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Are most toxic substances enzyme inhibitors?

by 1MileCrash
Tags: toxicology
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1MileCrash
#1
Mar14-11, 04:25 PM
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As I progress in this biology lab I'm currently taking, I'm starting to notice that most toxic substances (non-organic) seem to be enzyme inhibitors. This isn't really mentioned in lab but I look the substances up out of interest.

Do these just so happen to be the toxic substances I'm learning about or is there a reason for this?

A question out of pure curiosity.
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mishrashubham
#2
Mar15-11, 08:53 AM
P: 605
It would appear so that many inorganic toxins affect enzymes (arsenic, lead). Though we would need an expert on the subject to give a proper answer. All I could think of an inorganic toxin that does not affect enzymes is carbon monoxide.
nismaratwork
#3
Mar15-11, 12:43 PM
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Quote Quote by 1MileCrash View Post
As I progress in this biology lab I'm currently taking, I'm starting to notice that most toxic substances (non-organic) seem to be enzyme inhibitors. This isn't really mentioned in lab but I look the substances up out of interest.

Do these just so happen to be the toxic substances I'm learning about or is there a reason for this?

A question out of pure curiosity.
It's more a matter of what our weaknesses are; you stop our ability to saaaay, break down acetylcholine, and we're in deep DEEEEP trouble.

Then again, a lot of the toxins you'd be looking at are also carcinogenic

Anyway, inorganic usually means that it's interfering with enzyme pathways one way or another, either through inhibition (usually more toxic) or excitation. http://en.wikipedia.org/wiki/Aflatoxin is a good example of something a little different and organic.

There are relatively limited ways that inorganic substances hurt us; they need to somehow accumulate and damage us that way, or they do their damage during an attempt at metabolism... so.. enzymes.

Jon Richfield
#4
Mar15-11, 03:37 PM
P: 258
Are most toxic substances enzyme inhibitors?

Quote Quote by 1MileCrash View Post
As I progress in this biology lab I'm currently taking, I'm starting to notice that most toxic substances (non-organic) seem to be enzyme inhibitors. This isn't really mentioned in lab but I look the substances up out of interest.

Do these just so happen to be the toxic substances I'm learning about or is there a reason for this?

A question out of pure curiosity.
Not really; in fact some of our deadliest toxins (or venoms too) actually are
enzymes; examples lecithinases in some snake venoms hydrolyse lecithin to lysolecithin which does nasty things to our cell walls. Ricin is an enzyme (forgot its function, sorry!) and a lot of venom components that are not especially lethal in their own right, are adjuvants that assist the main components with their effects or penetration, such as hyaluronidases in many kinds of stings, such as bee and hornet.

Just a quick note, but you get the idea I'm sure. Notice that in principle it can take less of an enzyme to work on you and kill you than it could take to inhibit enough of your own enzymes to kill you.

Another option is to turn your own enzymes against you in a cascade effect.

Pleasant dreams!
Jon
nismaratwork
#5
Mar15-11, 03:48 PM
P: 2,284
Wel yeah Jon, but those are organic.
epenguin
#6
Mar15-11, 07:56 PM
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Quote Quote by mishrashubham View Post
It would appear so that many inorganic toxins affect enzymes (arsenic, lead). Though we would need an expert on the subject to give a proper answer. All I could think of an inorganic toxin that does not affect enzymes is carbon monoxide.
I think that blocks cytochromes, though I think before that you are killed by its blocking haemoglobin, which is often called an 'honorary enzyme' anyway. What does work by blocking cytochromes is cyanide.

Then everyone should have some awareness of the organophosphorus compounds, some the notorious nerve gases, others insecticides, which act by reacting covalently with acetyl cholinesterase so blocking transmission of nervous impulses. Curare on the other hand is a a blocker of acetylcholine receptors - and surprisingly in view of the previous an antidote such as physostigmine is also an acetylcholinesterase inhibitor - which works by letting acetylcholine build up to overcome the curare, but unlike the organophoshates is bound reversibly.http://en.wikipedia.org/wiki/Physostigmine OK the receptor is a protein controlling an ion gate, but between such physical-chemical and strictly chemical actions you find yourself not making distinction when you get into such areas.

I do not remember an example but some toxic substances not toxic as such but are transformed enzymatically into other substances that are. And then there are lots of enzymes that do the opposite and detoxify substances, oxidise them, methylate them, and I don't remember what else. Quite a big and practical area.

