Epidemiologic risk factors in LC 2

Folate, isothiocyanates, and phytoestrogens
Folate deficiency is implicated in in vitro studies
in alterations in DNA methylation, DNA synthesis,
and disruption of DNA repair activities [45]; how-
ever, observational studies have yielded inconsis-
tent results [46–49]. In the New York State [46] and
Netherland Cohort Studies [48], an inverse associa-
tion between folate intake and LC riskwas reported.
Shen et al. [49] also reported that dietary folate in-
take was associated with a 40%reduction in LC risk
among former smokers. In contrast, data from the
Nurse’s Health Study revealed a lack of association
[47].
Isothiocyanates (ITCs) are nonnutrient com-
pounds in cruciferous vegetables with anticarcino-
genic properties. One possible mechanism for their
protective action is through downregulation of cy-
tochrome P-450 biotransformation enzyme levels
and induction of phase II enzymes [50,51]. ITCs can
also induce apoptosis, cell cycle arrest, and cell dif-
ferentiation [52]. Brennan et al. [53] showed that
weekly consumption of cruciferous vegetables pro-
tected against LC in those who were GSTM1 null
(OR = 0.67; 95% CI, 0.49–0.91), GSTT1 null (0.63,
0.37–1.07), or both (0.28, 0.11–0.67). Similar pro-
tective results were noted for consumption of spe-
cific cruciferous vegetables.However, Spitz et al. [54]
reported that current smokers with both low ITC
dietary intake and the GSTM1 null genotype or the
GSTT1 null genotype exhibited increased LC risk,
with ORs of 2.22 (1.20–4.10) and 3.19 (1.54–6.62),
respectively. This association was confirmed by Gao
et al. [55]. The comparable OR in the presence of
both null genotypes was 5.45 (1.72–17.22). Results
in former smokers were not statistically significant.
Dietary phytoestrogens are plant-derived nons-
teroidal compounds with weak estrogen-like activ-
ity. A significant reductions in risk of LC with in-
creased phytoestrogen intake was observed [56].
The highest quartile of intake of total phytoestro-
gens from food sources was associated with a 46%
reduction in risk (OR = 0.54; 95% CI, 0.42–0.70;
p < 0.001 for trend). Several studies in Asian pop-
ulations, whose diet contains large quantities of
phytoestrogens, also reported reduced risk of LC
associated with high intakes of phytoestrogen
[57–61].