Discussion:
GLA beats EPA in 5 alpha-reductase inhibition
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Taka
2009-10-02 05:54:52 UTC
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J Steroid Biochem Mol Biol. 2002 Nov;82(4-5):393-400.

5 alpha-reductase-catalyzed conversion of testosterone to
dihydrotestosterone is increased in prostatic adenocarcinoma cells:
suppression by 15-lipoxygenase metabolites of gamma-linolenic and
eicosapentaenoic acids.

Pham H, Ziboh VA.
Department of Dermatology, School of Medicine, University of
California at Davis, TB-192, One Shields Avenue, 95616, USA.

Although the androgens, testosterone (T) and its highly active
metabolite dihydrotestosterone (DHT) play a role in the development
and progression of prostate cancer, the mechanism(s) are unclear.
Furthermore, 5 alpha-reductase which catalyze the conversion of T to
DHT, has been a target of manipulation in the treatment of prostatic
cancer, hence synthetic 5 alpha-reductase activity inhibitors have
shown therapeutic promise. To demonstrate that nutrients derived from
dietary sources can exert similar therapeutic promise, this study was
designed using benign hyperplastic cells (BHC) and malignant
tumorigenic cells (MTC) derived from Lobund-Wistar (L-W) rat model of
prostatic adenocarcinoma to test the effects of gamma-linolenic acid
(GLA), eicosapentaenoic acid (EPA) and their 15-lipoxygenase
metabolites on cellular 5 alpha-reductase activity. Our data revealed:
(i) that incubation of MTC with [3H]-T resulted in marked conversion
to [3H]-DHT when compared to similar incubation with BHC; (ii) that
DHT-enhanced activity of 5 alpha-reductase was inhibited 80% by 15S-
hydroxyeicosatrienoic acid, the 15-lipoxygenase metabolite of GLA,
when compared to 55% by 15S-hydroxyeicosapentaenoic acid, the 15-
lipoxygenase metabolite of EPA; and (iii) that their precursor fatty
acids, respectively, exerted moderate inhibition. Taken together, the
study underscores the biological importance of 15-lipoxygenase
metabolites of polyunsaturated fatty acids (PUFAs) in androgen
metabolism.
PMID: 12589947
Taka
2009-10-02 05:56:06 UTC
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Prostaglandins Leukot Essent Fatty Acids. 2005 May;72(5):363-72.

15-lipoxygenase metabolites of gamma-linolenic acid/eicosapentaenoic
acid suppress growth and arachidonic acid metabolism in human
prostatic adenocarcinoma cells: possible implications of dietary fatty
acids.

Vang K, Ziboh VA.
Department of Dermatology, School of Medicine, University of
California at Davis, One Shields Avenue, TB-192, Davis, CA 95616, USA.

Although gammalinolenic acid (GLA) and eicosapentaenoic acid (EPA)
have independently been reported to suppress growth of cancer cells,
their relative potencies are unknown. To determine the possible
attenuating efficacies of dietary GLA or EPA on prostate
carcinogenesis, we hereby report the in vitro effects of GLA, EPA and
their 15-lipoxygenase (15-LOX) metabolites: 15(S)-HETrE and 15(S)-
HEPE, respectively, on growth and arachidonic acid (AA) metabolism in
human androgen-dependent (LNCaP) and androgen-independent (PC-3)
prostatic cancer cells in culture. Specifically, both cells were
preincubated respectively with the above PUFAs. Growth was determined
by [3H]thymidine uptake and AA metabolism by HPLC analysis of the
extracted metabolites. Our data revealed increased biosynthesis of
prostaglandin E2 (PGE2) and 5-hydroxyeicosatetraenoic acid (5(S)-HETE)
by both cells. Preincubation of the cells with 15(S)-HETrE or 15(S)-
HEPE more markedly inhibited cellular growth and AA metabolism when
compared to precursor PUFAs. Notably, 15(S)-HETrE exerted the greatest
inhibitory effects. These findings therefore imply that dietary GLA
rather than EPA should better attenuate prostate carcinogenesis via
its in vivo generation of 15(S)-HETrE, thus warranting exploration.
PMID: 15850718


Prostaglandins Leukot Essent Fatty Acids. 2006 Apr;74(4):271-82. Epub
2006 Mar 29.

Dietary gamma-linolenate attenuates tumor growth in a rodent model of
prostatic adenocarcinoma via suppression of elevated generation of PGE
(2) and 5S-HETE.

Pham H, Vang K, Ziboh VA.
Department of Dermatology TB-192, School of Medicine, University of
California-Davis, Davis, CA 95616, USA.