Here is another enzyme with complicated action like those mentioned by Jon http://www.ebi.ac.uk/interpro/potm/2005_9/Page2.htm
nismaratwork
#7
Mar16-11, 01:21 AM
P: 2,284
Quote Quote by epenguin View Post
I think that blocks cytochromes, though I think before that you are killed by its blocking haemoglobin, which is often called an 'honorary enzyme' anyway. What does work by blocking cytochromes is cyanide.

Then everyone should have some awareness of the organophosphorus compounds, some the notorious nerve gases, others insecticides, which act by reacting covalently with acetyl cholinesterase so blocking transmission of nervous impulses. Curare on the other hand is a a blocker of acetylcholine receptors - and surprisingly in view of the previous an antidote such as physostigmine is also an acetylcholinesterase inhibitor - which works by letting acetylcholine build up to overcome the curare, but unlike the organophoshates is bound reversibly.http://en.wikipedia.org/wiki/Physostigmine OK the receptor is a protein controlling an ion gate, but between such physical-chemical and strictly chemical actions you find yourself not making distinction when you get into such areas.

I do not remember an example but some toxic substances not toxic as such but are transformed enzymatically into other substances that are. And then there are lots of enzymes that do the opposite and detoxify substances, oxidise them, methylate them, and I don't remember what else. Quite a big and practical area.

Here is another enzyme with complicated action like those mentioned by Jon http://www.ebi.ac.uk/interpro/potm/2005_9/Page2.htm
Hmmmm, Aflatoxin is reduced, but at high doses that metabolysis can cause an acute and fatal reaction?

If not for the "inorganic" stipulation, I'd agree with everything you listed.

Ohhh, Syndney Funnel Web venom contains a truly wicked acetylcholinesterase inhibitor... ugly way to go.

edit: Phosgene, if you don't choke on it, I believe becomes quite toxis during lysis... I could be wrong... will check tomorrow.
Jon Richfield
#8
Mar16-11, 05:10 AM
P: 258
Quote Quote by nismaratwork View Post
Wel yeah Jon, but those are organic.
Hi again Nismar,
Yeah, but though he uses the term inorganic, he doesn't strictly exclude organic, and it does not emerge in the title. I was dealing mainly with the principles, and as I apologised, I was writing in a hurry.
The principles that I had in mind at the time were mainly:
* that if one regards toxicity as a class of interference with the workings of a complex mechanism, then there are many ways in which damage can be done, beyond just clogging some of the components. One can break them, misdirect their action, over-rev them, jam switches open or shut, modify their effects, etc.
* That one sometimes could get more economical effects by introducing something directly harmful (possibly a single component; something that jams open a single channel in a cell membrane often can kill the whole cell, eukaryote or prokaryote. You can't achieve nearly as much just by wrecking a single enzyme molecule.
* I reckon that there are plenty of inorganics that behave in all such ways; it is just that, not being enzymatic in their mechanisms, they are far less specific in their effects.

At a guess I should say that apart from any incidental enzymatic inhibition, the likes of Be compounds, crocidolite (especially when it contains benzopyrenes from metamorphosed microbial fossils), O3 and NO2 might well be examples of substances that produce all such effects, often in multiple combinations. I go along with epenguin on some such points.

Just thumbsucks of course...
nismaratwork
#9
Mar16-11, 08:27 AM
P: 2,284
Quote Quote by Jon Richfield View Post
Hi again Nismar,
Yeah, but though he uses the term inorganic, he doesn't strictly exclude organic, and it does not emerge in the title. I was dealing mainly with the principles, and as I apologised, I was writing in a hurry.
The principles that I had in mind at the time were mainly:
* that if one regards toxicity as a class of interference with the workings of a complex mechanism, then there are many ways in which damage can be done, beyond just clogging some of the components. One can break them, misdirect their action, over-rev them, jam switches open or shut, modify their effects, etc.
* That one sometimes could get more economical effects by introducing something directly harmful (possibly a single component; something that jams open a single channel in a cell membrane often can kill the whole cell, eukaryote or prokaryote. You can't achieve nearly as much just by wrecking a single enzyme molecule.
* I reckon that there are plenty of inorganics that behave in all such ways; it is just that, not being enzymatic in their mechanisms, they are far less specific in their effects.

At a guess I should say that apart from any incidental enzymatic inhibition, the likes of Be compounds, crocidolite (especially when it contains benzopyrenes from metamorphosed microbial fossils), O3 and NO2 might well be examples of substances that produce all such effects, often in multiple combinations. I go along with epenguin on some such points.

Just thumbsucks of course...
Don't get me wrong, I'm just fuming that you beat me to it.
Simfish
#10
Mar20-11, 10:02 PM
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Yeah, there are toxins that are "protoxins" - meaning that they're often converted into more toxic compounds through the cytochrome p450 system. Methanol and formaldehyde are two such examples.

