Mutational spectra of aflatoxin B1 in vivo establish biomarkers of exposure for human hepatocellular carcinoma

Dan, GEITP might find this paper [attached] interesting.

It turns out that adult mice are essentially completely resistant to aflatoxin B1 (AFB1)-induced liver cancer, because adult mice express one particular form of glutathione S-transferase (encoded by Gsta3; my lab first cloned this gene in 1992 and characterized the enzyme’s unique activity toward aflatoxin B1-8,9-epoxide). GSTA3 has an incredibly high specific activity toward this particular epoxide of AFB.

Therefore, how can one explain the results of this study [attached] on AFB1-caused liver tumors in mice? It turns out that the mouse Gsta3 gene does not become expressed until at least a week after birth. Thus, neonatal mice are exquisitely sensitive to AFB1 –– because they have sufficient CYP activity to metabolically activate it to the epoxide, which binds to DNA remarkably effectively, and with high selectivity, to the N7 position of guanine. Once GSTA3 is expressed in liver, the 1-week-old mice become totally resistant to the carcinogenic effects of AFB. If not repaired quickly, the N7—guanine-AFB1 adduct undergoes rearrangement to a formamidopyrimidine adduct (FAPY), which is resistant to DNA repair and is highly mutagenic, leading almost exclusively to G:C→T:A transversion mutations.

It turns out that human liver is much more like neonatal mouse than adult mouse; humans have no glutathione S-transferase with high activity toward the AFB1-epoxide. Therefore, humans suffer from the same types of mutations in liver that neonatal mice do, following AFB1 exposure. This study reveals –– by deep sequencing using a new ‘double-strand DNA’ approach that is highly accurate –– a unique ‘carcinogenic’ mutation spectrum that is identifiable at 10 weeks following AFB1 exposure, in the absence of any histopathology, but is still present at 72 weeks of age when tumors have appeared.


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