Janet I. Clifford

Bio: Janet I. Clifford is an academic researcher. The author has contributed to research in topics: Purine metabolism & Hyperchromicity. The author has an hindex of 2, co-authored 2 publications receiving 244 citations.

The action of aflatoxin B1 on the rat liver.

Abstract: The administration of a single dose of aflatoxin B(1) to the rat (7mg./kg. body wt.) results in the slow development of a periportal necrosis. Hepatic enzymes are released into the serum in the second 24hr. of the poisoning, closely preceding the onset of the necrosis, which is followed by a rise in serum alkaline-phosphatase activity and bilirubin concentration. Aflatoxin B(1) has been detected in the nucleus of the poisoned liver cell and in vitro it has been shown to interact with DNA. The toxin inhibits the production of nuclear RNA, probably by preventing the transcription of DNA by the RNA polymerase. It is proposed that the interaction of the toxin with DNA gives rise to its inhibitory action on mitosis and its necrogenic action.

The interaction of aflatoxins with purines and purine nucleosides

Abstract: From measurements of thermal hyperchromicity and the behaviour of an aflatoxin–DNA mixture on a Sephadex column it was concluded that aflatoxin B1 is capable of weak binding to single-stranded DNA. The interactions of the aflatoxins (B1, G1 and G2) with nucleosides result in difference spectra and suggest that the purine bases and the amino group play a role in the binding of all the aflatoxins to DNA.

Liver microsomal metabolism of aflatoxin B 1 to a reactive derivative toxic to Salmonella typhimurium TA 1530.

Abstract: Summary A reduction in the survival of Salmonella tryphimurium TA 1530 was observed when the bacteria were incubated with aflatoxin B 1 , rat liver microsomes, and a reduced nicotinamide adenine dinucleotide phosphate-generating system. The lethality appeared to depend on the formation of a metabolite of aflatoxin B 1 by a mixed-function oxygenase system. The killing was very rapid; only 1% of the bacteria were able to form colonies after 2 min of incubation with large amounts of microsomes and aflatoxin B 1 . Attempts to separate the toxic metabolite from the microsomal system have not been successful. Toxic metabolites for S. typhimurium TA 1530 were also formed if aflatoxin B 1 was replaced by either aflatoxin G 1 or sterigmatocystin in the microsome-mediated toxicity assay. Except for aflatoxicol, the derivatives that were tested either had much less activity or were inactive. The livers from a number of other species of rodents and a single autopsy sample of human liver also were active in the microsome-mediated aflatoxin B 1 toxicity assay. The addition of RNA or DNA to the incubation mixture inhibited the killing of the bacteria. The RNA (which was reisolated after its incubation with aflatoxin B 1 ), liver microsomes, and a reduced nicotinamide adenine dinucleotide phosphate-generating system showed a low, broad absorption, with a maximum at 366 to 370 nm. This high wavelength absorption was not removed by Sephadex G-10 chromatography of the RNA or by extraction procedures and appeared to be attributable to covalently bound aflatoxin B 1 toxicity assay. The formation of the conjugated RNA was dependent on reduced nicotinamide adenine dinucleotide phosphate and was inhibited by the addition of aniline; the amount formed was a function of the activity of the mixed-function oxygenases in the incubation mixture. On the basis of the data presented, it is tentatively suggested that the derivative that is toxic to S. typhimurium TA 1530 and the one that reacts with nucleic acids are identical. The possible relationship of this derivative to the hepatocarcinogenicity of aflatoxin B 1 is discussed.

A review on biological control and metabolism of aflatoxin.

Abstract: The series of events that led to the discovery of aflatoxin as a potent carcinogen, its biosynthesis, mechanism of action, structure-function relationship provide interesting insight into the economical and technological factors involved in the development of an effective control measure for the toxin. Scientists all over the world are making continuous efforts to explore a generalized process of detoxification, which can bring down the toxin content in heterogeneous commodities to a threshold level. In this article biological control methods with special emphasis on in vivo and in vitro enzymatic detoxification of aflatoxin have been reviewed. Future areas of research involving large-scale enzymatic detoxification and modified atmosphere storage are also discussed. Referee: Dr. F. S. Chu, 16458 Denhave Court, Chino Hills, CA 91709

Structure-activity relationships in toxicity and carcinogenicity of aflatoxins and analogs.

Abstract: Summary Aflatoxins B1 and G1, in single doses, were lethal and had similar relative potencies in the duckling (50% lethal dose, 0.73 mg/kg versus 1.18 mg/kg) and in the rat (50% lethal dose, 1.16 mg/kg versus 2 to 4 mg/kg). Aflatoxins B2 and G2 were less potent in the duckling (50% lethal dose, 1.76 mg/kg versus 2.83 mg/kg) and were nontoxic to rats at doses of 200 mg/kg. Aflatoxin B1 induced hepatocellular carcinomas in rats dosed by stomach tube, the optimum carcinogenic regimen being 1.5 mg/rat given in 40 equal doses over 8 weeks. With this dosing regimen, aflatoxin G1 was carcinogenic to rat liver at doses of 2.0 and 1.4 mg/animal and also induced adenocarcinomas of the kidneys in 4/26 rats. When given by i.p. injection, aflatoxin B2 at a total dose of 150 mg/rat (40 equal doses over 8 weeks) induced hepatocellular carcinomas in 4/9 rats. Aflatoxin B1 dosed according to a comparable regimen induced liver tumors in 9/9 animals at a total dose of 1.3 mg per rat. Multiple s.c. injection of aflatoxin B1 resulted in sarcomas at the injection site in 9/9 rats within 44 to 58 weeks after a total dose of 0.4 mg/rat over 20 weeks. Aflatoxin B2 at a total dose of 12 mg/rat according to the same treatment schedule induced no tumors in 10 rats killed after 78 to 86 weeks. Tetrahydrodeoxyaflatoxin B1 and 3 synthetic compounds containing the substituted coumarin portion of the aflatoxin B configuration were nontoxic and noncarcinogenic at doses 100 to 200 times higher than aflatoxin B1. Collectively, these results indicate that the furofuran moiety of the aflatoxin structure is essential for toxic and carcinogenic activity. Moreover, the presence of the double bond in the terminal furan ring is an important determinant of potency, particularly for acute and chronic effects in rats. The importance of the substituents on the lactone portion of the molecule is also illustrated by the difference in potency of aflatoxins B1 and G1 in all systems studied.