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Accutane and the sebosuppressive effect. New study.

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J Invest Dermatol. 2006 Mar 30; [Epub ahead of print] Links

13-cis Retinoic Acid Induces Apoptosis and Cell Cycle Arrest in Human SEB-1 Sebocytes.

Nelson AM, Gilliland KL, Cong Z, Thiboutot DM.

1The Jake Gittlen Cancer Research Foundation, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA.

Isotretinoin (13-cis retinoic acid (13-cis RA)) is the most potent inhibitor of sebum production, a key component in the pathophysiology of acne, yet its mechanism of action remains largely unknown. The effects of 13-cis RA, 9-cis retinoic acid (9-cis RA), and all-trans retinoic acid (ATRA) on cell proliferation, apoptosis, and cell cycle proteins were examined in SEB-1 sebocytes and keratinocytes. 13-cis RA causes significant dose-dependent and time-dependent decreases in viable SEB-1 sebocytes. A portion of this decrease can be attributed to cell cycle arrest as evidenced by decreased DNA synthesis, increased p21 protein expression, and decreased cyclin D1. Although not previously demonstrated in sebocytes, we report that 13-cis RA induces apoptosis in SEB-1 sebocytes as shown by increased Annexin V-FITC staining, increased TUNEL staining, and increased cleaved caspase 3 protein. Furthermore, the ability of 13-cis RA to induce apoptosis cannot be recapitulated by 9-cis RA or ATRA, and it is not inhibited by the presence of a retinoid acid receptor (RAR) pan-antagonist AGN 193109. Taken together these data indicate that 13-cis RA causes cell cycle arrest and induces apoptosis in SEB-1 sebocytes by a RAR-independent mechanism, which contributes to its sebosuppressive effect and the resolution of acne.Journal of Investigative Dermatology advance online publication, 30 March 2006; doi:10.1038/sj.jid.5700289.

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what does it mean?

Taken together these data indicate that 13-cis RA causes cell cycle arrest and induces apoptosis in SEB-1 sebocytes by a RAR-independent mechanism, which contributes to its sebosuppressive effect and the resolution of acne.

They figured a little more about how Accutane can reduce sebum production, something not really understood before......and still not fully understood

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so.....is this good news for retinoids?

I use a retinoid....I hope it wont kill me. Please don't kill me, Green Cream.

No. Green Cream doesn't even contain a retinoid. It contain's retinol a precursor to retinoic acid (trans, cis-9 and cis-13).....The conversion of retinol to retinoic acid in the epidermis only occurs to a very small degree (this converison usually happens in the liver), as the enzymes reqiured for this conversion aren't present in signifigant quantities in the epidermis....it may happen to a limited degree in some (depending on the presence of the requried enzymes in the epidermis and dermis), but not enough to have an effect on sebum production........

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that's amazing how you answered my question yet I feel less educated now....

it has no effect on sebum production? that's one of the things GC says it helps over time....

anyways, do you think GC is a good idea? scientifically speaking?

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that's amazing how you answered my question yet I feel less educated now....

it has no effect on sebum production? that's one of the things GC says it helps over time....

anyways, do you think GC is a good idea? scientifically speaking?

I didn't see any clinical data posted on their site, just testimonials and before and after pics. The conversion of retinol to retinoic-acid does occur to a limited degree in the epidermal cells, but only in already differentiated keratinocytes (and not nearly to the degree it does in other tissues like the liver). And my main issue with Green Cream is that it contains ethanol as the second ingredient, which means it's at a pretty high level in the formula. I'm guessing it's meant to ease the penetration of the retinol into the skin, by disrupting the epidermal lipids (although retinol is lipid soluble, and can easily penetrate the epidermal barrier). The funny thing is that ethanol reduced the rate and the effectivenss of the conversion of retinol into retinoic acid in a study, because it is belived to tie up the enzyme required for the conversion, a non-specific alcohol dehydrogenase enzyme.......

I posted this on another thread......

