Species and diet related resistance to chemical carcinogens: biochemical mechanisms of aflatoxin B/sub 1/ detoxification
To provide insight into the biochemical mechanisms mediating species and diet related resistance to chemical carcinogens, the biotransformation and covalent binding to DNA of the potent hepatocarcinogen aflatoxin B/sub 1/(AFB) was investigated in resistant and susceptible species fed standard and butylated hydroxyanisole (BHA)-supplemented diets. The rat is sensitive to the hepatocarcinogenic effects of AFB, whereas the mouse, and rats fed BHA-supplemented diet, are resistant. To differentiate between enzyme induction and direct antioxidant effects, BHA was administered to rats for 9 days, or as a single dose 4-7 hrs prior to i.p. injection of /sup 3/H-AFB. Long-term treatment with BHA doubled the biliary excretion of the glutathione conjugate of AFB and the AFP/sub 1/-glucuronide, and reduced the binding of AFB to hepatic DNA to 16% of control. Single-dose BHA treatment had no effect. To determine if glutathione S-transferase (GST) activity towards the AFB-epoxide mediates both treatment and species related resistance to AFB carcinogenesis, a method was developed to measure the rate of formation of the AFB-epoxide, and the rate of inactivation of the epoxide via GST. To demonstrate the importance of GST-mediated detoxification of the AFB-epoxide in the mouse in vivo, depletion of hepatic GSH was accomplished by administration of L-buthionine-S,R-sulfoximine and diethyl maleate, prior to administration of AFB. GSH depletion was associated with a 30-fold increase in AFB-DNA binding.
- Research Organization:
- Washington Univ., Seattle (USA)
- OSTI ID:
- 6292490
- Resource Relation:
- Other Information: Thesis (Ph. D.)
- Country of Publication:
- United States
- Language:
- English
Similar Records
Sulforaphane, a cancer chemopreventive agent, induces pathways associated with membrane biosynthesis in response to tissue damage by aflatoxin B{sub 1}
A role for glutathione, independent of oxidative stress, in the developmental toxicity of methanol
Related Subjects
AFLATOXIN
DETOXIFICATION
ANTIOXIDANTS
BIOLOGICAL EFFECTS
TRANSFERASES
ENZYME ACTIVITY
BIOCHEMICAL REACTION KINETICS
CARCINOGENESIS
DIET
DNA
GENETIC VARIABILITY
LIVER
MICE
RATS
TRACER TECHNIQUES
TRITIUM COMPOUNDS
ANIMALS
ANTIGENS
BIOLOGICAL VARIABILITY
BODY
DIGESTIVE SYSTEM
ENZYMES
GLANDS
ISOTOPE APPLICATIONS
KINETICS
LABELLED COMPOUNDS
MAMMALS
MATERIALS
NUCLEIC ACIDS
ORGANIC COMPOUNDS
ORGANS
PATHOGENESIS
REACTION KINETICS
RODENTS
TOXIC MATERIALS
TOXINS
VERTEBRATES
550201* - Biochemistry- Tracer Techniques