Metabolization Questions

[Xareoshin]

I have went to different sources, each with different answers.
I would like to try to clear up some of the information that has been given to me about the metabolization of chemicals in our bodies.

I have a somewhat wide array of questions revolving around related subjects, so please bare with me. I apologize in advance for question variance.


A)How substantial are tests such as cytotoxicity/CYP450/greenscreen/hERG to the toxicity of a chemical? If these tests show non toxic readings, can the chemical still be quite toxic?

B)What are Epoxides and how do they fit in to the metabolization process?

C)If a chemical (jwh-018 series for example) shows not to be mutagenic, but it's metabolites are unknown. How toxic can the chemical actually be.

D)Can an explanation be given about JWH's metabolites? (This relates to the epoxide description question) Why are we all on the fence, and how does the metabolization of naphthalene fit into this.

 

[reformer]

My take on these questions:

A) The barrage of tests you mentioned are fairly good at predicting gentotoxicity (DNA damage) and cardiotoxicity. Inclusion of other in vitro tests would perhaps show whether there is the *potential* for liver (HepG2 cells), kidney (HEK cells) or intestinal (CaCo-2 cells) damage.

When companies see toxicity from one of their potential drugs in these high throughput screening assays, it usuaally spell the end of that drug's life. No one wants a genotoxic agent as their prescription. However, a negative result does NOT mean there will not be toxicity.

Even including "activating" steps in the screen (inclusion of S9 microsomes to provide CYP450 activation) doesn't always predict toxicity, but it does help to find drugs which are innocuous by themselves and toxic when bioactivated.

B) Epoxides are phase I metabolites, and are reactive enough to deplete cellular antioxidants and form adducts with DNA to cause mutagenesis. The point of epoxide formation is to introduce a site on the drug which can subsequently be utilized for hooking on a water-soluble group and promoting the urinary excretion of the "foreign substance" from the body. Epoxide formation is neccessary, but we certainly want out Epoxide Hydrolase to be working very well, so any epoxides produced in the body are immediately converted to diols, and then conjugated for excretion.

C) If the compound is shown to be non-toxic, and the metabolites produced during incubation with liver enzymes in a test tube (S9 microsome addition), then its likely that there is no genotoxicity... but that says nothing about the countless other toxicities that drug might possess.

D) Some, not all, JWH compounds contain a napthalene moeity. Napthalene is a polycyclic aromatic hydrocarbon (PAH) that can potentially be metabolized to epoxides, which then causes mutagenesis. There is some limited evidence that this can happen to JWH in vitro (in a test tube with screening assays), but in vivo studies carried out in rats didn't observe much if any toxicity at non-lethal doses. These are after all, RCs, and so we will simply not be able to get all the answers regarding toxicity.

In this case, it is WE who are the guinea pigs.

 

[MurphyClox]

JWH-018's metabolism is known, at least to some extend. Search through ADD for details.

 

[CuriousSunflower]

Metabolism is a huge mystery for me. I understand the basics, its the breaking down of whatever you ingest...does it have any relation to tolerance involving drugs? It appears the liver is mainly involved in metabolism, so I'm thinking if there is liver disease, metabolism is affected?

I realize tolerance levels vary hugely from one person to another, any ideas on how tolerance actually "works"? I apparently have a ridiculously high and quick tolerance to anything in the speed groups..grrrrr. Is it possible that if in fact my metabolism is unusually slow (most anything I take, legit or not, will take at least 1.5 hours before kicking in), that would effect tolerance in any way?

Obviously there's no way to alter tolerance other than temperance, but is it possible that long term abuse of vicoprofen (about two years taking 8-10 7.5/250 as maintenance daily five or six years ago, and the best amp ever) actually keep tolerance high now? I'm so frustrated, I just want to enjoy a pretty steady amp? Thanks for any info

 

[MurphyClox]

Metabolism is a huge mystery for me. I understand the basics, its the breaking down of whatever you ingest...does it have any relation to tolerance involving drugs?

Yes, it does, at least to some degree. Certain substances can induce the expression of metabolizing enzymes; some substances can inhibit the action of certain metabolizing enzymes. In particularly long term induction of metabolizing enzymes can contribute significantly to the tolerance towards a drug: The often you take that drug, the more the respective enzyme is produced, and therefore, the more the metabolism activated.
Please note that this kind of mechanism is usually just one part contributing to tolerance; receptor desensitization, receptor internalisation, depletion of neurotransmitters and irreversible neuronal damage usually play an important role, too (not necessarily in the named order and all with to different degree, of course).

It appears the liver is mainly involved in metabolism, so I'm thinking if there is liver disease, metabolism is affected?

Absolutely correct! People with impaired liver function are strongly advised not to fuck around with hardly researched substances.
The same goes to people suffering from impairment of kidney function (the main excreting organ!!!).


Peace! - Murphy

 

[CuriousSunflower]

Yes, it does, at least to some degree. Certain substances can induce the expression of metabolizing enzymes; some substances can inhibit the action of certain metabolizing enzymes. In particularly long term induction of metabolizing enzymes can contribute significantly to the tolerance towards a drug: The often you take that drug, the more the respective enzyme is produced, and therefore, the more the metabolism activated.
Please note that this kind of mechanism is usually just one part contributing to tolerance; receptor desensitization, receptor internalisation, depletion of neurotransmitters and irreversible neuronal damage usually play an important role, too (not necessarily in the named order and all with to different degree, of course).



Absolutely correct! People with impaired liver function are strongly advised not to fuck around with hardly researched substances.
The same goes to people suffering from impairment of kidney function (the main excreting organ!!!).


Peace! - Murphy

Murphy, thanks SO much...I've posted around, and you're the first to reply . Hardly researched substances? While adderall, dextroamphetime, etc may be researched...think its a really bad thing with impaired liver function? Pleeease say no jk I'm guessing how you take it doesn't matter as far as metabolism/damage is concerned, hmm? Oral only here...thanks again!