alchohol, estrogen and folate in breast cancer protection

[Guest guest]

This is an interesting piece of research from a friend who's

researching estrogen. She's extremely organized in her writing style

so it's easy to follow and gives permission for me to repost.

Lynn

Hi Lynn,

I've been studying the biological toxin,

peroxynitrite. It increases when we're under stress,

taking estrogen and in many other situations.

(1) states that peroxynitrite increases breast cancer.

(2) states that alcohol is protective against

peroxynitrite induced DNA changes. By limiting these

changes alcohol should protect against breast cancer.

But, studies show that alcohol increases breast

cancer. Did I miss something? No, but most of the

studies did.

(3) clarifies things by explaining that alcohol

increases breast cancer. But, it mentions that folate

blocks this increase. I maintain that the daily

recommended folate intake of 400 mcg/day is too low.

(4) clarifies things. The level of alcohol consumed

was about 1.5 drinks/day. At a folate level of 300

mcg/day drinking increased the risk of breast cancer

by 32% relative to nondrinkers. OTOH at a folate

intake of 600 mcg the breast cancer rate was 55% as

high as the drinkers with 300 mcg/day folate intake.

Run the math: 1.32 * 0.55 = approx. 0.73. So, drinking

moderately with a 600 mcg/day intake of folate lowers

breast cancer by 27% relative to non-drinkers. I

suspect higher intakes of folate would show even

better results.

http://jn.nutrition.org/cgi/content/full/132/8/2367S

mentions that alcohol lowers folate levels.

http://cancerres.aacrjournals.org/cgi/content/full/63/11/2820

mentions that estrogen blocks the folate receptor.

Various references mention that estrogen lowers folate

absorption.

Combining the negative effects on folate of alcohol

and estrogen it seems obvious that our folate intake

needs to be fairly high if we both drink alcohol and

are on estrogen supplementation. At a high intake of

folate, however, I propose that moderate alcohol

drinking offers considerable protection against breast

cancer.

Bonus information - lowering of choline kinase

activity in the breast should be quite synergistic

with folate and alcohol in lowering breast cancer

risk. Since insulin stimulates choline kinase I

predict that alcohol + folate will be much more

effective in limiting breast cancer in women who keep

their weight controlled. I.E. slimmer women have less

insulin. In addition to the effect on choline kinase

lowering of insulin by appropriate body weight control

lowers the production of peroxynitrite (5). Which has

considerable anti-cancer effects.

1. J Biol Chem. 2004 Feb 27;279(9):7708-14

Peroxynitrite irreversibly inactivates the human

xenobiotic-metabolizing enzyme arylamine

N-acetyltransferase 1 (NAT1) in human breast cancer

cells: a cellular and mechanistic study.

Dairou J, Atmane N, Rodrigues-Lima F, Dupret JM.

CNRS-Unité Mixte de Recherche 7000, Faculté de

Médecine Pitié-Salpêtrière, 75013 Paris, France.

Arylamine N-acetyltransferases (NATs) play an

important role in the detoxification and metabolic

activation of a variety of aromatic xenobiotics,

including numerous carcinogens. Both of the human

isoforms, NAT1 and NAT2, display interindividual

variations, and associations between NAT genotypes and

cancer risk have been established. Contrary to NAT2,

NAT1 has a ubiquitous tissue distribution and has been

shown to be expressed in cancer cells. Given that the

activity of NAT1 depends on a reactive cysteine that

can be a target for oxidants, we studied whether

peroxynitrite, a highly reactive nitrogen species

involved in human carcinogenesis, could inhibit the

activity of endogenous NAT1 in MCF7 breast cancer

cells. We show here that exposure of MCF7 cells to

physiological concentrations of peroxynitrite and to a

peroxynitrite generator (3-morpholinosydnonimine

N-ethylcarbamide, or SIN1) leads to the irreversible

inactivation of NAT1 in cells. Further kinetic and

mechanistic analyses using recombinant NAT1 showed

that the enzyme is rapidly (k(inact) = 5 x 10(4)

m(-1).s(-1)) and irreversibly inactivated by

peroxynitrite. This inactivation is due to oxidative

modification of the catalytic cysteine. We conclude

that the reducing cellular environment of MCF7 cells

does not sufficiently protect NAT1 from

peroxynitrite-dependent inactivation and that only

high concentrations of reduced glutathione could

significantly protect NAT1. Thus, cellular generation

of peroxynitrite may contribute to carcinogenesis and

tumor progression by weakening key cellular defense

enzymes such as NAT1.

