Further Studies on the Carcinogenic Action of Certain Lactones and Related Substances in the Rat and Mouse

Abstract

On the other hand, in the lactones hitherto tested, absence of xfl-unsaturation, as in the fly-unsaturated a-angelica lactone and in the fully saturated y-butyro lactone, or opening of the lactone ring by hydrolysis, resulted in loss of carcinogenicity.In the case of the remarkably highly carcinogenic unsaturated lactone represented by the mould-product aflatoxin, the chemical structure of this compound was not known at the time when groundnut meal infected with Aspergillus fiavus was first shown to constitute a hepato-carcinogenic diet for the rat (Lancaster, Jenkins and Philp, 1961 ; see also Butler and Barnes, 1963). The purified toxin (mixed aflatoxins B1 and G1), made available to us by the Tropical Products Institute, D.S.I.R., London, was shown to produce local malignant tumours at the injection site in rats in doses as low as 50 ,tg (Dickens and Jones, 1963b). Later, feeding similar purified toxin to rats was shown to lead to hepatoma formation, like the contaminated meal (Barnes and Butler, 1964). Chemical studies at the Massachusetts Institute of Technology have now revealed that both purified aflatoxins B1 and G1 contain respectively one or two 6-membered lactone rings possessing oc,-unsaturation which is conjugated directly with further double bonds in the molecule (Asao et al., 1963; see also Dickens and Jones, 1963b). Whether the remaining parts of these fairly complex molecules are involved in their carcinogenicity remains to be studied.In the present paper we have extended the above observations in various directions. In the first place, we have added further tests on coumarin (I) (since the coumarin ring is contained in the aflatoxins), and on coumalic acid (II) a near relative: unfortunately both compounds proved highly toxic. The same applied to N-ethyl maleimide (III), a nitrogen analogue of maleic anhydride and a powerful sulphydryl-reacting material.

Patulin Inhibition of Mycovirus Replication in Penicillium stoloniferum

“…This toxin has antibiotic activity, is toxic to animals (Hooper et al 1944;Norstadt & McCalla, 1968) and is carcinogenic in rats and mice (Dickens & Jones, 1961, 1965. As for mode of action, Jones & Young (1968) suggested that the SH group of thiol enzymes reacts with the double bond conjugated to the lactone carbonyl group of patulin, and Atkinson & Stanley (1943) suggested that the antibiotic activity of patulin may be due to its reaction with SH groups of microbial enzymes.…”

Pseudoacids. I. 4- and 5-Oxoacids

“…The cis-unsaturated analogs, such as mucochloric acid (Mowry, 1950), penicillic acid (Birkinshaw et aL, 1936) and 4-oxypentenoic acid derivatives (Sheffold & Dubs, 1967) have open-cyclic equilibria which favor the cyclic forms. In the case of penicillic acid, the cyclic lactol form is given credit in part for its carcinogenic .activity (Dickens, 1964(Dickens, , 1965. Among the aromatic analogs, the 'hydroxyphthalide' or cyclic structures of 2methanoylbenzoic acids were assigned by de Diesback & Riat (1937), and the cyclic forms of 2-methanoyl-and 2-ethanoylbenzoic acid could be inferred from lowresolution NMR spectra in solution and their solid-state IR spectra (Tyman & Najam, 1977).…”

Mycotoxins in review

“…Since the Penicillia are commonly found in/on foods and feeds, and are of considerable importance in production of cheeses and sausages, an intensive search for these mycotoxins was made, starting with patulin and penicillic acid. These two mycotoxins had been shown (Dickens and Jones 1965) to cause tumours in mice on subcutaneous injection. Given orally, patulin does not appear to be carcinogenic.…”