How do chemicals cause toxicity

What happens in phase 1 reactions

In phase 1 reactions most drugs are metabolized by cyt. P450 which produces a reactive intermediate

what happens in phase 2

the compound is conjugated with a molecule taht make the compound inactive and ready to be excreted.

What might the reactive intermediates cause

carcinogenicity and toxicity

Which phase is the rate limiting step

phase 1

How can you adapt to a drug

by producing more phase 2 enzymes.

For which drugs are phase 1 biotransformations crucial and give an example

For pro drugs the first biotransformation is crucial for it to be efficient. Codeine has no analgetic effect but when transformed into morphine by CYP2D6 it gives analgetic effect. UDP transferase can then transform morphine into either Morphine 3 glucuronide which is inactive or into morphine 6 glucuronide which is active.

What is necessary for cyt. P450 to work

NADPH

Which genes transcribe cyt. P450

CYP2E1 genes

Where is cyt. P450 localized?

in the liver mostly around the central vein, which means if you exceed your alcohol intake and you get fibrosis around the central vein you lose function of the enzyme.

How does paracetemol cause adverse effects during overdose

Paracetemol can be transformed into NAPQI by CYP3A4 and CYP2E1. In normal doses only a small part is converted into this metabolite, and it gets conjugated with glutathione to produce an inactive molecule. However, when you overdose glutathione is saturated and a larger fraction is metabolized as the toxic intermediate and can give toxicity by reaction with proteins and nucleic acids.

How do you treat overdosis of paracetemol?

Give the precursos of glutathione so more is converted into the inactive metabolite

Why is alcohol in combination with paracetemol not good

Alcohol increases the activity of CYP3A4 and CYP2E1 which means that more paracetemol will be converted into the toxic metabolite.

What are two other toxic metabolites?

• Dietyl nitrosamine produces tumours when metabolised with CYP2E1

• thioacetamide leads to necrosis in hepatocytes when metabolised

Explain how metabolism of aflatoxin caused toxicity

aflatoxin when metabolised by enzymes caused aflatoxin, exo 8,9, which can cause DNA damage leading to cancer

How does cigarette smoke cause toxic effects

pyren in smoke can induce CYP1A1 in the lungs which metabolise BP into a diol which is further metabolised by CYP1A1 into 9,10, epoxide which can make adducts on the DNA and cause lung cancer.

Why are animal models not always usefull in these studies?

They have different isoforms of cyt. P450

Why are human hepatocytes not useful in studies?

When you put them in a petridish they lose their functionn

What is a good way to study this

PHH spheroids that are grown in a medium so they are attached to eachother and keep their function.

What is an example that shows that the 3D hepatocytes are useful?

Fialuridine was not toxic in animal models and human hepatocytes, but in clincal trials 7/15 patients died. In 3d hepatocytes is showed that prolonged exposure caused toxicity.

How do you protect against fialuridine toxicity?

By knock down of ENT1 and TK2

What is important in toxicity

Toxicity of chemicals requires a target that binds the compound or a metabolite thereof and promote intracellular signaling which cause toxicity. This toxicity is very dose dependent and without a target nothing can happen.