169 RESERPINE AND CHEMICAL CARCINOGENESIS SiR,—Concerning the possible carcinogenicity of reserpine1 we should like to point out that the structure of reserpine incorporates certain features associated with chemical carcinogenesis. The hydroxyquinone, 4’,8’-dihydroxy-l,2,5,6-dibenzan9,10-thraquinone (2 in accompanying figure) was shown to be a metabolite of the carcinogenic polynuclear hydrocarbon, dibenz (a,h) anthracene (1) over two decades ago.22 This metabolite has recently been shown to disrupt oxidative in rat liver mitochondria.3 This finding phosphorylation and others 4-6 support an experimental confluence between chemical carcinogenesis and oxidative phosphorylation and has renewed consideration of mitochondria for a role in
carcinogenesis.7,8s These data and speculations have raised the question " can other known carcinogens be responsible for the delivery or generation of hydroxyquinones inside the cell "? The reports by Schoental and associates regarding the xtiology of nasal tumours among wood workers and nasopharyngeal tumours among certain communities in Africa and Asia have a strong bearing on this question. They reported that 3,4,5-trimethoxycinnamaldehyde 9-11 (3) and 2,6-dimethoxybenzoquinone 11 (4) were carcinogenic in rats or mice. Schoental 11 also implied that (3) could be metabolised to (4) via a process of p-demethylation (a type of reaction noted by Griffith 12) followed by oxidation. 1. 2.
Lancet, 1974, ii, 669, 672, 675, 701. Heidelberger, C., Hadler, H. I., Wolf, G. J. Am. chem. Soc. 1953,
Schoental 13 also attributed the carcinogenicity of redcedar-wood animal beddings (Juniperus virginiana L.) to the presence of a moiety related to (3) in podophyllotoxin, a constituent of red cedar wood. Anderson 14 found that pyrogallol (5) was strongly carcinogenic in an assay involving plant (Nicotinia hybrids) seedlings. The ready conversion of pyrogallol to a molecule with some of the features of the hydroxyquinone (6) is to be expected and is in keeping with the well-known use of pyrogallol to absorb oxygen. It is well known that 1,2,3-trimethoxybenzene (7) can be oxidised to (4). A hydroxyquinone may be considered a vinylogue of a carboxylic acid. It therefore follows that (4) resembles a methyl ester of an organic acid and the ready conversion of a compound such as (4) to a hydroxyquinone is to be expected. Thus, a metabolic and carcinogenic role for hydroxyquinones consolidates the carcinogenic data obtained with (3), red cedar wood, and (5), with that obtained with (1). Metabolic p-demethylation 12 of (8) (a moiety present in reserpine) leads to syringic acid (9) which is easily oxidised
(4).
to
The trimethoxybenzoic acid (8) moiety in reserpine thus could be responsible for the delivery of a hydroxyquinone inside the cell and thereby engender carcinogenesis. The number of drugs related to 1,2,3-trimethoxybenzene is considerable. Should the antihypertensive agent methyldopa turn out to be carcinogenic the conversion of methyldopa to a hydroxyquinone should also be examined before assigning a carcinogenic role to the stimulation of prolactin secretion1 by this drug. Department of Chemistry and Biochemistry, Southern Illinois University
75, 1303. 3. Hadler, H. I., Daniel, B. G., Demetriou, J., Pratt, R. C. J. Antibiot.,
Tokyo, 1971, 24, 835. 4. Hadler, H. I., Daniel, B. G., Pratt, R. D. ibid. p. 405. 5. Hadler, H. I., Daniel, B. G. Cancer Res. 1972, 32, 1037. 6. Hadler, H. I., Daniel, B. G. ibid. 1973, 33, 117. 7. 8.
9. 10. 11. 12.
Baum, H. Lancet, 1973, ii, 738. Schumacher, H. R., Szekeley, I. E., Patel, S. B., Fisher, D. R. ibid. p. 327. Schoental, R., Hard, G. C., Gibbard, S. J. natn. Cancer Inst. 1971, 47, 1037. Schoental, R., Gibbard, S. Br. J. Cancer, 1972, 26, 504. Schoental, R. Lab. Animals, 1973, 7, 47. Griffith, L. A. Biochem. J. 1969, 113, 603.
at Carbondale, Carbondale, Illinois 62901, U.S.A.
**** in
our
HERBERT I. HADLER.
A letter on this subject by Dr Schoental issue of Dec. 28 (p. 1571).-ED. L.
appeared
PARAQUAT SiR,—This district has lately suffered 2 paraquat fatalities ; our regional poisons centre has dealt with 12 cases in
t
the past ten months with only 1 survivor, a baby in whom the amount ingested was doubtful. Paraquat has commercial uses as a weed-killer and no doubt horticulturalists might mourn its passing; but other safer weed-killers were in use before paraquat, and paraquat is not indispensable. Reassuring naises are made suggesting that would-be suicides and homicides will find other poisons to use; but paraquat is so poisonous that more than 5 ml. will almost certainly cause death, and conventional poisons at least allow hysterical personalities the opportunity of a change of mind and the hope of a cure. The manufacturer’s laboratories have published a hopeful paper on the survival of rats after paraquat; but if some hard and certain facts could be produced of survival of patients after ingestion of paraquat, one might feel more optimistic about its safety in use. But there are no such facts available, to my knowledge. Paraquat is lethal; a 13. 14.
