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From: Taka on 13 Aug 2008 22:50
On Aug 13, 4:08 pm, soowhatdouth...(a)hotmail.com wrote:
> Chem Res Toxicol. 2008 Feb;21(2):282-7. Epub 2008 Jan 5.
> Effect of methyl substitution on the antioxidative property and
> genotoxicity of resveratrol.
> Fukuhara K, Nakanishi I, Matsuoka A, Matsumura T, Honda S, Hayashi M,
> Ozawa T, Miyata N, Saito S, Ikota N, Okuda H.
> Division of Organic Chemistry, National Institute of Health Sciences,
> Setagaya-ku, Tokyo 158-8501, Japan. fukuh...(a)nihs.go.jp
>
> Resveratrol ( trans-3,4',5-trihydroxystilbene) is a natural
> phytoalexin with various biological activities including inhibition of
> lipid peroxidation and free radical scavenging properties. In addition
> to its beneficial effects, resveratrol also has significant
> genotoxicity that leads to a high frequency of chromosome aberration
> together with micronucleus and sister chromatid exchanges. To enhance
> the radical scavenging activities and to reduce the genotoxicity of
> resveratrol, we designed 4'-methyl resveratrol analogues where a
> methyl group was introduced at the ortho position relative to the 4'-
> hydroxy group, which is responsible for both antioxidative activities
> and genotoxicity of resveratrol. These synthesized methyl analogues of
> resveratrol showed increased antioxidative activities against
> galvinoxyl radical as an oxyl radical species. Furthermore, the methyl
> analogues also surprisingly showed reduced in vitro genotoxicities,
> suggesting that methyl substitution may improve resveratrol efficacy.
>
> PMID: 18177016 [PubMed - indexed for MEDLINE]

All these "antioxidants" as well as Omega-3 fatty acids exert their
health "benefits" at least in part by damaging DNA leading to
apoptosis. Cancer chemotherapies also do this in a stronger way.
Apoptosis is in this context considered beneficial because it kills
any hyperproliferative cells which would like to turn into
malignancies preemptively. It may also help to knock down the dying
and damaged old cells faster. Cancer arises only when you allow for
the damaged cells to survive and start evolving what is mediated by
the cancer promoters. Cancer promoters allow for the damaged DNA to
be replicated resulting in mutations - this is true genotoxicity.
Some of the most significant cancer promoters are hormones like
estrogen and IGF-1 and the end mediators like the AA-derived
eicosanoids. IMO the best strategy leading to maximal longevity is to
minimize any damage to the DNA from these "antioxidants" and lipid
peroxides by avoiding them and you can then preserve your stem cell
pools till very old age and wakeup them on demand by the "cancer
promoters" to repair the body without risking getting cancer. Like
the young children running high on GH/IGF-1/TOR and later estrogen
when they hit puberty without getting cancer from it because they have
not accumulated too much damage in their DNA yet (from lifelong
consumption of vegetable oils ;-).

Taka
From: Taka on 14 Aug 2008 01:02
Mutat Res. 2002 Nov 26;521(1-2):29-35.

The 4'-hydroxy group is responsible for the in vitro cytogenetic
activity of resveratrol.

Matsuoka A, Takeshita K, Furuta A, Ozaki M, Fukuhara K, Miyata N.
Division of Medical Devices, National Institute of Health Sciences,
1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan.

We previously reported that 3,5,4'-trihydroxy-trans-stilbene
(resveratrol), a polyphenolic phytoalexin found in grapes, induces a
high frequency of sister chromatid exchanges (SCEs) in vitro. In this
study, to investigate structure activity relationships, we synthesized
six analogues of resveratrol differing in number and position of
hydroxy groups, and we investigated their activity in chromosomal
aberration (CA), micronucleus (MN) and sister chromatid exchange (SCE)
tests in a Chinese hamster cell line (CHL). Two of the six analogues
(3,4'-dihydroxy-trans-stilbene and 4-hydroxy-trans-stilbene) showed
clear positive responses in a concentration-dependent manner in all
three tests. Both were equal to or stronger than resveratrol in
genotoxicity. The 4'-hydroxy (OH) analogue had the simplest chemical
structure and was the most genotoxic. The other analogues did not have
a 4'-hydroxy group. These results suggested that a 4'-hydroxy group is
essential to the genotoxicity of stilbenes.
PMID: 12438001


Food Chem Toxicol. 2008 Mar;46(3):1125-30. Epub 2007 Nov 22.

