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3193. Carcinogens in the colon
370
Cancerresearch
reducing the level of available pulmonary epoxide Controls were injected with glycerine only. No renal hydrases; the other involves the possible inhibition carcinogenic or erythrogenic response was provoked by one carcinogen of the enzyme responsible for the after 12 months except in the case of Ni&. There hepatic metabolism of the other, thus. making more were no histological effects with the other comcarcinogen available for tumour induction in extra- pounds, except intense fibrosis around the metal salt hepatic tissues.The authors argue that since tobacco deposits and occasional calcification in the lower smoke contains both nitrosamines (including DMNA) nephron. and hydrocarbons (benzo[a]pyrene and benzo In the second study cited, rats were given single [/?]fluoranthene) similar in carcinogenic properties to intramuscular injections of various insoluble nickel3-methyIcholanthrene, synergism between carcino- containing powders (particles less than 2 pm in diagenic hydrocarbons and nitrosamines may be in- meter) suspended in a penicillin solution. The insolvolved in the genesis of lung tumours in smokers. uble nickel compounds NiS, Ni,S,, a partially conThe suggestion is also made that readier induction verted nickel-iron sulphide (Ni,FeS,) matte (resemof lung cancer in smokers might accompany the bling an intermediate encountered in the refining of choice of a diet rich in nitrosamines or nitrosamine pentlandite ore) and metallic nickel produced markprecursors. edly different incidences of local sarcomas after 2 yr. Thus sarcomas developed in 17 of 19 rats given a dose of 5 or 20mg Ni,S,, while amorphous NiS in3192. Sarcoma and the shape of nickel duced no tumours, tindings in agreement with the Jasmin, G. & Riopelle, J. L. (1976). Renal carcinomas results of the study described above. With the parand erythrocytosis in rats following intrarenal injec- tially converted Ni,FeS, matte in a dose of 9.2 or 36.8 mg, the incidence of sarcomas lay between the tion of nickel subsulphide. Lab. Invest. 35. 71. incidence with Ni& and that with metallic Ni. The Sunderman, F. W., Jr. & Maenza, R. M. (1976). Com- tumours were classifiedas fibrosarcomas (50x), rhabparisons of carcinogenicities of nickel compounds in domyosarcomas (32x), undifferentiated sarcomas (11%)and pleomorphic sarcomas(7%). It is suggested rats. Rex Commun. chew. Path. Pharmac. 14. 3 19. that differences in the chemical bonding in amorIt has previously been demonstrated that nickel phous NiS and in the rhombohedral crystals of Ni,S, and some nickel compounds, including nickel subsul- used in this study may be a factor in the different phide (NisS,), produce tumours at the site of intra- sarcoma-inducing potential of these two materials, muscular injection (Cited in F.C.7: 1964, 2. 33; Gil- since both compounds have a very low solubility in man, Cancer Rex 1962, 22. 158). The carcinogenic water. potential of nickel compounds seemsgenerally to be inversely proportional to their solubility in water 3193. Carcinogens in the colon (Cited in F.C.?: 1969, 7. 334). The two recent studies cited above shed further light on the potential of Renwick, A. G. & Drasar, B. S. (1976). Environmental various nickel compounds to induce tumours. carcinogens and large bowel cancer. Nature, Land. In the first study cited, rats were injected intra- 263, 234. renally with Ni,S, and other metallic compounds. The first experiment involved four groups of young There is strong evidence that environmental and female rats; one group was injected with 10 mg NisS, probably dietary factors are involved in large-bowel in 1 ml saline in the jugular vein, two groups were cancer (Cited in F.C.7: 1972, 10, 440). Diet influences injected with 10 mg N&S2 intrarenally in either 0.1 ml both bile-acid levels and the nature of the gut flora, glycerine or 0.1 ml saline (half of the dose into each both of which have been implicated in colon carcinopole of the right kidney), and a control group received genesis.It has been demonstrated (lot. cit.) that cerintrarenal glycerine only. None of the animals in- tain known carcinogens are absorbed in the upper jected iv had increased numbers of red blood cells reaches of the gut, that they are N-hydroxylated and or renal neoplasms, but intrarenal administration of conjugated with glucuronic acid in the liver, and that Ni,S, in either glycerine or saline caused an increase the conjugate is then excreted in the bile from which in red blood cells and an average renal tumour inci- the gut flora liberates the free N-hydroxy compound, dence of 40% after 12 months. the postulated active carcinogen. The paper cited Despite the complex morphology of the renal par- above describespreliminary investigations on an anaenchyma, the neoplastic renal cells appeared to be logous mechanism by which the carcinogen benzoepithelial in origin but showing a pronounced tend- [alpyrene may reach the large bowe1 without causing ency to evolve towards an anaplastic spindle-cell vari- cancer in other parts of the gut. ant. There was no indication that the erythrogenic Two bile-duct-cannulated