Susceptibility to hepatocellular carcinoma is associated with genetic variation in the enzymatic detoxification of aflatoxin B1
Date
1995
Journal Title
Journal ISSN
Volume Title
Publisher
Proceedings of the National Academy of Sciences (PNAS)
Abstract
Aflatoxin B1 (AFB1) has been postulated to
be a hepatocarcinogen in humans, possibly by causing p53
mutations at codon 249. AFB1 is metabolized via the phase I
and II detoxification pathways; hence, genetic variation at
those loci may predict susceptibility to the effects of AFB1. To
test this hypothesis, genetic variation in two AFB1 detoxification genes, epoxide hydrolase (EPHX) and glutathione
S-transferase Ml (GSTM1), was contrasted with the presence
of serum AFB,-albumin adducts, the presence of hepatocellular carcinoma (HCC), and with p53 codon 249 mutations.
Mutant alleles at both loci were significantly overrepresented
in individuals with serum AFB1-albumin adducts in a cross sectional study. Mutant alleles of EPHX were significantly
overrepresented in persons with HCC, also in a case-control
study. The relationship of EPHX to HCC varied by hepatitis
B surface antigen status and indicated that a synergistic effect
may exist. p53 codon 249 mutations were observed only among
HCC patients with one or both high-risk genotypes. These
results indicate that individuals with mutant genotypes at
EPHX and GSTM1 may be at greater risk of developing AFB1
adducts, p53 mutations, and HCC when exposed to AFB1.
Hepatitis B carriers with the high-risk genotypes may be an
even greater risk than carriers with low-risk genotypes. These
findings support the existence of genetic susceptibility in
humans to the environmental carcinogen AFB1 and indicate
that there is a synergistic increase in risk of HCC with the
combination of hepatitis B virus infection and susceptible
genotype.
Description
Research Article
Keywords
Aflatoxin B1 (AFB1), hepatocarcinogen, humans