Biochemical Aspects of Hepatic Drug Metabolism

Question 1

What is the 2 phases of Drug Metabolism?

Answer 1

Phase 1 - Addition of a Polar Group:

• the polarity of the drug is increased, usually by oxidation.
• this oxidation reaction is catalysed by a family of enzymes: Cytochrome P450 Oxidases

Phase 2 - Conjugation

• cytoplasmic enzymes conjugate the funtional groups introduced in Phase I by addition of an endogenous substance
• The resultant molecule is less active and polar, and can be excreted by the kidneys

Question 2

What are Cytochrome P450 Oxidases?

Answer 2

• Heme containing proteins
• They co-localise with NADPH:Cytochrome P450 reductase
• They are found in the Endoplasmic Reticulum
• Most metabolism related to these enzymes takes place in the liver

Question 3

What is the simplified version of The Role of the Cytochrome P450 System in the Metabolism of Drugs?

Answer 3

Simplified Version: Where R=Drug

RH + O₂ + NADPH + H⁺ → ROH + H₂O + NADP⁺

Question 4

What is Cytochrome P450 Gene Polymorphisms?

• Pharmacogenetics – how genetic determinants affect drug action

Answer 4

Genotyping Cytochrome P450 enzymes may become part of ‘personalised’ medicine providing information about how effectively an individual can process certain drugs.

Question 5

Oxidation of Ethanol results in over-production of NADH. This results in:

Answer 5

(1) A rise in the blood concentration of lactic acid and ketone bodies.
(2) Excess NADH causes excessive fat formation -> Fatty Liver.
(3) Fatty liver can be reversed, but can progress to hepatitis and cirrhosis.
(4) Generation of acetaldehyde, a reactive molecule, which if it builds up can damage proteins and lead to liver cell death