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various xenobiotics including carcinogens, influences the individual risk of cancer will help
to understand of the gene-gene and gene-environment interactions in the process of human
carcinogenesis, to identify individuals / populations who are at a very high risk because of
their increased genetic susceptibility and to change the approach of therapeutics and health
risk assessment >2@. Striking ethnic dissimilarities, as well as inter-individual differences, in
genes involved in drug metabolism are well known. This refers to the enzymes participating
in carcinogen metabolism phase I and to those participating in phase II >3@. Many
xenobiotic agents are activated or detoxified by these important metabolizing enzymes.
Given the fact that genetic polymorphisms in these enzymes may cause inter-individual
variability in the genotoxic damage induced by xenobiotics, individual risk assessment has
to be evaluated by taking into account individual genetics. The genetic principles of the
polymorphisms of enzymes participating in the metabolism of environmental carcinogens
have already been quite well explained at the DNA level. However, it is still difficult to
determine precisely the role of genetic diversity, and the associated variations of enzyme
functions in individual's susceptibility to the carcinogenic action of the chemicals present
in the occupational and communal environment >4@. Gene environmental interactions can
explain why some individuals develop cancer and others do not, for same level and quality
of exposure. Also, it can explain why some people are particularly sensitive to low levels of
carcinogenic exposures. Except for some occupational exposures, most human exposures to
carcinogens are through mixtures where single carcinogens have very low concentrations.
In cancer epidemiology, great deal of attention has been paid to the role of common
population polymorphisms in genes controlling carcinogen metabolism >5@.
As observed in drug and chemical metabolism, there is considerable interindividual
genetic variability in the metabolic and biosynthetic pathways in steroidogenesis. These
person to person differences might define subpopulations of women with higher lifetime
exposures to hormone dependent growth promotion or to cellular damage from particular
estrogens and estrogen metabolites. Such variation could explain a portion of the cancer
susceptibility associated with reproductive events and hormone exposure >6@. Many of the
low penetrance susceptibility genes involved in estrogen metabolism are polymorphically
distributed within the human population. cytochrome P450
1B1
(
CYP1B1),
Catechol
O
-
methyltransferase (
COMT),
Manganese superoxide dismutase (
MnSOD)
genes are known
common genetic polymorphisms with a gene-environment and gene-gene interaction in
steroid hormone metabolizing enzymes. Inherited alterations in the activity of any of these
enzymes hold the potential to define differences in cancer risk associated with estrogen
carcinogenesis like breast cancer.
Breast cancer is one of the most common and important diseases affecting women.
Epidemiological studies have indicated that environmental xenobiotics or their metabolites,
some with estrogenic or androgenic agonist and antagonist activities, may also play a
significant role in the development of breast cancer >7@.
The cytochrome P450 CYP1B1 (
CYP1B1)
is responsible for the hydroxylation of
estrogens to the 2-hydroxy estrogen (2-OH HE) and 4-OH HEs, as well as a number of
polycyclic aromatic hydrocarbons (PAH) and aryl amines, including several that are potent
mammary gland carcinogens in rodents. At least seven different SNPs in
CYP1B1
have
been described, of which one in exon 3, encodes the heme-binding domain, at codon 432
(ValoLeu) (
CYP1B1*3
). The CYP1B1*3 product, a lower Km value for both 2- and 4-
hydroxylation has been observed when compared to differ significantly from
CYP1B1*1
>8@. The
CYP1B1*1 and CYP1B1*3
alleles were detected by minor modifications of the
methods described by Fritsche et al. >9@. The
CYP1B1*3
allele was associated with a
significantly increased susceptibility of breast cancer [the adjusted OR for age, age at
menarche, age at first full-term pregnancy, BMI and smoking status; 2.32 (95% CI 1.26-
4.25, p=0.007)]. The comparision of genotype frequencies according to the basis of BMI,