A pilot study of evaluation of the antioxidative activity of
resveratrol and its analogue in a 6-month feeding test in young adult
mice.

Matsuoka A, Kodama Y, Fukuhara K, Honda S, Hayashi M, Sai K, Hasebe M,
Fujiwara Y.
Division of Medical Devices, National Institute of Health Sciences,
Tokyo, Japan.

Resveratrol, a polyphenolic phytoalexin, has free-radical scavenging
activity and we found that it induces chromosomal aberrations,
micronuclei, and sister chromatid exchanges in vitro. We synthesized
its analogue 4-hydroxy-trans-stilbene (4-OH) and found that it has the
same in vitro clastogenic activities as resveratrol, suggesting that
the 4' hydroxy group of resveratrol is responsible for the effect. We
fed resveratrol and 4-OH to young adult ICR mice at 0, 0.2, 2, or 20
ppm in their standard powder diet for 6 months and investigated the
antioxidative effects. Half of each group was given 3000 ppm potassium
bromate (KBrO(3)) in water for the last week to cause oxidative
damage. Body weight gain tended to increase in males at 0.2 ppm
resveratrol or 4-OH, and in females at 2 ppm 4-OH. Micronucleus (MN)
analysis in bone marrow erythrocytes showed that the KBrO(3) tendency
to induce MN was not prevented by the dietary resveratrol or 4-OH,
which themselves did not induce MN under the present conditions. In
this pilot study, resveratrol and 4-OH showed no obvious effect,
either beneficial or adverse, at doses that are feasible in daily life
for humans.
PMID: 18155340
From: Taka on 14 Aug 2008 02:14
More on the genotoxicity:

Mutat Res. 2001 Jul 25;494(1-2):107-13.

Resveratrol, a naturally occurring polyphenol, induces sister
chromatid exchanges in a Chinese hamster lung (CHL) cell line.

Matsuoka A, Furuta A, Ozaki M, Fukuhara K, Miyata N.
Division of Genetics and Mutagenesis, National Institute of Health
Sciences, 1-18-1 Kamiyoga, Setagaya-ku, 158-8501, Tokyo, Japan.

We tested the genotoxicity of 3,5,4'-trihydroxystilbene (resveratrol),
a polyphenolic phytoalexin found in grapes, in a bacterial reverse
mutation assay, in vitro chromosome aberration (CA) test, in vitro
micronucleus (MN) test, and sister chromatid exchange (SCE) test.
Resveratrol was negative in the strains we used in the bacterial
reverse mutation assay (S. typhimurium TA98 and TA100 and E. coli
WP2uvrA) in the absence and presence of a microsomal metabolizing
system. It induced structural CAs at 2.5-20 microg/ml and showed weak
aneuploidy induction in a Chinese hamster lung (CHL) cell line. It
induced MN cells and polynuclear and karyorrhectic cells after 48h
treatments in the in vitro MN test. In the SCE test, resveratrol
caused a clear cell-cycle delay; at 10 microg/ml, the cell cycle took
twice as long as it did in the control. Resveratrol induced SCEs dose-
dependently at up to 10 microg/ml, at which it increased SCE six-fold,
and the number was almost as large as mitomycin C, a strong SCE
inducer. No second mitoses were observed at 20 microg/ml even after
54h. Cell cycle analysis by FACScan indicated that resveratrol caused
S phase arrest, and 48h treatment induced apoptosis. Our results
suggest that resveratrol may preferentially induce SCE but not CA,
that is, it may cause S phase arrest only when SCEs are induced.
PMID: 11423350


Free Radic Biol Med. 2006 Dec 15;41(12):1807-16. Epub 2006 Sep 15.

DNA damage induced by resveratrol and its synthetic analogues in the
presence of Cu (II) ions: mechanism and structure-activity
relationship.