I've been doing a little side research as to weather or not topically applied retinol is actually converted into retinoic acid in epidermal cells. There is a presence of enzymes required for the oxidation of retinol into retinoic acid but they are not very active and in low concentrations in epidermal cells. So it seems that differentiating epidermal cells can make this conversion, but it only happens effectienly at pH of 8.5-9.0, and the pH of skin is 4.2-5.6.....this is why the conversion works in vitro.....but not in vivo....It's interesting that the Green Cream is carbomer based....carbomer requires neutrelization by a base to make it able to gel water. I believe (not looking at the ingredient listing) that it is TEA or triethanolamine....so the pH of the product must be at least 7.5, but probably higher.......

Also the conversion only occurs in differentiated keratinocytes, and not in non-differentiated ones........and also the results of this study confirm that retinal (retinyl aldehyde) is a better starting point than retinol for the conversion into retinoic acid.......

This study was super helpful....and I have the full text.....very informative....... here's an abstract....

Retinol and retinal metabolism. Relationship to the state of differentiation of cultured human keratinocytes.

G Siegenthaler, J H Saurat, and M Ponec

Clinique de Dermatologie, Hôpital Cantonal Universitaire, Geneva, Switzerland.

Abstract

Cultured keratinocytes offer an attractive model for studying the metabolism of retinol in relation to cell differentiation, since the extent of keratinocyte differentiation can be modulated experimentally. The metabolism of retinol and retinal was studied in cytosol fractions prepared from two distinct keratinocyte populations, differentiating and non-differentiated. The enzymic activities were analysed using physiological concentrations of [3H]retinol and [3H]retinal in the presence of cofactors. The products formed were quantified by h.p.l.c. In the population of differentiating keratinocytes, the formation of retinoic acid from retinol occurred at a rate of 4.49 +/- 0.17 pmol/h per mg of protein, but no such conversion was observed in the population of non-differentiated cells. However, when retinal was used as substrate, retinoic acid was formed in both cell populations, at rates of 14.4 pmol/h per mg of protein in non-differentiated and 51.6 pmol/h per mg of protein in differentiating keratinocytes. Using PAGE/radiobinding assay, we demonstrated that retinoic acid formed from retinol was bound in differentiating keratinocytes to endogenous cellular retinoic acid-binding protein (CRABP). Furthermore, retinal was reduced to retinol in the presence of NADH in both differentiating and non-differentiated keratinocytes at a similar rate (8 pmol/h per mg of protein). Although retinal could not be detected under physiological conditions, it was found in significant amounts at pH 8.5-9, which is optimal for enzymic activity. This indicates that in keratinocytes retinal is an intermediate metabolite in retinoic acid formation from retinol. The enzymes catalysing the conversion of retinol into retinoic acid were found to differ from other alcohol and aldehyde dehydrogenases, since the formation of retinoic acid was not significantly affected by specific inhibitors of alcohol metabolism, such as 4-methylpyrazole and disulfiram. Moreover, the cytosol of non-differentiated keratinocytes did not generate retinoic acid from retinol despite showing alcohol dehydrogenase activity. The results suggest that: (1) retinol metabolism in human keratinocytes is different from that of other alcohols, (2) retinal is an intermediate metabolite in the conversion of retinol into retinoic acid, and (3) differentiating keratinocytes rich in CRABP are probably target cells for retinoic acid action.

I've got big issues with that ethanol in Green Cream (I was actually starting to think some good things about it too.... ).........

In that study they mentiond that this conversion is carried out by a non-specific alcohol dehydrogenase, and not ethanol dehydrogenase, but ethanol may be able to be oxidized by the same enzymes that make the conversion from retinol to retinoic acid......it was shown that ethanol greatly reduced the rate of the conversion of the retinol to retinoic acid in differentiated epidermal cells......hmmm that ethanol isn't such a good thing in that product.....it reduces the effectivenss of the retinol......

So why on earth did thy put the ethanol in there??? Okay, because how else will the retinol be able to penetrate the epidermis in a water based gel.......hmmmm.....What's a great epidermal penetration enhancer that will disrupt the epidermal barrier lipids???.....Ethanol......

Sometimes formulation chemists don't think or read up when we formulate stuff.....we just do what we're taught..... the chemists who made that knew that ethanol is a treat penetration enhancer.....they didn't know that it may be able to further reduce the ability of epidermal cells to make that conversion of the retinol into retinoic acid......

