Mechanisms of aflatoxin B1 lung tumorigenesis.
Although aflatoxin B1 (AFB1) is best known as a hepatocarcinogen, the respiratory system can also be a target of this mycotoxin. In isolated lung cells from rabbits and mice, AFB1 is bioactivated by cytochromes P450, primarily in nonciliated bronchiolar epithelial (Clara) cells. However, mutagenesis experiments suggest that the DNA-binding AFB1 epoxide metabolite can leave the cells of origin, and potentially interact with other cell types. Consistent with DNA adduct studies, AFB1-induced AC3F1 mouse lung tumors contain point mutations at guanine residues in K-ras, with the anticipated bias for the A/J allele. Furthermore, following AFB1 treatment but prior to tumor development, K-ras mutations occur preferentially in mouse Clara cells. However, in contrast to findings with other carcinogens, AFB1-induced mouse lung tumors demonstrate frequent, but heterogeneously distributed, overexpression of p53 protein as well as p53 point mutations, suggesting a carcinogen-specific response. Unlike lung tissue from mice and rabbits, human peripheral lung bioactivates AFB1 primarily by prostaglandin H synthase--and/or lipoxygenase-catalyzed cooxidation, with activity concentrated in macrophages. In addition, although glutathione S-transferase M1-1 has high specific activity for AFB1 epoxide conjugation, lung tissues from GSTM1-null individuals do not demonstrate diminished rates of conjugation, compared to tissues from GSTM1-positive individuals. In summary, AFB1 tumorigenesis in mice demonstrates unique properties, and processes of bioactivation show significant species differences.
Massey
T E
TE
Department of Pharmacology and Toxicology, Queen's University, Kingston, Ontario, Canada. masseyt@post.queensu.ca
Smith
G B
GB
Tam
A S
AS
D016604:Aflatoxin B1 / Q000493:pharmacokinetics / Q000633:toxicity*; D000818:Animals; D002273:Carcinogens / Q000493:pharmacokinetics / Q000633:toxicity*; D018736:DNA Adducts; D004249:DNA Damage / Q000187:drug effects; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008658:Inactivation, Metabolic; D008175:Lung Neoplasms / Q000209:etiology* / Q000378:metabolism; D051379:Mice; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013045:Species Specificity
D002273:Carcinogens; D018736:DNA Adducts; D016604:Aflatoxin B1