o n s h i p s : RBR = k

x

+ k TT(19)

RBR = k

x

+ k ff - k 7 T ( 2 0 )

RBR

= k

1

2

2

x

2

+ k ir 2

2

3

k 7T 3

2

+ k a(22)

3

4

RBR i s the r e l a t i v e b i o l o g i c a l response, π i s d e f i n e d as log Ρ^ - l o g P where P^ i s g e n e r a l l y the water-octanol p a r t i t i o n c o e f f i c e n t f o r the parent molecule and Ρ i s the p a r t i t i o n c o e f f i c i e n t f o r the molecule c o n t a i n i n g s u b s t i t u e n t ' S . The a*s are standard Hammett or T a f t s u b s t i t u e n t constants (.26, 27) . These r e l a t i o n s h i p s have been u s e f u l t o a c e r t a i n extent as the b a s i s f o r r a t i o n a l methods o f drug design (24) , and have been v a l u a b l e a l s o as probes f o r a s s e s s i n g which molecular p r o p e r t i e s are a c t u a l l y involved i n determining drug potency and t o x i c i t y (23). H

f


156

N-NITROSAMINES


Despite the widespread use o f s t r u c t u r e - a c t i v i t y r e l a t i o n ships i n pharmacology, there have been r e l a t i v e l y few attempts to apply t h i s type of data a n a l y s i s i n the area of chemical c a r c i n o g e n e s i s , although some very general i n t u i t i v e s t r u c t u r e a c t i v i t y c o r r e l a t i o n s have o f t e n been noted f o r the nitrosamines. For example, nitrosamines with branching and, consequently, fewer hydrogens a t the α-carbon g e n e r a l l y have lower c a r c i n o g e n i c potency than t h e i r unbranched isomers (10, 28) and unsymmetrical nitrosamines, e s p e c i a l l y with methyl as one of the a l k y l groups, tend to be more s p e c i f i c towards the esophagus (.10, 11). Excep t i o n s and o v e r l a p , however, have tended to obscure any r i g o r o u s s y s t e m a t i z a t i o n of these observations. An i n t e r e s t i n g q u a n t i t a t i v e r e l a t i o n s h i p between d a i l y dose and i n d u c t i o n time was developed by Preussmann and coworkers (10): dt

n

= constant

In t h i s expression d i s the d a i l y dose and t i s the time r e q u i r e d f o r i n d u c t i o n of tumors i n 50% o f the animals. The exponent η i s then c h a r a c t e r i s t i c of a given nitrosamine. The value of η i s g e n e r a l l y about 2 and ranges from about 1 to 4. No systematic a s s o c i a t i o n between η and s t r u c t u r e , however, has been found and there i s consequently no apparent molecular r a t i o n a l e f o r t h i s relationship. Q u a n t i t a t i v e s t r u c t u r e - a c t i v i t y analyses i n chemical c a r c i n o g e n i c i t y may a l s o have appeared d i s c o u r a g i n g because of an i n t u i t i v e f e e l i n g t h a t the biochemical events l e a d i n g to cancer s i n c e they apparently i n v o l v e a d i s r u p t i o n of the t r a n s m i s s i o n of genetic information - are much more complex than those i n volved i n drug-host i n t e r a c t i o n s , and t h a t there would t h e r e f o r e be l i t t l e l i k e l i h o o d t h a t c a r c i n o g e n i c i t y could be d e s c r i b e d by r e l a t i o n s h i p s such as equations 1-3. In a d d i t i o n , there i s no generally-agreed-on q u a n t i t a t i v e c r i t e r i o n f o r c a r c i n o g e n i c potency; mean c a r c i n o g e n i c dose, D (1£) , mean i n d u c t i o n time, t s o (10), percent-tumor-bearing-animals (29), as w e l l as other c r i t e r i a (3£) , have been used by v a r i o u s i n v e s t i g a t o r s . Finally, the development of b i o l o g i c a l s t r u c t u r e - a c t i v i t y r e l a t i o n s h i p s r e q u i r e s a f a i r l y l a r g e sample of i n t e r n a l l y c o n s i s t e n t q u a n t i t a t i v e data, i . e . , the same s t r a i n of animal, the same dosing p r o t o c o l , and the same c r i t e r i o n f o r potency. T h i s l a s t set of c o n d i t i o n s has r a r e l y been met. The Druckrey-Preussmann review, however, contains reasonably q u a n t i t a t i v e data f o r a v a r i e t y of molecular types i n c l u d i n g N-nitrosoureas, and c y c l i c and a c y c l i c N - n i t r o s o d i a l k y l a m i n e s . We became i n t e r e s t e d i n whether or not b i o l o g i c a l s t r u c t u r e a c t i v i t y r e l a t i o n s h i p s could be developed f o r any of these sets of compounds. Only the a c y c l i c nitrosamines appeared to c o n s t i t u t e a s u f f i c i e n t l y extensive and w e l l - d e f i n e d s e r i e s , and we consequently c a r r i e d out computerized m u l t i p l e r e g r e s s i o n analyses on t h i s group of compounds, using l o g (1/D ) dependent v a r i a b l e analogous to RBR (12). 50

