Carcinogenesis, Vol 19, 873-879, Copyright © 1998 by Oxford University Press
EM Stone, JA Williams, PL Grover, BA Gusterson and DH Phillips
The heterocyclic amines, 2-amino-3-methylimidazo[4,5-f]quinoline (IQ),
2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ) and 2-amino-1-methyl-
6-phenylimidazo[4,5-b]pyridine (PhIP) are pyrolysis products formed when
meat is cooked and are rodent mammary carcinogens. They are thought to be
metabolically activated by N-hydroxylation, catalysed by cytochrome P450
(CYP), followed by O-acetylation catalysed by N- acetyltransferases.
Primary cultures of human mammary epithelial cells (HMECs) prepared from up
to 26 individuals for each compound, were treated with IQ, MeIQ, or PhIP
(500 microM) or with N-hydroxy-2-amino-1-
methyl-6-phenylimidazo[4,5-b]pyridine (N-OH-PhIP) or N-hydroxy-2-amino-
3-methylimidazo[4,5-f]quinoline (N-OH-IQ) (20 microM) and the levels of
adduct formation in their DNA analysed by 32P-post-labelling. In order to
investigate whether pharmacogenetic polymorphisms influence DNA adduct
formation, the NAT2 genotype of each individual was determined by a
polymerase chain reaction-restriction fragment length polymorphism
(PCR-RFLP) method that distinguishes between the wild-type and four variant
alleles. Presence of two variant alleles designates a slow NAT2 acetylator,
whereas individuals with one or two wild-type alleles are designated fast
NAT2 acetylators. Interindividual variations in total DNA adduct levels
ranged for IQ from 0.64-63.1 DNA adducts per 10(8) nucleotides (mean 7.80),
for MeIQ from 1.99-17.8 (mean 6.63), for PhIP from 0.13-4.0 (mean 0.96),
for N-OH-PhIP from 6.32-497 (mean 176) and for N-OH-IQ from 0.92-30.6 (mean
9.24). The higher adduct levels observed in cells treated with the N-OH
metabolites suggests that N- hydroxylation is the rate-limiting step in
HMECs and this may be due to low CYP levels. In contrast, the Phase II
reaction catalysed by N- acetyltransferases is probably the major step in
the metabolic activation of heterocyclic amines that occurs in the breast.
Higher mean levels of heterocyclic amine-DNA adduct formation were detected
in the cells of NAT2 fast acetylators compared with slow acetylators, with
mean adduct levels per 10(8) nucleotides following IQ treatment, of 12.74
and 3.57 respectively, following PhIP treatment, of 1.20 and 0.74,
respectively, following MeIQ treatment, of 7.90 and 5.08, respectively and
following N-OH-PhIP-treatment, of 243.1 and 130.0, respectively. However,
due to the large variations in adduct levels, these differences in mean
values were not statistically significant with the limited number of
individuals studied. This appears to be the first pilot study to
demonstrate interindividual variations in the metabolic activation of
heterocyclic amines and their metabolic intermediates in primary cultures
of HMECs in vitro.
ARTICLES
Interindividual variation in the metabolic activation of heterocyclic amines and their N-hydroxy derivatives in primary cultures of human mammary epithelial cells
Institute of Cancer Research, Haddow Laboratories, Sutton, Surrey, UK. elaines@icr.ac.uk
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