Prostate cancer poses considerable threat to the aging male population
as it has become a leading cause of cancer death to this group. Due to
the complexity of this age-related disease, the mechanism(s) and
factors resulting in prostate cancer remain unclear. Reports showing
an increase risk in prostatic cancer with increasing dietary fat are
contrasted by other studies suggesting the beneficial effects of
certain polyunsaturated fatty acid (PUFA) in the modulation of tumor
development. The n-6 PUFA, gamma-linolenic acid (GLA), has been shown
to suppress tumor growth in vitro. Therefore, using the Lobund-Wistar
(L-W) rat model of prostate cancer, we tested the hypothesis whether
dietary supplementation of GLA could suppress tumor growth and
development in vivo. Prostatic adenocarcinomas were induced in two
groups of L-W rats, the experimental group (N-nitroso-N-methylurea,
NMU/testosterone propionate, TP) and the GLA group (NMU/TP/GLA fed)
undergoing similar treatment but fed a purified diet supplemented with
GLA. Our findings revealed a decrease in prostate growth in the NMU/TP/
GLA-fed group as determined by weight, tissue size, DNA content and
prostate-specific antigen (tumor marker of prostate cancer).
Comparison between the two groups showed a significant increase in 5S-
hydroxyeicosatetraenoic acid and prostaglandin E(2) in the NMU/TP
group. These increases paralleled the increased protein expression and
activity of cyclooxygenase-2 as well as increased activity of 5-
lipoxygenase. Taken together, the findings showed that intake of GLA-
enriched diet does reduce prostatic cancer development in L-W rats and
could serve as a non-toxic adjunct in management of human prostatic
cancer.
PMID: 16567086
Existential Angst
2009-10-02 17:39:33 UTC
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Yeah, but gamma linolenic (and gamma linoleic) are w-6!

Didn't you just post on elevated w-6's in Jamaican men as causal in prostate
problems?
--
PV'd
Post by Taka
Prostaglandins Leukot Essent Fatty Acids. 2005 May;72(5):363-72.
15-lipoxygenase metabolites of gamma-linolenic acid/eicosapentaenoic
acid suppress growth and arachidonic acid metabolism in human
prostatic adenocarcinoma cells: possible implications of dietary fatty
acids.
Vang K, Ziboh VA.
Department of Dermatology, School of Medicine, University of
California at Davis, One Shields Avenue, TB-192, Davis, CA 95616, USA.
Although gammalinolenic acid (GLA) and eicosapentaenoic acid (EPA)
have independently been reported to suppress growth of cancer cells,
their relative potencies are unknown. To determine the possible
attenuating efficacies of dietary GLA or EPA on prostate
carcinogenesis, we hereby report the in vitro effects of GLA, EPA and
their 15-lipoxygenase (15-LOX) metabolites: 15(S)-HETrE and 15(S)-
HEPE, respectively, on growth and arachidonic acid (AA) metabolism in
human androgen-dependent (LNCaP) and androgen-independent (PC-3)
prostatic cancer cells in culture. Specifically, both cells were
preincubated respectively with the above PUFAs. Growth was determined
by [3H]thymidine uptake and AA metabolism by HPLC analysis of the
extracted metabolites. Our data revealed increased biosynthesis of
prostaglandin E2 (PGE2) and 5-hydroxyeicosatetraenoic acid (5(S)-HETE)
by both cells. Preincubation of the cells with 15(S)-HETrE or 15(S)-
HEPE more markedly inhibited cellular growth and AA metabolism when
compared to precursor PUFAs. Notably, 15(S)-HETrE exerted the greatest
inhibitory effects. These findings therefore imply that dietary GLA
rather than EPA should better attenuate prostate carcinogenesis via
its in vivo generation of 15(S)-HETrE, thus warranting exploration.
PMID: 15850718
Prostaglandins Leukot Essent Fatty Acids. 2006 Apr;74(4):271-82. Epub
2006 Mar 29.
Dietary gamma-linolenate attenuates tumor growth in a rodent model of
prostatic adenocarcinoma via suppression of elevated generation of PGE
(2) and 5S-HETE.
Pham H, Vang K, Ziboh VA.
Department of Dermatology TB-192, School of Medicine, University of
California-Davis, Davis, CA 95616, USA.
Prostate cancer poses considerable threat to the aging male population
as it has become a leading cause of cancer death to this group. Due to
the complexity of this age-related disease, the mechanism(s) and
factors resulting in prostate cancer remain unclear. Reports showing
an increase risk in prostatic cancer with increasing dietary fat are
contrasted by other studies suggesting the beneficial effects of
certain polyunsaturated fatty acid (PUFA) in the modulation of tumor
development. The n-6 PUFA, gamma-linolenic acid (GLA), has been shown
to suppress tumor growth in vitro. Therefore, using the Lobund-Wistar
(L-W) rat model of prostate cancer, we tested the hypothesis whether
dietary supplementation of GLA could suppress tumor growth and
development in vivo. Prostatic adenocarcinomas were induced in two
groups of L-W rats, the experimental group (N-nitroso-N-methylurea,
NMU/testosterone propionate, TP) and the GLA group (NMU/TP/GLA fed)
undergoing similar treatment but fed a purified diet supplemented with
GLA. Our findings revealed a decrease in prostate growth in the NMU/TP/
GLA-fed group as determined by weight, tissue size, DNA content and
prostate-specific antigen (tumor marker of prostate cancer).
Comparison between the two groups showed a significant increase in 5S-
hydroxyeicosatetraenoic acid and prostaglandin E(2) in the NMU/TP
group. These increases paralleled the increased protein expression and
activity of cyclooxygenase-2 as well as increased activity of 5-
lipoxygenase. Taken together, the findings showed that intake of GLA-
enriched diet does reduce prostatic cancer development in L-W rats and
could serve as a non-toxic adjunct in management of human prostatic
cancer.
PMID: 16567086
Taka
2009-10-03 01:47:04 UTC
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Post by Existential Angst
Yeah, but gamma linolenic (and gamma linoleic) are w-6!
Didn't you just post on elevated w-6's in Jamaican men as causal in prostate
problems?
Yes, there seems to be a big difference between GLA and AA. I.e.
those Jamaicans and most normal people who consume LA rich diets get
excess of AA relative to GLA in their bodies. But if you supplement
with GLA rich sources like the evening primose or borage oil, AA
doesn't increase (relative to GLA). My tentative hypothesis on this
is that GLA somehow forward inhibits the enzyme delta-5-desaturase
which manufactures AA (read arachidonic acid). We have already
discussed this with Matti here some time ago.