a

s

50


t

n

e

9.

N-Nitrosamine

wisHNOK

Carcinogenesis

157

A standard stepwise r e g r e s s i o n program (31) was used t o f i n d the f u n c t i o n that would best c o r r e l a t e carcinogenic potency with a s e t o f molecular p r o p e r t i e s . In t h i s procedure, a l i n e a r func t i o n i s developed by adding i n t u r n the independent v a r i a b l e t h a t y i e l d s the highest c o r r e l a t i o n between the l i n e a r f u n c t i o n and the dependent v a r i a b l e . The success o f the c o r r e l a t i o n i s i n d i cated by the m u l t i p l e R . The increase i n R , as each independent v a r i a b l e i s added, i s an i n d i c a t i o n o f the c o n t r i b u t i o n o f t h a t v a r i a b l e t o the c o r r e l a t i o n . The standard e r r o r o f the r e g r e s s i o n equation, s, i s an absolute measure o f how w e l l the equation can p r e d i c t RBR - i n t h i s case l o g ( l / D o ) · c o r r e l a t i o n analogous to equation 1 or 2 was found, but the i n c l u s i o n o f an e l e c t r o n i c f a c t o r , σ*, l e d t o the c o r r e l a t i o n described by equation 4 [Singer, T a y l o r , and L i j i n s k y have r e c e n t l y reported a c o r r e l a t i o n , f o r a small s e r i e s o f n i t r o s o p i p e r a z i n e s , with the form o f equation 1 (29). Using only p a r t i t i o n c o e f f i c i e n t s , they found no c o r r e l a t i o n f o r a c y c l i c nitrosamines (see, however, D i s c u s s i o n s e c t i o n ) . This i s i n agreement with our e a r l i e r observations based on the Druckrey-Preussmann data (13)]. 2

2

N

o


5

log

(1/D ) = i η = 21

7

- 0 . 2 6 7 Γ + 0.92π + 0.59σ* s = 0.31 R = 0.84

4

2

50

4

2

Table 4 shows the development o f R

2

for this

equation.

Table 4 Results o f stepwise r e g r e s s i o n a n a l y s i s o f l o g (1/D ) - ' * * (jL) v s

π

π

2

a

n

d

σ

2

50

Step 1 2 3

2

Variable

R

π2 π σ*

0.36 0.66 0.84

T

ζ

Increase i n R

2

0.30 0.18

The carbon adjacent t o the amine n i t r o g e n (the α-carbon) was considered t o be the r e a c t i o n center, and the compounds were g e n e r a l l y considered t o have two r e a c t i o n centers. Thus, f o r N-nitrosomethy1-(2-chloroethyl)amine, the σ*' s

