MECHANISMS OF AFLATOXIN B₁ LUNG TUMORIGENESIS

Author： Massey Thomas E. Smith Graeme B. J. Tam Andrew S.

ISSN： 1521-0499

Source： Experimental Lung Research, Vol.26, Iss.8, 2000-12, pp. : 673-683

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Abstract

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/Jallele. 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 lipoxygenasecatalyzed 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.