Target Organ Toxicity

Now I'm going to continue on with toxicology!

Oh, and by the way, a quick word about the 2nd lab for those of you who haven't done it yet. It's a great lab- very fun and relaxing. You'll be disappointed when it ends.

*cough*

Anyway, target organ toxicity. Here we go...

1) Demonstrate an awareness of the significance of “local” versus “systemic” toxic exposures.

This is fairly self-explanatory. Some chemicals can injure the site of exposure- hence "local" exposure. Others need to get into the systemic circulation- hence "systemic" exposure.

2) Understand why the toxicity of particular chemicals is expressed in just a handful of “target” organs.

Often, toxic responses occur in only a handful of "target" organs. This may be because there is preferential delivery to that target tissue. For example, the liver is often at risk because it's the first place that drugs go after being taken up via the GI tract. Another reason for target organ toxicity is that enzymes that break down the drug into its toxic metabolites may only be present in certain organs. Once again, the liver is often particularly vulnerable as it contains a lot of these enzymes.

3) Be able to define the term “bioactivation” and show awareness of its toxicological significance.

"Bioactivation" is basically the breakdown of a drug into a more toxic metabolite. Often this results in a drug becoming more electrophilic (i.e. contains electron-deficient sites that "love electrons"). Electrophilic sites can interact with nucleophilic sites in proteins or DNA, which obviously isn't too desirable. These toxic, electrophilic metabolites are sometimes also known as protein or DNA "adducts." It's not all doom and gloom, though, as the body often has ways of getting rid of these toxic metabolites before they become a huge problem.

4) Understand mechanistic basis for the classic toxicological responses that accompany paracetamol overdose and exposure to MPTP.

Paracetamol (known as acetaminophen in the US) is a drug that is pretty useful for relieving headaches in low doses, but can wreak havoc on your liver in high doses. It is an intrinsic hepatotoxicant, which means that its toxic effects are predictable and dose-related. (Other types of hepatotoxicants include idiosyncratic hepatotoxicants, which are less predictable and probably require prior exposure, and cholestatic hepatotoxicants, which inhibit the formation and flow of bile.)

Paracetamol can undergo three different routes of metabolism. It can undergo sulfation via sulfotransferases, which produces a safe, water-soluble metabolite that is more readily excreted by the kidneys. It can also undergo glucuronidation via UDP-glucuronosyltransferase, which again produces a water-soluble metabolite for easy excretion. The third pathway is a bit more problematic. Around 2% of paracetamol is bioactivated by CYP450 enzymes, particularly CYP2E1, CYP3A4 and CYP1A2. This forms a toxic metabolite known as NAPQI, which can go around using its electrophilicity to destroy proteins and cells. (Rude.) (And no, I'm not sure what NAPQI stands for, aside from that the QI bit probably stands for "quinone imine" because the slide says "toxic electrophilic quinone imine metabolite.")

But again, it's not all gloom and doom, as our bodies have ways of getting rid of NAPQI. NAPQI can be metabolised via glutathione conjugation, due to the action of a very nice enzyme called glutathione-S-transferase.

Unfortunately, at really high doses of paracetamol (much higher than regular doses), this might not be enough. Administering N-acetylcysteine may help, as it helps to replenish the body's supplies of glutathione and thus helps the body to get rid of NAPQI. The sooner this is done, the better. It takes several days to die from paracetamol poisoning, but by the time symptoms start to show, it might already be too late.

Another interesting point to make is the effects of alcohol on paracetamol hepatotoxicity. Ethanol is actually a competitive inhibitor of the CYP450 enzymes that bioactivate paracetamol (particularly CYP2E1). Hence, if you have normal levels of CYP450 enzymes (as do people who drink rarely), downing paracetamol with ethanol is actually decreasing your susceptibility to paracetamol toxicity. People who drink heavily don't get to experience this protective effect, though, as they have higher expression of CYP2E1 in their livers. Instead, they are more susceptible to paracetamol toxicity.

NOTE: If you are thinking of committing suicide, please call Lifeline on 13 11 14. And definitely don't try to go by overdosing on paracetamol, because that several day window is more than enough time for you to change your mind- and by then it might be too late. So yeah, call Lifeline, and if you don't like talking they also have a web chat function- as does Kids Helpline and eheadspace.

Alright, now time to talk about MPTP. Firstly, I'm going to answer the question that's probably on your mind right now- what is MPTP? Well, another drug known as MPPP (meperidine opioid) was found to induce Parkinson's-like symptoms in drug addicts. It was soon found that it wasn't so much MPPP that was the problem, though. You see, MPTP could be formed as a by-product of the reactions that make MPPP.

MPTP can cross the blood-brain barrier, where it is activated by the MAO-B enzyme located in astrocytes. It forms a toxic metabolite known as MPP+, which actually ends up affecting dopaminergic neurons, particularly in the substantia nigra, as MPP+ is a substrate for dopamine reuptake pathways. Aside from interfering with the distribution of dopamine in vesicles, MPP+ is also capable of forming reactive oxygen radicals. Further issues arise when MPP+ is sequestered by mitochondria, where it inhibits the electron transport chain and produces shitloads of oxygen radicals. This, in turn, oxidises DNA and activates apoptosis (cell death). This means that there's less dopamine to go around, which in turn causes many of the symptoms of Parkinson's.

As for how MPTP was found to cause neurotoxicity via oxidative stress? Well, that's a bit complicated, so you can probably afford to skip over this bit. One bit of evidence that MPTP causes toxicity in this manner is that Nrf2-knockout mice are more susceptible to MPTP toxicity. Nrf2 is usually bound to another protein called Keap-1, but during oxidative stress, it is released. When released, it acts as a transcription factor which regulates genes containing ARE (Antioxidant Response Element). Without Nrf2, mice are more susceptible to issues relating to oxidative stress.

5) Show understanding of the emerging role of HLA phenotypes in idiosyncratic hepatotoxicity

I mentioned idiosyncratic hepatotoxicity earlier on in this post. In case you've forgotten, idiosyncratic hepatotoxicity is unpredictable and rare, and may require prior exposure. Idiosyncratic responses may also be gene-related. Some variations of HLA (human leucocyte antigen) genes have found to be associated with hepatotoxicity; however, there is still a lot of work that is being done in this area.