Aflatoxin B-oxide generated by chemical or enzymic oxidation of aflatoxin B₁ causes guanine substitution in nucleic acids

Abstract

AFLATOXIN B₁ (AFB₁) has the highest biological activity of the four naturally occurring aflatoxins produced by the mould Aspergillus flavus¹. Feeding studies have shown it to be the most potent liver carcinogen known for the rat². Its ingestion by man is associated with the high primary liver cancer incidence in certain parts of Africa³. There is much evidence to suggest that AFB₁ requires metabolism to exert both its carcinogenic and mutagenic effects (reviewed in ref. 4). Structure-activity⁵, as well as chemical studies^6,7 indicate that the major route for activation proceeds through mixed function oxidase attack yielding the 8,9-oxide (previously called the 2,3-oxide but renumbered according to IUPAC recommendations). Attempts to chemically synthesise this metabolite have so far been unsuccessful. We report here that peracid oxidation of AFB₁ generates AFB₁-8,9-oxide, and that this latter compound reacts readily with nucleic acids to give adducts identical to those obtained after liver mixed function oxidase (MFO) activation in vitro and in vivo.