H - C H

2

J>INO CI-CH CH ^ 2

2


158

7V-NITROSAMINES

for H (0.49) and C1CH (1.05) were used. Table 5 l i s t s a s e r i e s of nitrosamines along with the values f o r π, σ* a t each α-carbon, the observed value f o r l o g (I/D50) l 1°9 ( l / 5 o ) as c a l c u l a t e d u s i n g equation 4. The compounds designated 'a' were used i n the d e r i v a t i v e of equation 4 and the l o g (I/D50) values for the remaining compounds were c a l c u l a t e d l a t e r . A more de t a i l e d d e s c r i p t i o n of the development of equation 4 i s contained i n r e f e r e n c e 12. The r e l a t i o n s h i p d e s c r i b e d by equation 4 i n d i c a t e s t h a t most of the v a r i a t i o n i n c a r c i n o g e n i c i t y w i t h i n the s e r i e s of a c y c l i c nitrosamines can be a s s o c i a t e d with water-hexane p a r t i t i o n coef f i c i e n t s and e l e c t r o n i c i n d u c t i v e e f f e c t s of s u b s t i t u e n t s on the α-carbons. T h i s equation i s a f a i r l y t y p i c a l b i o l o g i c a l s t r u c t u r e a c t i v i t y r e l a t i o n s h i p with a strong dependence on p a r t i t i o n c o e f f i c i e n t s , and i t t h e r e f o r e suggests t h a t the n i t r o s a m i n e s , and perhaps other chemical carcinogens as w e l l , are s i m i l a r - i n the pharmacological sense - t o a n a l g e s i c s or t o x i c agents. The v a r i a t i o n of a b i o l o g i c a l response with v a r i a t i o n s i n s o l u b i l i t y p r o p e r t i e s i s u s u a l l y i n t e r p r e t e d i n terms of the a b i l i t y of the a c t i v e molecules t o reach an i n t r a c e l l u l a r s i t e of a c t i o n (18-22). In many c a s e s , p a r t i t i o n c o e f f i c i e n t s dominate most other molecular f a c t o r s i n determining v a r i a t i o n s i n b i o l o g i c a l a c t i v i t y , i n d i c a t i n g t h a t t r a n s p o r t t o the s i t e of a c t i o n may be the r a t e l i m i t i n g process i n the o v e r a l l sequence of events g i v i n g r i s e t o the b i o l o g i c a l response. In cases of t h i s type, the a d d i t i o n of terms f o r e l e c t r o n i c or s t e r i c e f f e c t s do not lead t o s i g n i f i c a n t l y improved c o r r e l a t i o n s . The appearance of an e l e c t r o n i c term i n the nitrosamine c a r c i n o g e n i c i t y r e l a t i o n s h i p i s t h e r e f o r e i n t e r e s t i n g and p o t e n t i a l l y i n f o r m a t i v e i n terms of the mode of a c t i o n of these compounds. The mechanism of nitrosamine c a r c i n o genesis has not been f i r m l y e s t a b l i s h e d but there i s a growing body of evidence which i n d i c a t e s t h a t the i n i t i a l and biochemical r a t e - l i m i t i n g step i s enzymatic o x i d a t i o n a t an α-position (2_, 10, 32). T h i s i s apparently followed by a s e r i e s of chemical steps l e a d i n g f i n a l l y to a h i g h l y e l e c t r o p h i l i c species such as a diazonium i o n or carbonium i o n which r e a c t s with a n u c l e o p h i l i c s i t e on a macromolecule such as DNA (2_, 10, 33^, 34) . In our a n a l y s e s , c o r r e l a t i o n of c a r c i n o g e n i c potency with T a f t σ* values was obtained only when the α-position was assumed to be the r e a c t i o n center on the nitrosamine molecule. This observation i s c o n s i s t e n t with the above hypothesis and, f o r the f i r s t time, d i r e c t l y a s s o c i a t e s the α-position with c a r c i n o g e n i city. I t i s a l s o i n t e r e s t i n g to note t h a t t h i s r e l a t i o n s h i p accounts for most of the v a r i a t i o n i n potency on the b a s i s of p r o p e r t i e s of the unmetabolized precarcinogen. S p e c i f i c s t r u c t u r a l requirements f o r the u l t i m a t e carcinogen at the s i t e of the s i g n i f i c a n t b i o l o g i c a l i n t e r a c t i o n thus appear to be r e l a t i v e l y unimportant. 2


a

n

d

t

h

e

v

a

u

e

f

o

r


D

9.