rats were each given and carcinogenic responses to NisS, were interre- 1 mg [7,10,14-i4Cjbenzo[a]pyrene. The bile was collated, as the high haemoglobin and erythrocyte values lected for 4 hr and contained 6.7 and 12.5% of the tended to fall again with the development of the renal 14C. Analysis by thin-layer chromatography showed carcinoma. a single peak of radioactivity corresponding to conjuIn the second experiment, rats were given renal in- gated metabolites. Aliquots of the pooled bile conjections of Ni&, nickel monosulphide (NiS), metallic taining the 14C-labelled metabolites of benzo[a]pyrnickel, cobalt sulphide, metallic cobalt, metallic chro- ene were incubated with samples of human and rat mium, metallic cadmium, metallic lead or metallic faeces,or with pure cultures of bacteria representing gold (5 mg suspended in 0.05 ml glycerine being in- the major types found in the intestine, for 72-96 hr jected into each pole of the right kidney, as before). under anaerobic conditions. The reaction mixtures
Cancerresearch were then analysed by thin-layer chromatography, which revealed that almost all the bacteria hydrolysed the conjugates to release the oxidative metabolites of benzo[a]pyrene. These reactions are a reversal of the detoxication processesoccurring within the liver. The organism releasing most parent hydrocarbon in the test, Clostridium paraputrijicum, is found in larger numbers in the faecesof high-risk (‘western’) subjects than in those of low-risk groups. Diet probably affects the metabolism of polycyclic aromatic hydrocarbons through its influence on the bile acids and on mucosal enzymes such as aryl hydrocarbon hydroxylases. Bile acids may influence in two ways the metabolism of polycyclic aromatic hydrocarbons excreted in the bile. They are important in the formation of mixed micelles in fat digestion,
371
and polar conjugates of benzo[a]pyrene may be incorporated into the micelles, aiding their passage through the gut. Further, polycyclic aromatic hydrocarbons are lipid soluble, which could make them inactive in the aqueous gut en’vironment. Bile acids are powerful solubilizing agents and would maintain the carcinogens in solution, thus aiding their interaction with cell surfaces. The authors conclude with the suggestion that . large-bowel cancer results from retoxification, by the gut flora, of liver metabolites of po\ycyclic aromatic hydrocarbons, a process influenced by diet. The disease is thus more common in western’ countries because western diets favour this retoxihcation and because industrial activity increases the amount of polycyclic aromatic carcinogens in the environment.
Cancerresearch
reducing the level of available pulmonary epoxide Controls were injected with glycerine only. No renal hydrases; the other involves the possible inhibition carcinogenic or erythrogenic response was provoked by one carcinogen of the enzyme responsible for the after 12 months except in the case of Ni&. There hepatic metabolism of the other, thus. making more were no histological effects with the other comcarcinogen available for tumour induction in extra- pounds, except intense fibrosis around the metal salt hepatic tissues.The authors argue that since tobacco deposits and occasional calcification in the lower smoke contains both nitrosamines (including DMNA) nephron. and hydrocarbons (benzo[a]pyrene and benzo In the second study cited, rats were given single [/?]fluoranthene) similar in carcinogenic properties to intramuscular injections of various insoluble nickel3-methyIcholanthrene, synergism between carcino- containing powders (particles less than 2 pm in diagenic hydrocarbons and nitrosamines may be in- meter) suspended in a penicillin solution. The insolvolved in the genesis of lung tumours in smokers. uble nickel compounds NiS, Ni,S,, a partially conThe suggestion is also made that readier induction verted nickel-iron sulphide (Ni,FeS,) matte (resemof lung cancer in smokers might accompany the bling an intermediate encountered in the refining of choice of a diet rich in nitrosamines or nitrosamine pentlandite ore) and metallic nickel produced markprecursors. edly different incidences of local sarcomas after 2 yr. Thus sarcomas developed in 17 of 19 rats given a dose of 5 or 20mg Ni,S,, while amorphous NiS in3192. Sarcoma and the shape of nickel duced no tumours, tindings in agreement with the Jasmin, G. & Riopelle, J. L. (1976). Renal carcinomas results of the study described above. With the parand erythrocytosis in rats following intrarenal injec- tially converted Ni,FeS, matte in a dose of 9.2 or 36.8 mg, the incidence of sarcomas lay between the tion of nickel subsulphide. Lab. Invest. 35. 71. incidence with Ni& and that with metallic Ni. The Sunderman, F. W., Jr. & Maenza, R. M. (1976). Com- tumours were classifiedas fibrosarcomas (50x), rhabparisons of carcinogenicities of nickel compounds in domyosarcomas (32x), undifferentiated sarcomas (11%)and pleomorphic sarcomas(7%). It is suggested rats. Rex Commun. chew. Path. Pharmac. 14. 