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200. Liver tumours with acetamide
156
CANCER RESEARCH
specialized in evil . . . Such a 'familiar' changes within 2 to 4 yr into a black spider which, as it develops, slowly occludes the gullet and starves its victim to death." This extract from a fascinating paper relates to cancer of the oesophagus in the Bantu. Here is a rare condition whose incidence today is as high at 200 per 100,000 in some parts of the Transkei (South Africa) and as low as I0 per 100,000 in others. Against a background of tremendous difficulties imposed by primitive superstition, ignorance, backwardness and migrant labour, the author recounts the epidemiological investigations he has carried out in order to seek the cause of this phenomenon. He discusses the possible factors in terms of local habits, customs, foods such as edible weeds, food containers and particularly the weird assortment of receptacles in which kaffir beer is brewed. Zinc and other heavy metals may perhaps be implicated, but there is no clear evidence on this point. The chances are that what is being witnessed now is the consequence of some event which occurred 15-20 yr ago. The suggestion has been made to us (Murray, personal communication) that the increase in oesophageal cancer stems from the use of kerosene tins for fermenting liquors. During the war these tins were lined with "terre plate" (which contains lead) because of the shortage of tin plate. Both in Johannesburg and Nairobi the police have records of an exceptional number of cases of acute lead poisoning among the Bantu during the war. Now the incidence of oesophageal cancer in the Bantu in these 2 centres exceeds the well-known high rate of liver cancer. [Here is an opportunity for some scientific body with the appropriate skills to make an important contribution to our knowledge of environmental carcinogenesis. This stimulating account holds more interest than most scientific 'whodunits'. That fact alone makes it fascinating reading.] Burrell, R. J. W. (1962). Esophageal cancer among Bantu in the Transkei. J. nat. Cancer Inst. 28, 495. 200. LIVER T U M O U R S WITH ACETAMIDE Diets containing 1.25, 2.5 and 5~o acetamide (analytical reagent with less than 0.2 ~o impurities) produced liver tumours in rats, provided that the administration was continued for at least 4 months. Discontinuing acetam~de after this time affected other pathological changes but not apparently turnout development. [Surprisingly, acetamide is not metabolized at all readily; it is slowly hydrolyzed by liver amidases in vitro; the most rapid breakdown is seen with Ce and C~ amides. Rabbits, given doses of between 1.5-5.0 g excreted 60°./0 in 24 hr. Dogs and cats also excrete acetamide largely unchanged. In rats it is only onetenth as effective a precursor compared to acetic acid in the synthesis of fatty acid and cholesterol. Thioacetamide, used for preventing the decay of oranges, also has been shown to cause liver cirrhosis in rats (Nelson & Fitzhugh, Science 1948. 108, 626).
Given at 0.1 ~o of the diet, survival was less than 1 month. Gupta (Nature, Lond. 1955, 175, 257) fed rats a diet containing approximately 0.3 % of thioacetamide which killed 50 out of 150 rats in 9 weeks, due primarily to liver cirrhosis. Of 36 animals examined between 9 and 23 weeks, 18 had bile duct tumours.] Jackson, B. & Dessau, F. I. (1961). Liver tumours in rats fed acetamide. Lab. Invest. 10, 909. 201. EFFECT OF DIMETHYLNITROSAMINE ON BLOOD ENZYMES The selective liver damage brought about by injecting dimethylnittosamine (I) reveals itself within 3 hr by impaired incorporation of labelled amino acids into liver protein (Magee, Biochem. J. 1958, 70, 606). A study has now been carried out of the enzymes leaking out from the damaged liver into the serum and of the biochemical state of the subcellular fractions of the liver in the hour that follow poisoning by I. The authors demonstrate that mitochondria are not the target but that I acts primarily on microsomes. This observation is in striking contrast to the effect of other liver poisons such as carbon tetrachloride, where anti-histamines exercise protective action (Bangham et aL Nature, Lond. 1962, 193, 754). No such protection is seen in poisoning with I. Rees, K. R., Shotlander, V. L. & Sinha, K. P. (1962). Blood enzymes in liver injury following dimethylnitrosamine poisoning. J. Path. Bact. 83, 483. 202. TOXIC LIVER INJURY A N D CARCINOGENESIS The toxicity of dimethylnitrosamine (I) is thought to exercise its action through the release of diazomethane. In the first of the two present papers, the authors have used I labelled with t4C to study the manner in which rat liver slices incorporate the radioactive label into proteins and nucleic acids. Since I is partly metabolized to labelled formaldehyde which promptly enters the metabolic pool of compounds possessing a single carbon, it is no surprise to find labelled serine and methionine being formed. Circumventing such pitfalls, the authors demonstrate the likely formation of a methylating agent (? diazomethane) by oxidative N-demethylation of I; and that the outcome is methylation of the imidazole group of histidine and possibly some free carboxyl groups of proteins. In the second paper the nucleic acid aspect is studied in rats given I by intraperitoneal injection. The dose was sufficient to cause liver necrosis and even kidney tumours. The striking observation is reported that liver nucleic acids (DNA and RNA) undergo methylation with formation of at least one new purine, 7-methylguanino (II); this is probably also formed in the kidney. While it is tempting to suggest that therein lies the explanation for the carcinogenic action of I, the authors mention that II has been known to be present in human urine since
