Investigations into the mechanisms of aflatoxin B sub 1 genotoxicity and carcinogenicity

Thesis/Dissertation · Sun Jan 01 04:00:00 EST 1989

OSTI ID:5545117

Olsen, H E

Aflatoxin B{sub 1} (AFB{sub 1}) was used as a model carcinogen for investigations into the initiation, promotion and progression phases of chemically induced carcinogenesis. In initial experiments {sup 3}H-AFB{sub 1} was evaluated for its rate of tritium exchange in vitro and in vivo. Tritium exchange form {sup 3}H-AFB{sub 1} to water in vitro (pH 7.4, 37{degree}C) and in-vivo from covalently bound AFB{sub 1} had a half-life of {approx}1 week. The physical interaction of AFB{sub 1} with DNA was examined to further characterize the steps involved in initiation. Using Nuclear Magnetic Resonance spectroscopy it was established that AFB{sub 1} binds to the outside of the DNA double helix and does not intercalate between the base pairs in spite of its relatively planar structure. In contrast to results obtained from NMR experiments, AFB{sub 1} and AFM{sub 1} were found to be direct acting mutagens in the Ames test and strain sensitivity indicated the direct mutagenicity was a result of a frameshift mutation suggesting intercalation. To determine if a free radical mechanism was converting the parent compound to a mutagenic derivative, the effect of the free radical inhibitor, butylated hydroxytoluene (BHT), on the mutagenicity of AFB{sub 1} to Salmonella typhimurium TA98 was determined. DNA sequences believed responsible for reversion of different Salmonella typhimurium strains were compared to the direct mutagenicity of AFB{sub 1} in these strains and with the rules reported in the literature for the sequence specific covalent binding of AFB{sub 1}. An alternative mechanism for the metabolic activation of AFB{sub 1} and AFM{sub 1} to genotoxic metabolites was investigated.

• Research Organization: California Univ., Davis, CA (United States)
• OSTI ID: 5545117
• Country of Publication: United States
• Language: English

Related Subjects

550501* -- Metabolism-- Tracer Techniques
59 BASIC BIOLOGICAL SCIENCES
AFLATOXINS
ANTIGENS
BACTERIA
BIOLOGICAL EFFECTS
BIOLOGICAL HALF-LIFE
CARCINOGEN SCREENING
DNA
GENETIC EFFECTS
HYDROGEN COMPOUNDS
IN VITRO
IN VIVO
ISOTOPE APPLICATIONS
MATERIALS
METABOLIC ACTIVATION
MICROORGANISMS
MOLECULAR STRUCTURE
MUTAGEN SCREENING
NMR SPECTRA
NUCLEIC ACIDS
ORGANIC COMPOUNDS
SALMONELLA
SALMONELLA TYPHIMURIUM
SCREENING
SPECTRA
TOXIC MATERIALS
TOXICITY
TOXINS
TRACER TECHNIQUES
TRITIUM COMPOUNDS