Zheng LF, Wei QY, Cai YJ, Fang JG, Zhou B, Yang L, Liu ZL.
National Laboratory of Applied Organic Chemistry, Lanzhou University,
Lanzhou, Gansu 730000, China.

The prooxidant effect of resveratrol (3,5,4'-trihydroxy-trans-stibene)
and its synthetic analogues (ArOH), that is, 3,4,4'-trihydroxy-trans-
stibene (3,4,4'-THS), 3,4,5-trihydroxy-trans-stibene (3,4,5-THS), 3,4-
dihydroxy-trans-stibene (3,4-DHS), 4,4'-dihydroxy-trans-stibene (4,4'-
DHS), 2,4-dihydroxy-trans-stilbene (2,4-DHS), 3,5-dihydroxy-trans-
stilbene (3,5-DHS) and 3,5,4'-trimethoxy-trans-stibene (3,5,4'-TMS),
on supercoiled pBR322 plasmid DNA strand breakage and calf thymus DNA
damage in the presence of Cu (II) ions has been studied. It was found
that the compounds bearing ortho-dihydroxyl groups (3,4-DHS, 3,4,4'-
THS, and 3,4,5-THS) or bearing 4-hydroxyl groups (2,4-DHS, 4,4'-DHS,
and resveratrol) exhibit remarkably higher activity in the DNA damage
than the ones bearing no such functionalities. Kinetic analysis by UV-
visible spectra demonstrates that the formation of ArOH-Cu (II)
complexes, the stabilization of oxidative intermediate derived from
ArOH and Cu (II)/Cu (I) redox cycles, might be responsible for the DNA
damage. This study also reveals a good correlation between antioxidant
and prooxidant activity, as well as cytotoxicity against human
leukemia (HL-60 and Jurkat) cell lines. The mechanisms and
implications of these observations are discussed.
PMID: 17157183
From: Taka on 14 Aug 2008 02:46
and RSV scavenges lipid peroxides which form more pre-carcinogenic DNA
adducts than RSV itself, therefore the positive overall effects from
RSV supplementation in those high on AA I guess:

Free Radic Res. 2000 Jul;33(1):105-14.

Resveratrol inhibition of lipid peroxidation.

Tadolini B, Juliano C, Piu L, Franconi F, Cabrini L.
Dipartimento di Scienze Biomediche, Università di Sassari, Istituto
Nazionale Biostrutture e Biosistemi, Osilo, Italy.

To define the molecular mechanism(s) of resveratrol inhibition of
lipid peroxidation we have utilized model systems that allow us to
study the different reactions involved in this complex process.
Resveratrol proved (a) to inhibit more efficiently than either Trolox
or ascorbate the Fe2+ catalyzed lipid hydroperoxide-dependent
peroxidation of sonicated phosphatidylcholine liposomes; (b) to be
less effective than Trolox in inhibiting lipid peroxidation initiated
by the water soluble AAPH peroxyl radicals; (c) when exogenously added
to liposomes, to be more potent than alpha-tocopherol and Trolox, in
the inhibition of peroxidation initiated by the lipid soluble AMVN
peroxyl radicals; (d) when incorporated within liposomes, to be a less
potent chain-breaking antioxidant than alpha-tocopherol; (e) to be a
weaker antiradical than alpha-tocopherol in the reduction of the
stable radical DPPH*. Resveratrol reduced Fe3+ but its reduction rate
was much slower than that observed in the presence of either ascorbate
or Trolox. However, at the concentration inhibiting iron catalyzed
lipid peroxidation, resveratrol did not significantly reduce Fe3+,
contrary to ascorbate. In their complex, our data indicate that
resveratrol inhibits lipid peroxidation mainly by scavenging lipid
peroxyl radicals within the membrane, like alpha-tocopherol. Although
it is less effective, its capacity of spontaneously entering the lipid
environment confers on it great antioxidant potential.
PMID: 10826926


Chemistry. 2002 Sep 16;8(18):4191-8.

Antioxidant effects of resveratrol and its analogues against the free-
radical-induced peroxidation of linoleic acid in micelles.