And then there are competitive antagonists (which often have the simplest-to-explain mechanisms). Tetrodotoxin, CO, and cyanide are all famous competitive antagonists. Their mechanism is often quick, selective, and fatal in super-low doses, but at the same time, they're not necessarily toxic to all living organisms (their mechanisms are also predictable). And it's easy to evolve resistance to some of them (although some of these toxins do involve very early molecular pathways). Since their effects are the most predictable, I'm actually less freaked about them than I am about more unpredictable toxins, like the mutagens.

Then you also have corrosive agents. Or things that increase the number of corrosive agents in your body (free radicals such as hydrogen peroxide). Corrosion is often less selective in the damage it does throughout your body, so its damage is more distributed.

Then you have agents that upregulate pathways that are potentially destructive.

And some agents that are hard to classify (http://en.wikipedia.org/wiki/2,4-Dinitrophenol for example).

Also, there's neurotoxins as well. They might not directly kill you, but they may kill your working memory by doing things like damaging the synapses of dopamine neurons. Amphetamines, for example, simply reposition the dopamine molecules in your neurons. It just so happens that the dopamine molecules are positioned in a way that they auto-oxidize in the place where they damage your neuron terminals in the process of auto-oxidation.

Even Vitamin D is used as a toxin. It's actually used as a rodenticide since it somehow increases calcium levels in the blood to levels high enough that it calcifies rodent arteries.

I actually just created a "toxicology resources" thread at http://physicsforums.com/showthread.php?t=482585. Feel free to contribute!

==

In terms of inorganic substances, hm. Yeah, most are enzyme inhibitors. Some of them (like arsenic) do much more than just enzyme inhibition though.

And there's also particulate matter. That scares me a lot since I don't even know what's in it, and how it acts.
nismaratwork
#11
Mar21-11, 07:46 AM
P: 2,284
How the hell did you learn about DNP?! That is some truly nasty stuff... wasting disease in a crystalline form. I'm heading over to your thread!
Jon Richfield
#12
Mar21-11, 12:30 PM
P: 258
Quote Quote by nismaratwork View Post
How the hell did you learn about DNP?! That is some truly nasty stuff... wasting disease in a crystalline form. I'm heading over to your thread!
Been away, and I seem to have lost a post as well, probably forgot to submit in my hurry. Sorry Nismar!

Anyway, the DNP thing reminds me that the organic-inorganic separation is a bit artificial. There is of course no really undebatable and sharp distinction. One could speak of something like inorganic non-biochemical (or non-metabolic or something?) like say BeF2, inorganic biochemical (eg NO (and what about CO? How organic is that? If it is organic, then so is CO2 and HCN and Tl2CO3 and Ca2C...) ) Then there are organic metabolic, or biochemicals, such as C2H2, epinephrine, MSG, cholecalciferol and tetrodotoxin. And what about DNP and dioxins etc? They are totally alien to our metabolism, but they are "organic" by definition, just like homeopathy-friendly, fertiliser-free beans with their bacterial loads intact.

Now, I am sure that you can think of all kinds of objections to such classifications (I could raise a few myself). I am less sure how or even whether to attempt a classification. Usually I just think about such materials by their working effects... Or something like that.
Simfish
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Mar21-11, 03:03 PM
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Surprisingly, I actually learned about DNP from an anti-aging blog. *Surprisingly* enough, it actually extends mouse lifespan in VERY SMALL doses (through a mechanism pretty similar to calorie restriction).
nismaratwork
#14
Mar21-11, 06:45 PM
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Quote Quote by Jon Richfield View Post
Been away, and I seem to have lost a post as well, probably forgot to submit in my hurry. Sorry Nismar!

Anyway, the DNP thing reminds me that the organic-inorganic separation is a bit artificial. There is of course no really undebatable and sharp distinction. One could speak of something like inorganic non-biochemical (or non-metabolic or something?) like say BeF2, inorganic biochemical (eg NO (and what about CO? How organic is that? If it is organic, then so is CO2 and HCN and Tl2CO3 and Ca2C...) ) Then there are organic metabolic, or biochemicals, such as C2H2, epinephrine, MSG, cholecalciferol and tetrodotoxin. And what about DNP and dioxins etc? They are totally alien to our metabolism, but they are "organic" by definition, just like homeopathy-friendly, fertiliser-free beans with their bacterial loads intact.

