Why the AMES test does not say DNP is safe

[bigrand]

Now we shouldnt go around yelling "DNP can cause cancer" and shit....
The truth is, the AMES test is/was vastly used to detect carcinogens and DNP passed the test.
Instead of stating reasons as to why DNP isnt a good candidate for the AMES test, how about showing us proof that DNP IS carcinogenic.
Are you ready to base your opinions off of one persons belief on how the AMES test is inadiquate?

 

[sk*]

bump

 

[sk*]

.

 

[bigrand]

Another thing, just becase somthing can act as an antineoplastic agent, doesnt mean its incapable of geing mutanagenic.
Take for example the Cis isomer of Pt(Cl)2(NH3)2, otherwise known as Cis-Platin. This is a widely used chemotherapy drug effective against all kinds of cancers. It targets fast proliferating cells such as cancer cells (and bone marrow, hair ect). It is a square planar molecule that is an intercalating agent meaning it can slide itself into a DNA strand dissrupting it, damaging, mutating it, and killing the cell, or stoping its reproduction as was seen in Cis-platins earlier days (hopefully, mostly cancer cells). Bad thing is, it can mutate non cancerous cells.

Just becasue DNP acts agains cancer cells (through a specific pathway) doesnt mean that it can be carcinogenic (through another pathway).

But, the AMES test is what we have to go on at this point.

 

[Andy13]

Another thing, just becase somthing can act as an antineoplastic agent, doesnt mean its incapable of geing mutanagenic.
Take for example the Cis isomer of Pt(Cl)2(NH3)2, otherwise known as Cis-Platin. This is a widely used chemotherapy drug effective against all kinds of cancers. It targets fast proliferating cells such as cancer cells (and bone marrow, hair ect). It is a square planar molecule that is an intercalating agent meaning it can slide itself into a DNA strand dissrupting it, damaging, mutating it, and killing the cell, or stoping its reproduction as was seen in Cis-platins earlier days (hopefully, mostly cancer cells). Bad thing is, it can mutate non cancerous cells.

Just becasue DNP acts agains cancer cells (through a specific pathway) doesnt mean that it can be carcinogenic (through another pathway).

But, the AMES test is what we have to go on at this point.

Wow... Now this is a guy who has done some reading!

Just a few things to add...

There is a difference between a "mutagen" and a "carcinogen." A "mutagen" is generally thought to pocess intrinsic DNAmutating abillity-- these are detected by the Ames test. On the other hand, a compound can result in cancer but cause no direct or intrinsic mutations in DNA. A good example of this is an analog of diaclylglycerol (I forget the name). It is not readily degraded, at least nearly as fast as DAG, and results in unregulated growth.. Let us not forget that a cell that has lost the ability to control it's growth is the stuff that tumors are made of. In the case of the DAG analog, no DNA mutagenesis occurs, yet the cell becomes cancerous.

Now, cis-platinum, on the other hand, causes cell death but in a different mechanism than pure DNA mutation. This cell death is acutally systematic cell suicide (apoptosis). Cis-platinum induces tumor supressor protein p53, which is the biological kommisar. P53 induction is well characterized in the face of DNA damage caused by uv radiation or chemical agents such as etoposide and cis-platinum. Acutally though, p53 is sometimes induced in the absence of DNA damage, but that is going beyond the scope. The point is: an increase in p53 causes an up-reguation of machinery required for DNA repair, cell cycle arrest, or programed cell death. Does DNP increase p53 levels?

Does DNP cause an increase in reactive oxygen species derived from aerobic metabolism? I used to think so... But now I'm not so sure. An increase in membrane potential or electrochemical gradient in the mito caused inhibition of one of the carriers (cyanide) results in a blockade of electron carrying intermediates. When the half life of one of these intermediates (ubquinone) is increased, it can result in deviant reductions of O2 to superoxide radical--- this fucks shit up.. not just in the mito, but also in the cell (I was wrong before when I said that superoxides formed in the mito stay there).

Now, the interesting thing, and something I carelessly over-looked before is the case during REDUCED membrane potential... This is the scinario DNP causes... A reduced membrane potential may actually result in a reduction in reactive oxygen species.. In vitro? Perhaps. In vivo? Who knows.. I think it's doubtful that a measurable reduction could occur.. But I don't know. If you like, I encorage you to search medline for this...

Bottom line:
Passing the Ames test does not mean a compound cannot cause cancer.... Cadmium is a great example of an agent that has little to no mutagenic power... yet is a carcinogen.