Fang JG, Lu M, Chen ZH, Zhu HH, Li Y, Yang L, Wu LM, Liu ZL.
National Laboratory of Applied Organic Chemistry, Lanzhou University,
Lanzhou, Gansu 730000, China.

The antioxidant effect of resveratrol (3,4',5-trihydroxy-trans-
stilbene) and its analogues, that is, 4-hydroxy-trans-stilbene (4-HS),
3,5-dihydroxy-trans-stilbene (3,5-DHS), 4,4'-dihydroxy-trans-stilbene
(4,4'-DHS), 3,4-dihydroxy-trans-stilbene (3,4-DHS), 3,4,5-trihydroxy-
trans-stilbene (3,4,5-THS) and 3,4,4'-trihydroxy-trans-stilbene
(3,4,4'-THS), against the peroxidation of linoleic acid has been
studied in sodium dodecyl sulfate (SDS) and cetyltrimethyl ammonium
bromide (CTAB) micelles. The peroxidation was initiated thermally by a
water-soluble azo initiator 2,2'-azobis(2-methylpropionamidine)
dihydrochloride (AAPH), and the reaction kinetics were studied by
monitoring the formation of linoleic acid hydroperoxides. The
synergistic antioxidant effect of these compounds with alpha-
tocopherol (vitamin E) was also studied by following the decay
kinetics of alpha-tocopherol and the reaction intermediate, the alpha-
tocopheroxyl radical. Kinetic analysis of the antioxidant process
demonstrates that these compounds are effective antioxidants in
micelles used either alone or in combination with alpha-tocopherol.
The antioxidative action involves trapping the propagating lipid
peroxyl radical and reducing the alpha-tocopheroxyl radical to
regenerate alpha-tocopherol. It was found that the antioxidant
activity of resveratrol analogues depends significantly on the
position of the hydroxyl groups, the oxidation potential of the
molecule and the reaction medium. Molecules with ortho-dihydroxyl and/
or para-hydroxyl functionalities possess high activity.
PMID: 12298009


Arch Biochem Biophys. 2001 Jul 1;391(1):79-89.

Efficiency and mechanism of the antioxidant action of trans-
resveratrol and its analogues in the radical liposome oxidation.

Stojanović S, Sprinz H, Brede O.
Research Unit Time-Resolved Spectroscopy, University of Leipzig,
Permoserstrasse 15, D-04318 Leipzig, Germany.

trans-Resveratrol (trans-3,5,4'-trihydroxystilbene) is a nonflavonoid
polyphenol reported to exert different biological activities, among
them inhibition of the lipid peroxidation, scavenging of the free
radicals, inhibition of the platelet aggregation, and anticancer
activity as the most important. In order to enlighten the radical-
scavenging mechanism of trans-resveratrol, stationary gamma-radiolytic
experiments in liposomes and pulse radiolytic experiments in aqueous
solutions were performed. Applying the stationary gamma-radiolysis
together with the subsequent product analysis, reactions of lipid
peroxyl radicals, LOO*, with trans-resveratrol and other natural
antioxidants were investigated. It was found that trans-resveratrol
was a better radical scavenger than vitamins E and C but similar to
the flavonoids epicatechin and quercetin. The comparison of the
radical-scavenging effects of trans-resveratrol and its analogues
trans-4-hydroxystilbene and trans-3,5-dihydroxystilbene revealed that
trans-resveratrol and trans-4-hydroxystilbene showed almost the same
effect and were more efficient than trans-3,5-dihydroxystilbene. These
findings indicate greater radical-scavenging activity of trans-
resveratrols para-hydroxyl group than its meta-hydroxyl groups. Using
the pulse radiolysis, reactions of trans-resveratrol and its analogues
with trichloromethylperoxyl radicals, CCl(3)OO*, were studied.
Spectral and kinetic properties of the observed transients showed
great similarity between trans-resveratrol and trans-4-hydroxystilbene
which seems to confirm that para-hydroxyl group of trans-resveratrol
scavenges free radicals more effectively than its meta-hydroxyl
groups. Copyright 2001 Academic Press.
PMID: 11414688


But does it work like this even in the in vivo situation when RSV is
modified by the liver passage?

Taka
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