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Liver Microsomal Metabolism of Aflatoxin B₁ to a Reactive Derivative Toxic to Salmonella typhimurium TA 1530¹

McArdle Laboratory for Cancer Research, University of Wisconsin Medical Center, Madison, Wisconsin 53706

A reduction in the survival of Salmonella tryphimurium TA 1530 was observed when the bacteria were incubated with aflatoxin B₁, 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 B₁ 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 B₁. 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 B₁ was replaced by either aflatoxin G₁ 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 B₁ 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 B₁), 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 B₁ 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 B₁ is discussed.

¹ This work was supported by Grant CA-07175 of the National Cancer Institute, USPHS.

² Recipient of a Damon Runyon Postdoctoral Fellowship, 1970 to 1972. Present address: Department of Experimental Pathology and Cancer Research, University of Leeds, 171 Woodhouse Lane, Leeds LS2 3AR, Yorkshire, England.

³ To whom reprint requests should be addressed.

Received 4/ 3/72. Accepted 6/ 9/72.

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