Also- Take your anti-oxidants! NAC has been shown to protect DNA from damage caused by cigarette smoke. Will ALA work in this respect as well? Probably.

Andy

 

[bigrand]

Well then Andy, is your opinion on the use of DNP still positive? Or am i giving myself cancer as we speak??!!
Im being lazy, it will take me awhile to figure out what you said and put it all together with info i dig up on DNP....

 

[NFG123]

Im working on figuring out what you wrote, but it will take time, im not far into college, yet.....
You are getting into molecular bio/genetics with that cytochrome shit, its interesting though....
Isnt cytochrome p53 mutated in a lot of adenocarcinomas of the pancreas? I think my dads cancer over had mutated p53.
What classed do you take to learn all this type of shit, this is the direcion i want to go......

Andy has obviously done graduate work. Im sure he holds a PhD. Otherwise, Im impressed as shit. p53 isnt a cytochrome. And p53 is mutated in a number of cancers period since is a tumor suppressor, loss of a tumor suppressor promotes cancer growth in most cases. Also, Andy, there are many characterized non p53 mediated paths to apoptosis. Rb is a good example. Also, p21 which is normally thought to act in a p53 pathway has been shown to have apoptotic effects independent of p53. Great discussion on mutagen vs carcinogen. Well put. Another example would be anything that constitutively actives the MapK family or Ras ... doesnt need to cause a mutation but can be growth promoting, destroy a cell cycle checkpoint, increase cellular invasion and adhesion (differential regulation of integrins) ... there are a number of factors. Point is: DNP isnt safe for a number of reasons, if you want to talk about hyperpyrexia, everyone will agree ... cancer ... maybe there is some dispute ... however, whatever your goal is in weight loss, there are safer methods to achieve it than by going down the DNP pathway...gotta love those ICE ENEMAS!

 

[bigrand]

I just wish i knew where to look myself to try to figure this shit out myself. My bad on the cytochrome thing, i havent talked about p53 or Ras-Onc or any of that shit in years (i didnt really know much about it anyway, except that there was an overexpression in pancreatic cancer cells). Junior college isnt teaching me too much about this shit, its up to you bros to fill me in!!!!
I understand DNP can be very dangerous, im just scared shitless of cancer for obvious reasons. I know oncologists cant help me if i get it anyway, so i definetly dont want to get it from DNP.
From what i was gathering, there is no real evidence DNP can cause cancer.

BTW....i thought the main reason of cisplatin's ability to kill cancer cells is its ability to bind into the helix and make bonds that dont redially dissacociate(intercalating agent), making adducts and killing the cell (inhibition of DNA synthesis)? And a reason for cisplatin (and carboplatin) resistance is the ability of the cancer cells to repair the adduct........damnit i dont know, ill have to go check.

Anyway, let me know how wrong i am NFG and Andy, im trying though!!!!

 

[bigrand]

What about you NFG, where have your studies taken you, i might just go there.....I feel biological science/medicine is the most important and interesting thing out there to learn.

 

[Andy13]

And p53 is mutated in a number of cancers period since is a tumor suppressor, loss of a tumor suppressor promotes cancer growth in most cases. Also, Andy, there are many characterized non p53 mediated paths to apoptosis. Rb is a good example. Also, p21 which is normally thought to act in a p53 pathway has been shown to have apoptotic effects independent of p53. Great discussion on mutagen vs carcinogen. Well put. Another example would be anything that constitutively actives the MapK family or Ras ... doesnt need to cause a mutation but can be growth promoting, destroy a cell cycle checkpoint, increase cellular invasion and adhesion (differential regulation of integrins) ...

Exactly.. p53 is non-functional in 50% of tumor cells! This alone illustrates it's importance.

I agree that there are p53 independent apoptotic pathways, but I never knew p21, classically induced by p53, and generally considered "anti-apoptotic" (by causing an arrest in growth) was one.

Aside, I think Lithium may be a focus for future thereputic intervention--- very interesting stuff. Li+ inhibits glycogen synthase kinase-3 (GSK-3). GSK-3, as of late, has been viewed as "pro-apoptotic" and is a player in the wnt signalling pathway.. Li+ has been shown to protect neuro cells from apoptosis in the face of glutamate and other neuro toxic agents by blocking GSK-3. In addition, over-expression of GSK-3 leads to an increased release of cytochrome c into the cytosol--- prime apoptotic behaviour here.

I look for Li+ to take on a larger pharmaceutical role in the future-- possibly as Alzsheimer's and Parkinson's disease therapies and/or part of cancer therapy.

NFG- you obviously know your stuff.. What is your background?

Andy