There are people here who swear by the stuff. Does it actually work.....as far as speeding up the skin cell renweal cycle and thickening up the dermis go... probably. I'm doubting it really does shrink the sebaceous glands though, since the topical conversion og the retinol into retinoic acne seems to make only all trans-retinoic acid (like tretonin), not cis-9 or cis-13-retinoic acid (isotretonin). It's only the -cis version that has the potenital to shrink the sebaceous glands. And even when isotretonin is applied topically it's converted to all trans-retinoic acid by the differentated keratinocytes.........this is why isotrex has similar effectivenss to retin-a......

If Green Cream's retinol really does shrink the sebaceous glands than the have more than just an OTC retinol.....thay have a drug (it changes the structure and function of the body).....and may get in trouble with the FDA (although they use the term "helps" reduce oil production).....I don't really believe anything that follows the term "helps" in an OTC cosmetic product.....because they're's no way of kmnowing if the statment it precedes statment can be proven.......

Should you use it??

Depends on your situation. If you have very mild acne and some fine lines you want to get rid of....it might be all you need.....but it you have excessively oily skin and more than just mild acne.....you might want to look into someting a bit stronger..........

I think it a decent OTC retinol product (although it's pricey for what it is), and I'd reccomend it more often if it weren't for the ethanol situation........

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Good news. I don't have problems with oil at all, and just wanted to purge these comedos out of my skin. It's working great!

please check my log labgirl, its nice to have someone who knows what they're doing. It's kinda like blind leading the blind around these boards most of the time....

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About time to at least find out how it works.

Keep in mind that knowing how it works to reduce sebum and knowing how it works to help acne aren't necessarily the same thing.

Bryan

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that's amazing how you answered my question yet I feel less educated now....

it has no effect on sebum production? that's one of the things GC says it helps over time....

anyways, do you think GC is a good idea? scientifically speaking?

I didn't see any clinical data posted on their site, just testimonials and before and after pics. The conversion of retinol to retinoic-acid does occur to a limited degree in the epidermal cells, but only in already differentiated keratinocytes (and not nearly to the degree it does in other tissues like the liver). And my main issue with Green Cream is that it contains ethanol as the second ingredient, which means it's at a pretty high level in the formula. I'm guessing it's meant to ease the penetration of the retinol into the skin, by disrupting the epidermal lipids (although retinol is lipid soluble, and can easily penetrate the epidermal barrier). The funny thing is that ethanol reduced the rate and the effectivenss of the conversion of retinol into retinoic acid in a study, because it is belived to tie up the enzyme required for the conversion, a non-specific alcohol dehydrogenase enzyme.......

I posted this on another thread......

I've been doing a little side research as to weather or not topically applied retinol is actually converted into retinoic acid in epidermal cells. There is a presence of enzymes required for the oxidation of retinol into retinoic acid but they are not very active and in low concentrations in epidermal cells. So it seems that differentiating epidermal cells can make this conversion, but it only happens effectienly at pH of 8.5-9.0, and the pH of skin is 4.2-5.6.....this is why the conversion works in vitro.....but not in vivo....It's interesting that the Green Cream is carbomer based....carbomer requires neutrelization by a base to make it able to gel water. I believe (not looking at the ingredient listing) that it is TEA or triethanolamine....so the pH of the product must be at least 7.5, but probably higher.......

Also the conversion only occurs in differentiated keratinocytes, and not in non-differentiated ones........and also the results of this study confirm that retinal (retinyl aldehyde) is a better starting point than retinol for the conversion into retinoic acid.......

This study was super helpful....and I have the full text.....very informative....... here's an abstract....

Retinol and retinal metabolism. Relationship to the state of differentiation of cultured human keratinocytes.

G Siegenthaler, J H Saurat, and M Ponec

Clinique de Dermatologie, Hôpital Cantonal Universitaire, Geneva, Switzerland.