CANCER RESEARCH
specialized in evil . . . Such a 'familiar' changes within 2 to 4 yr into a black spider which, as it develops, slowly occludes the gullet and starves its victim to death." This extract from a fascinating paper relates to cancer of the oesophagus in the Bantu. Here is a rare condition whose incidence today is as high at 200 per 100,000 in some parts of the Transkei (South Africa) and as low as I0 per 100,000 in others. Against a background of tremendous difficulties imposed by primitive superstition, ignorance, backwardness and migrant labour, the author recounts the epidemiological investigations he has carried out in order to seek the cause of this phenomenon. He discusses the possible factors in terms of local habits, customs, foods such as edible weeds, food containers and particularly the weird assortment of receptacles in which kaffir beer is brewed. Zinc and other heavy metals may perhaps be implicated, but there is no clear evidence on this point. The chances are that what is being witnessed now is the consequence of some event which occurred 15-20 yr ago. The suggestion has been made to us (Murray, personal communication) that the increase in oesophageal cancer stems from the use of kerosene tins for fermenting liquors. During the war these tins were lined with "terre plate" (which contains lead) because of the shortage of tin plate. Both in Johannesburg and Nairobi the police have records of an exceptional number of cases of acute lead poisoning among the Bantu during the war. Now the incidence of oesophageal cancer in the Bantu in these 2 centres exceeds the well-known high rate of liver cancer. [Here is an opportunity for some scientific body with the appropriate skills to make an important contribution to our knowledge of environmental carcinogenesis. This stimulating account holds more interest than most scientific 'whodunits'. That fact alone makes it fascinating reading.] Burrell, R. J. W. (1962). Esophageal cancer among Bantu in the Transkei. J. nat. Cancer Inst. 28, 495. 200. LIVER T U M O U R S WITH ACETAMIDE Diets containing 1.25, 2.5 and 5~o acetamide (analytical reagent with less than 0.2 ~o impurities) produced liver tumours in rats, provided that the administration was continued for at least 4 months. Discontinuing acetam~de after this time affected other pathological changes but not apparently turnout development. [Surprisingly, acetamide is not metabolized at all readily; it is slowly hydrolyzed by liver amidases in vitro; the most rapid breakdown is seen with Ce and C~ amides. Rabbits, given doses of between 1.5-5.0 g excreted 60°./0 in 24 hr. Dogs and cats also excrete acetamide largely unchanged. In rats it is only onetenth as effective a precursor compared to acetic acid in the synthesis of fatty acid and cholesterol. Thioacetamide, used for preventing the decay of oranges, also has been shown to cause liver cirrhosis in rats (Nelson & Fitzhugh, Science 1948. 108, 626).
Given at 0.1 ~o of the diet, survival was less than 1 month. Gupta (Nature, Lond. 1955, 175, 257) fed rats a diet containing approximately 0.3 % of thioacetamide which killed 50 out of 150 rats in 9 weeks, due primarily to liver cirrhosis. Of 36 animals examined between 9 and 23 weeks, 18 had bile duct tumours.] Jackson, B. & Dessau, F. I. (1961). Liver tumours in rats fed acetamide. Lab. Invest. 10, 909. 201. EFFECT OF DIMETHYLNITROSAMINE ON BLOOD ENZYMES The selective liver damage brought about by injecting dimethylnittosamine (I) reveals itself within 3 hr by impaired incorporation of labelled amino acids into liver protein (Magee, Biochem. J. 1958, 70, 606). A study has now been carried out of the enzymes leaking out from the damaged liver into the serum and of the biochemical state of the subcellular fractions of the liver in the hour that follow poisoning by I. The authors demonstrate that mitochondria are not the target but that I acts primarily on microsomes. This observation is in striking contrast to the effect of other liver poisons such as carbon tetrachloride, where anti-histamines exercise protective action (Bangham et aL Nature, Lond. 1962, 193, 754). No such protection is seen in poisoning with I. Rees, K. R., Shotlander, V. L. & Sinha, K. P. (1962). Blood enzymes in liver injury following dimethylnitrosamine poisoning. J. Path. Bact. 83, 483. 202. TOXIC LIVER INJURY A N D CARCINOGENESIS The toxicity of dimethylnitrosamine (I) is thought to exercise its action through the release of diazomethane. In the first of the two present papers, the authors have used I labelled with t4C to study the manner in which rat liver slices incorporate the radioactive label into proteins and nucleic acids. Since I is partly metabolized to labelled formaldehyde which promptly enters the metabolic pool of compounds possessing a single carbon, it is no surprise to find labelled serine and methionine being formed. Circumventing such pitfalls, the authors demonstrate the likely formation of a methylating agent (? diazomethane) by oxidative N-demethylation of I; and that the outcome is methylation of the imidazole group of histidine and possibly some free carboxyl groups of proteins. In the second paper the nucleic acid aspect is studied in rats given I by intraperitoneal injection. The dose was sufficient to cause liver necrosis and even kidney tumours. The striking observation is reported that liver nucleic acids (DNA and RNA) undergo methylation with formation of at least one new purine, 7-methylguanino (II); this is probably also formed in the kidney. While it is tempting to suggest that therein lies the explanation for the carcinogenic action of I, the authors mention that II has been known to be present in human urine since