Taka

P.S.: There also seems to be a "natural" inhibitor of the delta-5-
desaturase in the sesame oil (used for cooking in Japan). When this
desaturase goes up e.g. during the cooling autumn months many immunity-
related things go haywire such as the viral infections causing
colds ...
Kofi
2009-10-03 19:14:29 UTC
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Great for prostate cancer and/or baldness. Not necessarily so great for
neurology.

5 alpha reductase (5AR) not only converts testosterone (T) to
dihydrotestosterone (DHT, a ketone), it also converts progesterone to
allopregnanolone and deoxycorticosterone(DOC) to tetrahydroDOC (THDOC;
tetrahydrodeoxycorticosterone), both allosteric enhancers of the GABA(a)
receptor; monthly drops in women¹s progesterone prior to their periods
is a factor in PMS and epileptic seizure; progesterone lozenges
ameliorate seizures; both estrogen and progesterone are important for
TMJ remodelling [PMID 10670598]

the neurosteroid tetrahydrodeoxycorticosterone
(5alpha-pregnan-3alpha-21-diol-20-one; THDOC) affects pain sensitivity
in two experimental models of pain sensitivity in mice; THDOC (2.5, 5
mg/kg, i.p.) dose dependently decreased the licking response in the
formalin test and increased tail flick latency (TFL) in the tail flick
test; GABA-A antagonist bicuculline (2 mg/kg, i.p.) blocked the
antinociception in TFL test but failed to modulate the formalin licking
response; opioid antagonist naloxone (1 mg/kg, i.p.) attenuated THDOC
analgesia in both the models; THDOC pretreatment potentiated the
antinociceptive response to the opioid morphine and nimodipine, a
calcium channel blocker in both tests; THDOC has an analgesic effect,
which may be mediated by modulating GABA-ergic and/or opioid-ergic
mechanisms and voltage-gated calcium channels [PMID 12018528]

5AR type I inhibitors like proscar/finasteride; synthetic forms of
progestrone like the progestin found in some birth control pills and
hormone replacements; social isolation depletes endogenous
allopregnanolone which supresses seizure susceptability [PMID 12957225]

5AR inactivates cortisol; two women and five men were diagnosed with
type 2 diabetes; in women, adipose 11beta-HSD1 expression was increased
in patients with impaired glucose tolerance (IGT) and correlated with
glucose levels across the oral glucose tolerance testing but was
independent of fat mass; total glucocorticoid secretion was higher in
men with and without IGT and in women, it was higher in those with IGT;
in both sexes, 5alphaR activity correlated with fasting insulin, insulin
secretion across an OGTT and homeostasis model assessment of insulin
resistance; increased adipose 11beta-HSD1 expression in women may
contribute to glucose intolerance (which is inhibited by DHEA); enhanced
5alpha reductase (5AR) activity in both sexes is associated with insulin
resistance but not body composition; augmented glucocorticoid
inactivation may serve as a compensatory, protective mechanism to
preserve insulin sensitivity [PMID 18633104]

progesterone blocks 5AR activity, blocked DHT production and making more
dihydroprogesterone (DHP) which competes with residual DHT for nuclear
binding; minoxidil is much less effective in patients with significant
microinflammation and fibrosis of the follicles [Intl. Journal of
Dermatology, v39, issue 8 p576]

treatment with the 5AR inhibitor finasteride for benign prostate
hyperplasia increases HDL-C greatly [PMID 10996351]

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