wisHNOK

N-Nitrosamine

159

Carcinogenesis

Examination o f the observed and p r e d i c t e d values f o r l o g (1/D ) i n Table 5 r e v e a l s t h a t there are a t l e a s t four types o f compounds t h a t are apparently not w e l l - d e s c r i b e d by equation 4. These i n c l u d e compounds with hydroxy groups (e.g. compounds 20, 21, 22), compounds with c h e m i c a l l y r e a c t i v e α-hydrogens (e.g., a l l y l i c or b e n z y l i c systems, No's 9, 14), and compounds with ex t e n s i v e branching a t the α-carbon (No's 4, 11). A c y c l i c n i t r o samines, with one or two apparent exceptions (12!}, appear t o c o n s t i t u t e a separate r e a c t i o n s e r i e s (29). In the f i r s t three cases the c a l c u l a t e d values f o r l o g (I/D50) are a l l higher than the observed v a l u e s . In the cases o f the OH-bearing compounds and the a l l y l i c and b e n z y l i c compounds, t h i s may r e f l e c t a l t e r n a t e metabolic pathways i n which the mole c u l e s are converted t o non-carcinogenic or l e s s - c a r c i n o g e n i c metabolites. The low observed l o g ( 1 / D 5 Q ) ' S f o r compounds with branching at the α-position probably i n d i c a t e the importance o f a s t e r i c f a c t o r which was not r e v e a l e d i n the r e g r e s s i o n a n a l y s i s because of the small number o f examples o f t h i s s t r u c t u r a l type. For a s e t o f c y c l i c compounds, the N - n i t r o s o p i p e r i d i n e s , Singer, T a y l e r , and L i j i n s k y - u t i l i z i n g the r e l a t i v e number o f tumor-bearing animals (RTBA) or the r e l a t i v e mean l i f e t i m e (RML) as i n d i c e s o f c a r c i n o g e n i c potency - obtained c o r r e l a t i o n s be tween potency and p a r t i t i o n c o e f f i c i e n t s as shown below (29):


50

l o g RTBA = 0.098 - 0.08 l o g Ρ η = 6 r = 0.940 s = 0.019 2

l o g RML = 0.01 - 0.26(log P ) + 0.2 l o g Ρ η = 6 r = 0.99 s = 0.047 2

M u l t i p l e r e g r e s s i o n a n a l y s i s on t h i s data (29), with the a d d i t i o n of σ* v a l u e s , gave no improvement on these r e l a t i o n s h i p s . For a s e r i e s o f d i n i t r o s o p i p e r a z i n e s , however, f o r which no c o r r e l a t i o n was detected with l o g Ρ values alone, a f a i r c o r r e l a t i o n could be generated when σ* was i n c l u d e d : 2

l o g RTBA = 0.09 - 0.75(log P ) + 0.762 l o g Ρ - 0.62σ* η = 5 R = 0.86 R = 0.73 s = 0.11 2

Although a d d i t i o n a l data would be d e s i r a b l e f o r a l l three o f these r e l a t i o n s h i p s , there seems l i t t l e doubt t h a t they are r e a l and t h a t s t r u c t u r e - a c t i v i t y r e l a t i o n s h i p s can t h e r e f o r e probably be generated f o r a d d i t i o n a l subclasses o f N - n i t r o s o d e r i v a t i v e s given s u f f i c i e n t q u a n t i t a t i v e data. In summary, i t appears t h a t the d i f f e r e n c e s i n c a r c i n o g e n i c potency f o r both c y c l i c and a c y c l i c N - n i t r o s o d i a l k y l a m i n e s are r e a l and systematic, and t h a t the p o t e n c i e s o f environmental nitrosamines should be considered i n a s s e s s i n g the r e l a t i v e hazards a s s o c i a t e d with these compounds. In a d d i t i o n , i t can be shown t h a t the c a r c i n o g e n i c i t y o f nitrosamines can be a s s o c i a t e d



2

a

a

a

a

a

8 9 i oa 11 12 13 14 15

a

a a

6

a a

a

a

a

3 4

i

N-nitroso compound

3

3

3

3

3

3

3

3

3

3

3

3

3

3

2

2

2

2

3

2

1+

CH (CH ) (CH ) CH CH (CH ) CH (CH ) CH CH CH CH CH CH CH CH CH

CH3CH2

CH

Rl

2

3

2

2

2

2

2

2

2

+

2

+

3

6

6

6

3

5

5

5

2

6

2

2

C H C H CH C H CH CH

CH (CH )