3 19. that differences in the chemical bonding in amorIt has previously been demonstrated that nickel phous NiS and in the rhombohedral crystals of Ni,S, and some nickel compounds, including nickel subsul- used in this study may be a factor in the different phide (NisS,), produce tumours at the site of intra- sarcoma-inducing potential of these two materials, muscular injection (Cited in F.C.7: 1964, 2. 33; Gil- since both compounds have a very low solubility in man, Cancer Rex 1962, 22. 158). The carcinogenic water. potential of nickel compounds seemsgenerally to be inversely proportional to their solubility in water 3193. Carcinogens in the colon (Cited in F.C.?: 1969, 7. 334). The two recent studies cited above shed further light on the potential of Renwick, A. G. & Drasar, B. S. (1976). Environmental various nickel compounds to induce tumours. carcinogens and large bowel cancer. Nature, Land. In the first study cited, rats were injected intra- 263, 234. renally with Ni,S, and other metallic compounds. The first experiment involved four groups of young There is strong evidence that environmental and female rats; one group was injected with 10 mg NisS, probably dietary factors are involved in large-bowel in 1 ml saline in the jugular vein, two groups were cancer (Cited in F.C.7: 1972, 10, 440). Diet influences injected with 10 mg N&S2 intrarenally in either 0.1 ml both bile-acid levels and the nature of the gut flora, glycerine or 0.1 ml saline (half of the dose into each both of which have been implicated in colon carcinopole of the right kidney), and a control group received genesis.It has been demonstrated (lot. cit.) that cerintrarenal glycerine only. None of the animals in- tain known carcinogens are absorbed in the upper jected iv had increased numbers of red blood cells reaches of the gut, that they are N-hydroxylated and or renal neoplasms, but intrarenal administration of conjugated with glucuronic acid in the liver, and that Ni,S, in either glycerine or saline caused an increase the conjugate is then excreted in the bile from which in red blood cells and an average renal tumour inci- the gut flora liberates the free N-hydroxy compound, dence of 40% after 12 months. the postulated active carcinogen. The paper cited Despite the complex morphology of the renal par- above describespreliminary investigations on an anaenchyma, the neoplastic renal cells appeared to be logous mechanism by which the carcinogen benzoepithelial in origin but showing a pronounced tend- [alpyrene may reach the large bowe1 without causing ency to evolve towards an anaplastic spindle-cell vari- cancer in other parts of the gut. ant. There was no indication that the erythrogenic Two bile-duct-cannulated rats were each given and carcinogenic responses to NisS, were interre- 1 mg [7,10,14-i4Cjbenzo[a]pyrene. The bile was collated, as the high haemoglobin and erythrocyte values lected for 4 hr and contained 6.7 and 12.5% of the tended to fall again with the development of the renal 14C. Analysis by thin-layer chromatography showed carcinoma. a single peak of radioactivity corresponding to conjuIn the second experiment, rats were given renal in- gated metabolites. Aliquots of the pooled bile conjections of Ni&, nickel monosulphide (NiS), metallic taining the 14C-labelled metabolites of benzo[a]pyrnickel, cobalt sulphide, metallic cobalt, metallic chro- ene were incubated with samples of human and rat mium, metallic cadmium, metallic lead or metallic faeces,or with pure cultures of bacteria representing gold (5 mg suspended in 0.05 ml glycerine being in- the major types found in the intestine, for 72-96 hr jected into each pole of the right kidney, as before). under anaerobic conditions. The reaction mixtures
Cancerresearch were then analysed by thin-layer chromatography, which revealed that almost all the bacteria hydrolysed the conjugates to release the oxidative metabolites of benzo[a]pyrene. These reactions are a reversal of the detoxication processesoccurring within the liver. The organism releasing most parent hydrocarbon in the test, Clostridium paraputrijicum, is found in larger numbers in the faecesof high-risk (‘western’) subjects than in those of low-risk groups. Diet probably affects the metabolism of polycyclic aromatic hydrocarbons through its influence on the bile acids and on mucosal enzymes such as aryl hydrocarbon hydroxylases. Bile acids may influence in two ways the metabolism of polycyclic aromatic hydrocarbons excreted in the bile. They are important in the formation of mixed micelles in fat digestion,
371
and polar conjugates of benzo[a]pyrene may be incorporated into the micelles, aiding their passage through the gut. Further, polycyclic aromatic hydrocarbons are lipid soluble, which could make them inactive in the aqueous gut en’vironment. Bile acids are powerful solubilizing agents and would maintain the carcinogens in solution, thus aiding their interaction with cell surfaces. The authors conclude with the suggestion that . large-bowel cancer results from retoxification, by the gut flora, of liver metabolites of po\ycyclic aromatic hydrocarbons, a process influenced by diet. The disease is thus more common in western’ countries because western diets favour this retoxihcation and because industrial activity increases the amount of polycyclic aromatic carcinogens in the environment.