Now, I am sure that you can think of all kinds of objections to such classifications (I could raise a few myself). I am less sure how or even whether to attempt a classification. Usually I just think about such materials by their working effects... Or something like that.
That's not a bad way of looking at things, some of our divides are very odd.

@SimFish: Anti-aging?! Wow... I wouldn't have guessed that in a million years.
Simfish
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Mar21-11, 06:54 PM
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Yup

http://ouroboros.wordpress.com/2008/...e-restriction/

In 1954, Denham Harman proposed the free radical theory of aging (FRTA), which posits that the accumulation of lipid, protein, and nucleic acid damage from free radicals results in a decline of function over time. Although the FRTA is one of the leading theories on aging today, it is still being modified. One major breakthrough was the identification of mitochondria as the major source of oxygen free radicals, such as superoxide and hydroxyl radical, and other reactive oxygen species (ROS), like hydrogen peroxide.

Support for the FRTA includes a decrease in ROS production in calorie restricted (CR) animals, a dietary strategy known to increase lifespan in a whole host of animals. A hot area of research is the search for calorie restriction mimetics, which mimic the lifespan extending effects of CR. By using CR mimetics therapeutically, we may be able to have lower cholesterol, blood glucose, and blood pressure, as well as lower instances of cancer, diabetes, neurodegeneration, and heart disease — and still be able to eat a hot fudge sundae every night.

Caldeira da Silva and Cerqueira suggest that mitochondrial uncoupling is an effective mimic of CR. In mitochondria, the electron transport chain uses electrons from glucose and lipids to pump protons across a membrane. This proton gradient can be used to make energy in the form of ATP through oxidative phosphorylation. The process is kind of like generating hydropower. Uncouplers work by putting a leak in the dam, which lets water through without going to the generator. They “uncouple” the electron transport chain from oxidative phosphorylation, thus reducing the efficiency of energy production. Although animals have uncoupling proteins (these proteins are important for thermogenesis, especially during hibernation), so far there are no known agonists. The researchers instead used low doses of the mitochondria uncoupler DNP. DNP was actually used as a diet pill because the body makes up for inefficient energy production by burning more fat. Unfortunately, all that potential energy in the proton gradient is released as heat, which can cause fatal fevers. (The FDA deemed DNP unfit for human consumption in 1938, although supplements are now sold online to bodybuilders).

Notably, the mice in the study had no change in body temperature. They were given doses 1000X below the lethal dose and plenty of space to let off any extra heat. The DNP treated mice ate the same amount of food as control mice but had lower body mass. The DNP treated mice showed many phenotypes observed in calorie restricted mice. Like CR mice, DNP treated mice had higher rates of respiration with lower production of ROS. These mice also had lower oxidative damage to their DNA and proteins, another hallmark of CR. They showed lowered blood glucose, lower triglycerides, and lower insulin. Most importantly, DNP treated mice showed an extended lifespan. This study suggests that mitochondrial uncouplers are an effective mimic of calorie restriction and might be a realistic therapeutic intervention for delaying aging and extending lifespan. Uncouplers may be even more effective than resveratrol, which may - or may not – only work on mice on a high fat diet.
nismaratwork
#16
Mar21-11, 06:56 PM
P: 2,284
I'm just... wow... it seems like a way to slowly waste someone away, or KILL the elderly in a cruel fashion, not an anti-geriatric agent. It seems to be healthy in the sense that there is no metabolic waste when you're dead.
Jon Richfield
#17
Mar22-11, 11:55 AM
P: 258
Quote Quote by nismaratwork View Post
@SimFish: Anti-aging?! Wow... I wouldn't have guessed that in a million years.
Well, it might not have been in my first thousand guesses, but I cannot pretend to be surprised. Nauseated ---? Maybe a little, but not as badly as by the attack of traveller's diarrhoea I am trying to shake off. DNP used to be an anti-obesity drug you know! But then (CHOH)2 used to be a solvent for children's sulphonamide potions...!

You can't afford to be nauseated by everything nauseating...

"Scuse me... Gotta run...
nismaratwork
#18
Mar22-11, 11:57 AM
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Quote Quote by Jon Richfield View Post
Well, it might not have been in my first thousand guesses, but I cannot pretend to be surprised. Nauseated ---? Maybe a little, but not as badly as by the attack of traveller's diarrhoea I am trying to shake off. DNP used to be an anti-obesity drug you know! But then (CHOH)2 used to be a solvent for children's sulphonamide potions...!

You can't afford to be nauseated by everything nauseating...

"Scuse me... Gotta run...
Ooooh... hope you feel better Jon...


...btw, wasn't it discontinued for weight loss in the 30's? Man, it really is a scary effect to have on our metabolism...


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