Phase 1/2 metabolism

Question 1

What is Phase 1 metabolism?

Answer 1

• Involve oxidation, reduction, and hydrolysis
• Most of these reactions occur in the liver, some (such as the hydrolysis of esters and amides) can also occur in the gut wall, blood plasma, and other tissues.
• Some of the structures most prone to oxidation are:
  o N-methyl groups, aromatic rings, the terminal positions of alkyl chains, and the least hindered positions of alicyclic rings. Alicyclic rings are cyclic + aliphatic e.g., cyclopentane
  o Nitro, azo, and carbonyl groups are prone to reduction by reductases, while amides and esters are prone to hydrolysis by peptidases and esterases respectively

Question 2

What is cytochrome P450 $$$

Answer 2

• The enzymes that constitute the cytochrome P450 family Are located in liver cells.
• They are haemoproteins (containing haem and iron)
• Catalyse a reaction that splits molecular oxygen, such that one of the oxygen atoms is introduced into the drug and the other ends up in water; because of this they belong to a general class of enzymes called the monooxygenases

Question 3

What are the main families of CYP enzymes? (not really that important)

Answer 3

• There are at least 33 different cytochrome P450 (CYP) enzymes, grouped into four main families: CYP1–CYP4.
• Within each family there are various subfamilies designated by a letter, and each enzyme within that subfamily is designated by a number. For example, CYP3A4 is enzyme 4 in the subfamily A of the main family 3.
• Most drugs in current use are metabolized by five primary CYP enzymes (CYP3A, CYP2D6, CYP2C9, CYP1A2, and CYP2E1).
• The isozyme CYP3A4 is particularly important in drug metabolism and is responsible for the metabolism of most drugs. Initial step for oxidation

Question 4

What is the end goal of metabolisation?

Answer 4

Excretion
Oxidative reactions are catalysed by cytochrome P450 enzymes on saturated carbon centres.

There are drugs that don’t have a reactive handle and therefore cannot become hydrolysed due to not being hydrophilic, cytochrome p450 provides that by oxidising them. May not always work (e.g., a ketone which can be less polar than starting chemical).

(For examples look at the phase 1 metabolism first lectures slides for the images, but the most important part is understanding why it’s done)

Question 5

What is an imine and how is it hydrolysed?

Answer 5

Via proton transfer - causes a proton to attack the N atom, forming an iminium ion. Then a nucleophilic attack occurs where an oxygen atom on a water molecule attacks the double bond. Another proton transfer happens where a proton moves from the water molecule to the NH molecule. After this, the CH3CH2NH2+ is lost via dissociation, the last proton on the oxygen is lost also via proton transfer, forming a ketone.

This reaction is in equilibrium in every step of the reaction.

Look up images of hydrolysis of Imines to aldehydes and ketones (second image on google) for an idea.

Question 6

How is an epoxide formed?

Answer 6

Oxidation of alkenes

Epoxide Toxicity – alkylation of nuclear bases, codon and anti-codon misrepresentation – imperfect copy of gene – can give rise to cancer and disease - therefore must be rid of ASAP in the body, not the safest way of excreting molecules.

Question 7

CARRY ON FROM FLAVIN OXYGENASES

Answer 7

YO