2

cyclo-C0Hi1

3

2

2

3

3

3

3

3

3

CH CH CH CH (CH ) (CH ) CH CH (CH ) CH (CH )i CH CH CH =CH CH =CHCH CH (CH )i

R2

2

0.49 0 -0.1 -0.49 -0.115 -0.125 0.49 0.49 0.49 0.49 0.49 0.49 0.49 0.49 0.49

σ*ι

52— CH2

51- CH

0.6 0.22

D

0.2 -0.125 -0.71 -0.135

D

β

0.49 0 -0.1 -0.49 -0.115 -0.125

σ*2

^ N-N=0

log(l/g ) Obs. 2.3 3.2 2.1 1.0 1.6 0.6 2.3 2.9 2.1 2.6 3.0 1.5 1.6 3.1 3.0

ττ 0 1.24 2.49 2.24 3.59 4.22 0.60 1.84 1.17 2.51 1.26 3.54 4.03 1.92 3.22

5 0

2.3 2.5 2.3 1.9 1.5 0.8 2.5 2.8 2.9 2.6 2.4 1.9 1.5 3.2 2.4

5 0

log(l/D ) Cale.

Carcinogenic A c t i v i t y o f N-Nitroso Compounds ( N-N=0) (12) R " The f o l l o w i n g compounds, with no observed c a r c i n o g e n i c a c t i v i t y , are not included i n the t a b l e : N-nitrosodiphenylamine, N-nitrosodicyclohexylamine, N - n i t r o s o d i a l l y l a m i n e and N-nitrosodibenzylamine. Substituent constants (σ*) are based on the f o l l o w i n g s t r u c t u r e :

Table 5



2

a

a

a

3

3

2

CH

3

3

CH CH CH

CH

3

CH NCCH

2

2

3

3

3

2

2

C

3

2

2

2

0.49

3

3

2

0.49

0.49

0.49 1.25

CH3NNOCH2

2

0

0.56 -0.115

0.49 0

2

3

2

2

-0.115

0 0

0

CH CH OOC CH CH OOC

CH3CO

NCCH NCCH

2

C1CH CH

2

2

HOCH CH HO(CH ) CH

2

HOCH CH

3

CH (CH2)if

3

(CH ) CH CH (CH )

2

CH =CH

2

^Compounds included i n equation 2. No " r e a c t i o n center" on R . From Druckrey e t a l . (10).

29

27 28

26

24 25

3

3

a

CH

&

23

2

HOCH CH CH (CH )

21 22

2

CH3CH2

3

CH (CH )

20

a

CH3CH2 CH3CH2

17 18

19

3

2

CH CH

16

0.49

b b

D

-0.49 -0.115 -0.125 0.56 0.56 -0.12 1.05 1.25 1.25

b

Table 5 (continued) 2.55 1.15 2.52 4.17 0.57 -0.12 2.92 1.30 -0.58 -1.15 0.10 0.06 0.69 0.48


2.6 1.5 2.1 1.0 1.8 0.05 2.0 3.2 2.2 1.9 2.3 2.0 2.0 2.4

2.4 2.2 2.3 0.9 2.5 2.3 2.1 3.4 2.1 1.8 2.1 2.1 2.3 2.7

162

N-NITROSAMINES


with fundamental molecular properties via quantitative structurea c t i v i t y relationships which may prove useful as methods of predicting carcinogenicity and as tools for probing mechanisms of carcinogenicity. Acknowledgements. A l l of the original work described in this paper is a result of my very f r u i t f u l continuing collaboration with Dr. Michael Archer. The coding of molecular properties and the actual computer work was done by Mr. Andrew Edelman. Dr. Will Rand furnished invaluable advice on a l l aspects of the regression analyses. This work was supported by the M.I.T. Health Sciences Fund, Hoffmann-La Roche, Inc., The Marjorie Merriwether Post Foundation, and Public Health Services Contract N01 CP33315 with the Division of Cancer Cause and Prevention, National Cancer Institute. Literature cited. 1. 2. 3. 4. 5. 6. 7. 8.

9. 10. 11.

12. 13. 14. 15.

