The chemistry and biology of aflatoxin B(1): from mutational spectrometry to carcinogenesis.
Dietary exposure to aflatoxin B(1) (AFB(1)) is associated with an increased incidence of hepatocellular carcinoma (HCC), especially in populations in which exposure to hepatitis B virus (HBV) is a common occurrence. Most HCC samples from people living where HBV is prevalent have one striking mutational hotspot: a GC-->TA transversion at the third position of codon 249 of the p53 gene. In this review, the chemical reaction of an electrophilic derivative of aflatoxin with specific DNA sequences is examined, along with the types of mutations caused by AFB(1) and the sequence context dependence of those mutations. An attempt is made to assign the source of these mutations to specific chemical forms of AFB(1)-DNA damage. In addition, epidemiological and experimental data are examined regarding the synergistic effects of AFB(1) and HBV on HCC formation and the predominance of one hotspot GC-->TA transversion in the p53 gene of affected individuals.
Smela
M E
ME
Department of Chemistry and Division of Bioengineering and Environmental Health Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Currier
S S
SS
Bailey
E A
EA
Essigmann
J M
JM
D016604:Aflatoxin B1 / Q000737:chemistry* / Q000378:metabolism*; D000818:Animals; D002273:Carcinogens; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced* / Q000235:genetics; D005399:Fishes; D016158:Genes, p53 / Q000235:genetics; D006515:Hepatitis B virus / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000139:chemically induced* / Q000235:genetics; D008954:Models, Biological; D008956:Models, Chemical; D009153:Mutagens; D009154:Mutation; D051381:Rats; D013045:Species Specificity
D002273:Carcinogens; D009153:Mutagens; D016604:Aflatoxin B1