160 THE CHEMICAL ENVIRONMENT

2469. Another alkylation mechanism?

Lawley, P. D., Orr, D. J. & Shah, S. A. (1971/72). Reaction of alkylating mutagens and carcinogens with nucleic acids: N-3 of guanine as a site of alkylation by N-methyl-N- nitrosourea and dimethyl sulphate. Chemico-Biol. Interactions 4, 431.

Alkylating mutagens and carcinogens have been shown to act at various sites on purine residues (Cited in F.C.T. 1970, 8, 79; Lawley, Fd Cosmet. Toxicol. 1968, 6, 573). The present report demonstrates some in vitro alkylation at the N-3 atom of guanine with both SN1 and SN2 reagents, and suggests a possible in vivo mechanism for the miscoding induced by this base.

Alkylating agents of the SN1 and SN2 types, typified by N-methyl-N-nitrosourea and dimethyl sulphate, respectively, were incubated with DNA and the denatured product was hydrolysed to the individual base residues. These were separated initially on a Dowex 50 column and methylated derivatives of the purine bases were identified by studying the UV absorption spectra of the elements. Alkylating agents labelled with [~4C]methyl were used as a more sensitive method of detecting 3-methyl-guanine, which was also formed as a result of methylation of both/z2 RNA and poly(G) by di[14C]methyl sulphate.

A tautomeric form of 3-methylguanine nucleosideswaspostulated, with an imino group at the C-2 position, which would be conducive to mispairing of 3-methylguanine with thymine. Mutagenesis caused by an SN1 reagent, for example in the bacteriophage T2, has been explained in terms of alkylation of the 0-6 atom of guanine; in the light of this report, miscoding induced by 3-methylguanine could be the key to a mechanism whereby SN2 alkylating agents initiate mutagenic activity.

2470. Keep chlorinated hydrocarbons cool

Glass, W. I., Harris, E. A. & Whitlock, R. M. L. (1971). Phosgene poisoning: Case report. N.Z. rned. J. 74, 386.

We reported once before a case of phosgene poisoning due to the action of heat on a chlorinated hydrocarbon (methylene chloride) in a paint-stripper (Cited in F.C.T. 1964, 2, 427). Another case, due to the incautious use of trichloroethylene (TCE), has now been reported. The solvent was being used to de-grease metal studs before they were welded. The studs, held in a wire basket, were immersed in an open bucket of solvent situated on the work bench close to the area where carbon dioxide arc welding (which produces temperatures of 3500-4000°C) was being carried out. The studs were welded when still damp, and by the end of the morning shift the affected welder's gloves were soaked with TCE. By this time, he was experiencing chest congestion, respiratory difficulties and general malaise. Although he had apparently recovered by the end of the day, during which further exposure was avoided, some of the effects returned when he woke the next morning. Physiological tests then showed a reduction in vital capacity and forced expiratory volume indicating airways obstruction, an increase in alveolar deadspace and venous admixture, arterial hypoxia and impaired carbon monoxide transfer.

Interpretation of these effects was complicated by the patient's history of chronic bron- chitis, but they did not correspond to anything he had experienced before, and this pattern of initial onset, disappearance and recurrence seems characteristic of phosgene poisoning. Further support for this diagnosis is provided by reference to similar cases involving exposure to other heated hydrocarbons, such as carbon tetrachloride from a fire-extinguisher

NATURAL PRODUCTS 161

(Seidelin, Thorax 1961, 16, 91) and, again, methylene chloride from paint-strippers used in heated, ill-ventilated rooms (Gerritsen & Buschmann, Br. J. ind. Med. 1960, 17, 187). It has been proposed that the signs of phosgene poisoning result from its slow hydrolysis, after inhalation, to hydrochloric acid and carbon dioxide (Everett & Overholt, J. Am. reed. Ass. 1968, 205, 243).

The danger of using chlorinated aliphatic hydrocarbons at elevated temperatures is stressed and a temperature of 400°C is cited as sufficient for the formation of phosgene.

NATURAL PRODUCTS

2471. Bitter almond poisoning

Pack, W. K., Raudonat, H. W. u. Schmidt, K. (1972). t3ber eine t6dliche Blaus~iurever- giftung nach dem Genuss bitterer Mandeln (Prunus Amygdalus). Z. Rechtsmedizin 70, 53.

A fatal case of cyanide poisoning following the ingestion of bitter almonds, which contain the cyanogenetic glycoside amygdalin, was reported once before (Cited in F.C.T. 1965, 3, 358) and a comment on the surprisingly large number of such cases was made at that time. Since then a similar, but non-fatal, event has resulted from the consumption of apricot kernels (Gunders et al. J. Israel Med. Ass. 1969, 76, 536). The present short paper is worth attention, not only as a reminder of the danger of eating this culinary commodity in its uncooked state, but also because the results of the post-mortem examination of the victim provide the sceptic with convincing evidence that bitter almonds can indeed be the source of a lethal dose of cyanide.

The victim, a 40-yr-old man, was found dead by his bed, his mouth full of reddish foam. When analysis of blood and urine had demonstrated the absence of alcohol, the stomach contents were examined and the presence therein of about 150 ml of a semi-fluid white material smelling strongly of bitter almonds gave a clue to the source of the trouble. Analysis of various body tissues and fluids confirmed the presence of cyanide, and the blood level (312/~g/100 ml, calculated as the anion) was in accordance with values found in other cases of lethal cyanide poisoning. Measurable amounts were also detected in the stomach contents (4380/~g/100 ml), kidneys (69.3 /~g/100 g), liver (7.4/~g/100 g), brain (24.7 /~g/100 g), muscle (122.9/~g/100 g) and urine (11/~g/100 inl).

These findings, together with microscopic evidence of bitter almond husks in the stomach and the presence therein of benzaldehyde and benzoic acid (which, together with hydro- cyanic acid and glucose, are breakdown products of amygdalin) left little doubt as to the cause of death and the source of the cyanide.

2472. Pyrrolizidine alkaloids and the competitive spirit

Jago, Marjorie V. (1971). Factors affecting the chronic hepatotoxicity of pyrrolizidine alkaloids. J. Path. 105, 1.

Numerous theories about the mechanism of the hepatotoxic action of pyrrolizidine alkaloids have been discussed (Cited in F.C.T. 1970, 8, 607; ibid 1971, 9, 307), and the latest idea is that chronic liver damage is mediated by toxic pyrrole metabolites (ibid 1971, 9,