H. Druckrey, R. Preussmann, and S. Ivancovic, Ann. N.Y. Acad. S c i . , 163, 676 (1969). P.N. Magee and J.M. Barnes, Adv. Cancer Res., 10, 163 (1967). G.N. Wogan and S.R. Tannenbaum, Toxicol. Appl. Pharmicol., 31, 375 (1975). D. Shapley, Science, 191, 268 (1976). D.H. Fine, D.P. Rounbehler, N.M. Belcher, and S.S. Epstein, i b i d . , 192, 1328 (1976). D.H. Fine, D.P. Rounbehler, T. Fan, and R. Ross, in Origins of Human Cancer, Cold Spring Harbor Conferences on Human Cell Proliferation, Vol. 4, 293 (1977). T.S. Mysliwy, E.L. Wick, M.C. Archer, R.C. Shank, and P.M. Newberne, Brit. J . Cancer, 30, 279 (1974). S.R. Tannenbaum, M.C. Archer, J.S. Wishnok, P. Correa, C. Cuello, and W. Haenszel, in Origins of Human Cancer, Cold Spring Harbor Conferences on C e l l Proliferation, Vol. 4, 1609 (1977) S.R. Tannenbaum, M.C. Archer, J.S. Wishnok, and W. Bishop, J . Nat'l Cancer Inst., 60, 251 (1978) H. Druckrey, R. Preussmann, S. Ivankovic, and D. Schmähl, Z. Krebsforsch., 69, 103 (1967). L.Y.Y. Fong and P.M. Newberne, Proceedings of F i f t h Meeting on Analysis and Formation of N-Nitroso Compounds, International Agency for Research on Cancer, Durham, N.H., 1977, in press. J.S. Wishnok, M.C. Archer, A.S. Edelman, and W.M. Rand, Chem.-Biol. Interactions, 20, 43 (1978). J.S. Wishnok and M.C. Archer, Brit. J . Cancer, 33, 307 (1976). R.A. Scanlan, C r i t . Rev. Food Technol., 5, 357 (1975). N.P. Sen, B. Donaldson, S. Seaman, J.R. Iyengar, and W.F. Miles, J . Agric. Food Chem., 24, 397 (1976), and references


9.

16. 17. 18. 19. 20.


21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34.

WISHNOK

N-Nitrosamine

Carcinogenesis

163

T. Hansen, W. Iwaoka, L. Green, and S.R. Tannenbaum, i b i d . , 25, 1427 (1977), and references M.C. Archer and J.S. Wishnok, Fd. Cosmet. Toxicol., 15, 233 (1977). C. Hansch, Accounts Chem. Res., 2, 232 (1969) C. Hansch and T. Fujita, J . Amer. Chem. Soc., 86, 1616 (1964). W.J. Dunn III and C. Hansch, Chem.-Biol. Interactions, 9, 75 (1974). C. Hansch and W.J. Dunn III, J . Pharm. S c i . , 61, 1 (1972). C. Hansch and J.M. Clayton, i b i d . , 62, 1 (1973). C. Hansch, N. Smith, R. Engle, and H. Wood, Cancer Chemother. Rep., 56, 443 (1972). C. Hansch, i b i d . , 56, 433 (1972). A. Leo, C. Hansch, and D. Elkins, Chem. Rev., 71, 525 (1971). E.S. Gould, Mechanism and Structure in Organic Chemistry, Holt, Rinehart, and Winston, New York, 1959, pp. 227-230. R.D. Gilliam, Introduction to Physical-Organic Chemistry, Addison-Wesley, Reading, Mass., 1970, pp. 156-160. W. Lijinsky, New Scientist, 216 (1977). G.M. Singer, H.W. Taylor, and W. Lijinsky, Chem.-Biol. Interactions, 19, 133 (1977). D. Schmähl, Oncology, 33, 73 (1976). W.J. Dixon (Ed.), in BMDP Biomedical Computer Programs, University of California Press, Berkeley, 1975, pp. 491-539. D. Dagani and M.C. Archer, J . N a t ' l Cancer Inst., 57, 955 (1976). C.C. Irving in H. Busch (Ed.), Methods in Cancer Res., Vol. 7, Academic Press, New York, 1973, pp. 189-244. K.K. Park, M.C. Archer, and J.S. Wishnok, Chem.-Biol. Interactions, 18, 349 (1977).

R E C E I V E D F e b r u a r y 21,

1979.


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