Abstract

Cultured keratinocytes offer an attractive model for studying the metabolism of retinol in relation to cell differentiation, since the extent of keratinocyte differentiation can be modulated experimentally. The metabolism of retinol and retinal was studied in cytosol fractions prepared from two distinct keratinocyte populations, differentiating and non-differentiated. The enzymic activities were analysed using physiological concentrations of [3H]retinol and [3H]retinal in the presence of cofactors. The products formed were quantified by h.p.l.c. In the population of differentiating keratinocytes, the formation of retinoic acid from retinol occurred at a rate of 4.49 +/- 0.17 pmol/h per mg of protein, but no such conversion was observed in the population of non-differentiated cells. However, when retinal was used as substrate, retinoic acid was formed in both cell populations, at rates of 14.4 pmol/h per mg of protein in non-differentiated and 51.6 pmol/h per mg of protein in differentiating keratinocytes. Using PAGE/radiobinding assay, we demonstrated that retinoic acid formed from retinol was bound in differentiating keratinocytes to endogenous cellular retinoic acid-binding protein (CRABP). Furthermore, retinal was reduced to retinol in the presence of NADH in both differentiating and non-differentiated keratinocytes at a similar rate (8 pmol/h per mg of protein). Although retinal could not be detected under physiological conditions, it was found in significant amounts at pH 8.5-9, which is optimal for enzymic activity. This indicates that in keratinocytes retinal is an intermediate metabolite in retinoic acid formation from retinol. The enzymes catalysing the conversion of retinol into retinoic acid were found to differ from other alcohol and aldehyde dehydrogenases, since the formation of retinoic acid was not significantly affected by specific inhibitors of alcohol metabolism, such as 4-methylpyrazole and disulfiram. Moreover, the cytosol of non-differentiated keratinocytes did not generate retinoic acid from retinol despite showing alcohol dehydrogenase activity. The results suggest that: (1) retinol metabolism in human keratinocytes is different from that of other alcohols, (2) retinal is an intermediate metabolite in the conversion of retinol into retinoic acid, and (3) differentiating keratinocytes rich in CRABP are probably target cells for retinoic acid action.

I've got big issues with that ethanol in Green Cream (I was actually starting to think some good things about it too.... ).........

In that study they mentiond that this conversion is carried out by a non-specific alcohol dehydrogenase, and not ethanol dehydrogenase, but ethanol may be able to be oxidized by the same enzymes that make the conversion from retinol to retinoic acid......it was shown that ethanol greatly reduced the rate of the conversion of the retinol to retinoic acid in differentiated epidermal cells......hmmm that ethanol isn't such a good thing in that product.....it reduces the effectivenss of the retinol......

So why on earth did thy put the ethanol in there??? Okay, because how else will the retinol be able to penetrate the epidermis in a water based gel.......hmmmm.....What's a great epidermal penetration enhancer that will disrupt the epidermal barrier lipids???.....Ethanol......

Sometimes formulation chemists don't think or read up when we formulate stuff.....we just do what we're taught..... the chemists who made that knew that ethanol is a treat penetration enhancer.....they didn't know that it may be able to further reduce the ability of epidermal cells to make that conversion of the retinol into retinoic acid......

There are people here who swear by the stuff. Does it actually work.....as far as speeding up the skin cell renweal cycle and thickening up the dermis go... probably. I'm doubting it really does shrink the sebaceous glands though, since the topical conversion og the retinol into retinoic acne seems to make only all trans-retinoic acid (like tretonin), not cis-9 or cis-13-retinoic acid (isotretonin). It's only the -cis version that has the potenital to shrink the sebaceous glands. And even when isotretonin is applied topically it's converted to all trans-retinoic acid by the differentated keratinocytes.........this is why isotrex has similar effectivenss to retin-a......

If Green Cream's retinol really does shrink the sebaceous glands than the have more than just an OTC retinol.....thay have a drug (it changes the structure and function of the body).....and may get in trouble with the FDA (although they use the term "helps" reduce oil production).....I don't really believe anything that follows the term "helps" in an OTC cosmetic product.....because they're's no way of kmnowing if the statment it precedes statment can be proven.......

Should you use it??

Depends on your situation. If you have very mild acne and some fine lines you want to get rid of....it might be all you need.....but it you have excessively oily skin and more than just mild acne.....you might want to look into someting a bit stronger..........

I think it a decent OTC retinol product (although it's pricey for what it is), and I'd reccomend it more often if it weren't for the ethanol situation........

I've been hearing good things about the Vivant retinoids (yes I am using the term "retinoids" loosely and incorrectly for my own convenience) ... I believe they are retinaldehyde-based and don't contain ethanol.

Know anything about them, LabGirl?

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