Enzyme Inhibition in relation to Aspirin?

Question

I see that aspirin (in part) works by inhibiting cycloxygenase isoenzymes and that this inhibiting is irreversible. I've had a few classes mentioning this topic in passing, but never with depth.I guess my question regards the permanence of the word "irreversible." I assume enzymes have a life span, so to speak, and that the same isoenzymes both die and are being replenished at some given rate. Am I correct in thinking that the cycloxygenase enzyme is permanently inhibited until its death (catabolism)?

Answer 1

Aspirin irreversibly attaches an acetyl group (see below) to the cyclooxygenase enzyme, inactivating it. You're correct in thinking that, once this change occurs, it will be permanent for the life of that particular enzyme molecule. Of course, new cyclooxygenase molecules are continually being produced in the cell and if continued inhibition is desired, more aspirin must be taken.

Figure from: http://www.chem.ucla.edu/~harding/IGOC/A/acetyl_group.html

Answer 2

Yes, the term "irreversibly inhibited" means that the bound enzyme is rendered useless, ineffective, permanently disabled indefinitely. This concept is to be contrasted with NSAIDs (non-steroidal anti-inflammatory drugs) that will bind to COX (cyclooxygenase isoenzymes) but will ultimately let go, allowing the enzymes to resume normal function.

Best,

Starlyte

Answer 3

In general, one can't directly relate lethality to effects on the central nervous system (CNS). In the given example, cocaine has effects not only on the CNS, but on many other organ systems as well, namely adverse cardiovascular effects. So, the answer to your initial question as to whether psychoactive drugs with higher lethality (lower lethal doses) are more toxic (more damaging to the brain), would be not necessarily. You can't make that generalization. As far as I am aware, there is no mathematical relationship between neurotoxicity and lethal doses. There are some drugs that are neurotoxic (kainic acid, ethanol, glutamic acid), but not all that lethal, and drugs that are quite lethal, but not neurotoxic.