298 E. BOYLAND VOL. 4 {1950) 



shows that a carcinogen can react with tissue protein. As the hydrocarbons react with 

 perbenzoic acid almost as rapidly as dimethylaminobenzene and the azo group of the 

 latter compound is expected on theoretical grounds to have an electron density of the 

 same order as the carcinogenic hydrocarbons, the carcinogenic hydrocarbons might also 

 be expected to combine with some tissue protein in a similar way. 



Although the French theoretical chemists have concentrated on the K region of a 

 particular carcinogenic hydrocarbon it is perhaps worth noticing that these substances 

 have two active regions. Many carcinogens such as 1:2: 5 : 6-dibenzanthracene and 3:4- 

 benzphenanthrene contain two active phenanthrene double bonds or K regions. In those 

 carcinogenic hydrocarbons with only a single K region the groups which activate that 

 region may also increase the activity of a second part of the molecule. Thus, in the potent 

 carcinogen 9: io-dimethyl-i:2-benzanthracene, the two methyl groups not only make 

 the 3 : 4 bond more active than in the unsubstituted i : 2-benzanthracene but also 

 increase the chemical reactivity of the 9:10 or meso positions. Such meso substituted 

 anthracene derivatives are extremely susceptible to many chemical reactions, such as 

 photo-oxidation. The metabolism of carcinogens also shows that another region of the 

 molecule (the benzene ring adjoining the K region) is liable to attack in vivo. Although 

 it is quite clear that carcinogenic hydrocarbons must have one centre of high chemical 

 reactivity, they also have a second active centre, either a second phenanthrene double 

 bond, active meso positions, or an amino group as in the aminostilbenes or the amino- 

 azobenzene derivatives. 



The reactivity of hydrocarbons is also shown by metabolism experiments with non- 

 carcinogenic hydrocarbons such as naphthalene (Booth and Boyland^^); (Young*^) 

 and anthracene (Boyland and Levi*^) as well as with the carcinogenic hydrocarbon 

 3 : 4-benzpyrene (Weigert and Mottram^*). These hydrocarbons undergo the reaction 

 of perhydroxylation involving the addition of the elements of hydrogen peroxide with 

 formation of dihydroxydihydro derivatives or diols. In the case of the non-carcinogenic 

 hydrocarbons the addition of the hydroxyl groups occurs at the centres with highest 

 electron density. But in the carcinogenic hydrocarbons which have been examined the 

 oxidation occurs in positions in a ring adjacent to the K region — not in the reactive 

 K region itself. This may be because the more reactive carcinogens combine with some 

 tissue constituent through the double bond so that only regions of secondary activity 

 are available for the oxidative process. The investigation of 3 : 4-benzpyrene metabolism 

 showed that the dihydroxydihydro-benzpyrene formed by metabolism in isolated skin 

 was combined to some tissue constituent. The combination, however, could be destroyed 

 by treatment with wet acetone. Studies with i : 2 : 5 : 6-dibenzanthracene containing 

 radioactive carbon (Heidelberger and Jones^^) have shown that a small part of the 

 carcinogen remains in animals for many months after injection. Thus there are several 

 indications, that the carcinogenic hydrocarbons can react with some, as yet unidentified, 

 tissue constituents. 



Although these hydrocarbons have some of the biological effects of nitrogen mus- 

 tards they do not appear to inhibit the hexokinase of tumours; the anaerobic glycolysis 

 and respiration of tumours is the same whether they are growing normally or are in- 

 hibited by 1 : 2 : 5 : 6-dibenzanthracene (Boyland and Boyland*^). On the other hand 

 inhibition of tumour growth by nitrogen mustard is accompanied by a decrease in the 

 anaerobic glycolysis of the tissue (Boyland et al.''-^). This inhibition of tumour growth 

 by carcinogens, such as 4-dimethylaminostilbene or 1:2:5: 6-dibenzanthracene, is only 



References p. 300. 