PMID: 14672957

2. Pharmacol Res. 2004 Jul;50(1):13-9

*Potent inhibition of peroxynitrite-induced DNA strand

breakage by ethanol: possible implications for

ethanol-mediated cardiovascular protection.*

Cao Z, Li Y.

Department of Pharmaceutical Sciences, St. 's

University College of Pharmacy and Allied Health

Professions, 8000 Utopia Parkway, Jamaica, NY 11439,

USA.

Epidemiological studies have conclusively demonstrated

that moderate consumption of ethanol is causally

associated with a significant reduction in

cardiovascular events. However, the exact mechanisms

underlying the ethanol-mediated cardiovascular

protection remain to be elucidated. Because

peroxynitrite has been extensively implicated in the

pathogenesis of various forms of cardiovascular

disorders via its cytotoxic effects, this study was

undertaken to investigate if ethanol could inhibit

peroxynitrite-induced DNA strand breaks, a critical

event leading to peroxynitrite-elicited cytotoxicity.

Toward this goal, phiX-174 RF I plasmid DNA was used

as an in vitro model to determine the protective

effects of ethanol on peroxynitrite-induced DNA strand

breaks. Incubation of phiX-174 plasmid DNA with the

peroxynitrite generator, 3-morpholinosydnonimine

(SIN-1) led to the formation of both single- and

double-stranded DNA breaks in a concentration- and

time-dependent fashion. The presence of ethanol at

concentrations ranging from 0.01 to 1% (w/v) resulted

in a significant inhibition of SIN-1-induced DNA

strand breaks. Ethanol also showed inhibitory effects

on SIN-1-induced DNA strand breakage in the presence

of bicarbonate. The inhibition of SIN-1-induced DNA

strand breaks by ethanol exhibited a

concentration-dependent manner. Notably, a marked

inhibition of SIN-1-elicited DNA strand breaks was

observed with 0.01% ethanol. Ethanol at 0.01-1% was

unable to affect SIN-1-mediated oxygen consumption,

indicating that ethanol did not affect the

auto-oxidation of SIN-1 to form peroxynitrite.

Furthermore, incubation of the plasmid DNA with

authentic peroxynitrite resulted in a significant

formation of DNA strand breaks, which could be

dramatically inhibited by the presence of 0.02-0.1%

ethanol. Taken together, this study demonstrates for

the first time that ethanol at physiologically

relevant concentrations can potently inhibit

peroxynitrite-induced DNA strand breakage. In view of

the critical involvement of peroxynitrite in

cardiovascular disorders, the results of this study

might have implications for the cardiovascular

protection associated with moderate consumption of

ethanol in humans.

PMID: 15082025

3.

http://www.cancer.org/docroot/SPC/content/SPC_1_Scientific_Explanation_of_Alcoho\

l_Breast_Cancer_Connection.asp

The Scientific Explanation

Alcohol May Boost Hormones Linked to Breast Cancer

It is not known exactly why alcohol increases the risk

of breast cancer. Two current theories focus on

hormonal effects and vitamins, namely folate.

Careful studies have found that regular, moderate use

of alcohol affects the levels of important female

hormones, especially for postmenopausal women whose

bodies make much less estrogen and progesterone than

before they entered menopause.

One study carefully monitored the food and alcohol

consumed by a group of postmenopausal women. A form of

estrogen in the blood increased in the women who drank

alcohol compared to the women who did not receive

alcohol as part of their diet. Taking the equivalent

of one drink a day increased the hormone levels;

taking the equivalent of two drinks a day increased

the levels even more.

That means that the breast cells were exposed to

higher levels of estrogen if the women consumed

alcohol. This may in turn trigger the cells, which are

estrogen sensitive in these women, to become

cancerous.

Other studies have examined the role of the vitamin

folate in either decreasing or preventing breast

cancer in women who drink alcoholic beverages.

There have been reports that folate may counteract the

effect of alcohol on increased breast cancer risk.

Research performed in China, where women get folate

almost exclusively from their diet and not from

vitamin pills, showed that increased amounts of folate

in the diet decreased the risk of breast cancer. But,

Chinese women don't usually drink much alcohol, so

whether having more folate in the diet would decrease

the risk of breast cancer in United States women who

drink alcohol remains unknown.