Schoental, R. Cancer Res. 1974, 34, 2419. Anderson, R. A. ibid. 1973, 33, 2450.
carcinogenesis.7,8s These data and speculations have raised the question " can other known carcinogens be responsible for the delivery or generation of hydroxyquinones inside the cell "? The reports by Schoental and associates regarding the xtiology of nasal tumours among wood workers and nasopharyngeal tumours among certain communities in Africa and Asia have a strong bearing on this question. They reported that 3,4,5-trimethoxycinnamaldehyde 9-11 (3) and 2,6-dimethoxybenzoquinone 11 (4) were carcinogenic in rats or mice. Schoental 11 also implied that (3) could be metabolised to (4) via a process of p-demethylation (a type of reaction noted by Griffith 12) followed by oxidation. 1. 2.
Lancet, 1974, ii, 669, 672, 675, 701. Heidelberger, C., Hadler, H. I., Wolf, G. J. Am. chem. Soc. 1953,
Schoental 13 also attributed the carcinogenicity of redcedar-wood animal beddings (Juniperus virginiana L.) to the presence of a moiety related to (3) in podophyllotoxin, a constituent of red cedar wood. Anderson 14 found that pyrogallol (5) was strongly carcinogenic in an assay involving plant (Nicotinia hybrids) seedlings. The ready conversion of pyrogallol to a molecule with some of the features of the hydroxyquinone (6) is to be expected and is in keeping with the well-known use of pyrogallol to absorb oxygen. It is well known that 1,2,3-trimethoxybenzene (7) can be oxidised to (4). A hydroxyquinone may be considered a vinylogue of a carboxylic acid. It therefore follows that (4) resembles a methyl ester of an organic acid and the ready conversion of a compound such as (4) to a hydroxyquinone is to be expected. Thus, a metabolic and carcinogenic role for hydroxyquinones consolidates the carcinogenic data obtained with (3), red cedar wood, and (5), with that obtained with (1). Metabolic p-demethylation 12 of (8) (a moiety present in reserpine) leads to syringic acid (9) which is easily oxidised
(4).
to
The trimethoxybenzoic acid (8) moiety in reserpine thus could be responsible for the delivery of a hydroxyquinone inside the cell and thereby engender carcinogenesis. The number of drugs related to 1,2,3-trimethoxybenzene is considerable. Should the antihypertensive agent methyldopa turn out to be carcinogenic the conversion of methyldopa to a hydroxyquinone should also be examined before assigning a carcinogenic role to the stimulation of prolactin secretion1 by this drug. Department of Chemistry and Biochemistry, Southern Illinois University
75, 1303. 3. Hadler, H. I., Daniel, B. G., Demetriou, J., Pratt, R. C. J. Antibiot.,
Tokyo, 1971, 24, 835. 4. Hadler, H. I., Daniel, B. G., Pratt, R. D. ibid. p. 405. 5. Hadler, H. I., Daniel, B. G. Cancer Res. 1972, 32, 1037. 6. Hadler, H. I., Daniel, B. G. ibid. 1973, 33, 117. 7. 8.
9. 10. 11. 12.
Baum, H. Lancet, 1973, ii, 738. Schumacher, H. R., Szekeley, I. E., Patel, S. B., Fisher, D. R. ibid. p. 327. Schoental, R., Hard, G. C., Gibbard, S. J. natn. Cancer Inst. 1971, 47, 1037. Schoental, R., Gibbard, S. Br. J. Cancer, 1972, 26, 504. Schoental, R. Lab. Animals, 1973, 7, 47. Griffith, L. A. Biochem. J. 1969, 113, 603.
at Carbondale, Carbondale, Illinois 62901, U.S.A.
**** in
our
HERBERT I. HADLER.
A letter on this subject by Dr Schoental issue of Dec. 28 (p. 1571).-ED. L.
appeared
PARAQUAT SiR,—This district has lately suffered 2 paraquat fatalities ; our regional poisons centre has dealt with 12 cases in
t
the past ten months with only 1 survivor, a baby in whom the amount ingested was doubtful. Paraquat has commercial uses as a weed-killer and no doubt horticulturalists might mourn its passing; but other safer weed-killers were in use before paraquat, and paraquat is not indispensable. Reassuring naises are made suggesting that would-be suicides and homicides will find other poisons to use; but paraquat is so poisonous that more than 5 ml. will almost certainly cause death, and conventional poisons at least allow hysterical personalities the opportunity of a change of mind and the hope of a cure. The manufacturer’s laboratories have published a hopeful paper on the survival of rats after paraquat; but if some hard and certain facts could be produced of survival of patients after ingestion of paraquat, one might feel more optimistic about its safety in use. But there are no such facts available, to my knowledge. Paraquat is lethal; a 13. 14.
Schoental, R. Cancer Res. 1974, 34, 2419. Anderson, R. A. ibid. 1973, 33, 2450.