Another study found that women who had more than one

alcoholic drink daily and who took less than the

recommended daily amount of folate had much a much

higher risk of breast cancer than women with the same

alcohol intake, but who had adequate folate in their

diet.

4. JAMA. 1999 May 5;281(17):1632-7

A prospective study of folate intake and the risk of

breast cancer.

Zhang S, Hunter DJ, Hankinson SE, Giovannucci EL,

Rosner BA, Colditz GA, Speizer FE, Willett WC.

Department of Epidemiology, Harvard School of Public

Health, Boston, Mass, USA.

Shumin.Zhang@...

CONTEXT: Folate is involved in DNA synthesis and

methylation and may reduce breast cancer risk,

particularly among women with greater alcohol

consumption. OBJECTIVES: To assess the association

between folate intake and risk of breast cancer and

whether higher folate intake may reduce excess risk

among women who consume alcohol. DESIGN: Prospective

cohort study performed in 1980, with 16 years of

follow-up. SETTING AND PARTICIPANTS: A total of 88818

women who completed the dietary questionnaire section

of the Nurses' Health Study in 1980. MAIN OUTCOME

MEASURE: Incidence of invasive breast cancer by levels

of folate and alcohol intake. RESULTS: A total of 3483

cases of breast cancer were documented. Total folate

intake was not associated with overall risk of breast

cancer. However, among women who consumed at least 15

g/d of alcohol, the risk of breast cancer was highest

among those with low folate intake. For total folate

intake of at least 600 microg/d compared with 150 to

299 microg/d, the multivariate relative risk (RR) was

0.55 (95% confidence interval [CI], 0.39-0.76; P for

trend = .001). This association was only slightly

attenuated after additional adjustment for intake of

beta carotene, lutein/zeaxanthin, preformed vitamin A,

and total vitamins C and E. The risk of breast cancer

associated with alcohol intake was strongest among

women with total folate intake of less than 300

microg/d (for alcohol intake > or =15 g/d vs <15 g/d,

multivariate RR, 1.32; 95% CI, 1.15-1.50). For women

who consumed at least 300 microg/d of total folate,

the multivariate RR for intake of at least 15 g/d of

alcohol vs less than 15 g/d was 1.05 (95% CI,

0.92-1.20). Current use of multivitamin supplements,

the major source of folate, was associated with lower

breast cancer risk among women who consumed at least

15 g/d of alcohol (for current users of supplements vs

never users, RR, 0.74; 95% CI, 0.59-0.93).

CONCLUSIONS: Our findings suggest that the excess risk

of breast cancer associated with alcohol consumption

may be reduced by adequate folate intake.

PMID: 10235158

5.

http://www.ingentaconnect.com/content/maney/rer/2001/00000006/00000004/6400251

Insulin-induced peroxynitrite production in human

platelet-rich plasma

Authors: Wittmann, I.1; Köszegi, T.2; Wagner, L.1;

Wagner, Z.1; Mazák, I.1; Nagy, J.1

Recent data support the possible role of nitric oxide

(NO•) in the development of insulin signalling. The

aim of this study was to examine the effect of insulin

on NO• production by platelets. The chemiluminescence

of platelet-rich plasma prepared from the blood of

healthy volunteers was measured in the presence of

luminol. Indirect detection of NO• by luminol is

possible in the form of peroxynitrite produced in the

reaction of NO• with a superoxide free radical.

Luminol oxidation induced by hydroxyl free radical and

lipid peroxidation was prevented by 150 µmol/l of

desferrioxamine mesylate. Insulin, in the range of

0.084–840 nmol/l, induced a concentration-dependent

increase in chemiluminescence, which was inhibited

both by the competitive antagonist of the NO• synthase

enzyme, N-nitro-L-arginine methyl ester (at

concentrations of 2.0–4.0 mmol/l, P <0.001), and by

the elimination of superoxide free radicals using

superoxide dismutase (72–144 IU/ml, P <0.001). In

conclusion, we assume that the insulin-induced

increase in chemiluminescence of platelet-rich plasma

was due to increased production of NO• and superoxide

free radicals forming peroxynitrite. The data are

consistent with production of peroxynitrite from human

platelets under insulin stimulation.