Lecture 6: Flashcards
Biotransformation
the metabolic conversion of toxicants in the body.
• How that is done depends on the properties of the compound…. And the dose… And this process can be very complicated.
liver
is the main site of detoxification.
Why? Compounds that are absorbed through the GI tract move through the hepatic portal into the liver first.
Where does biotransformation occur?
• But biotransformation occurs in other tissues too. • Kidneys, lungs, GI tract, etc
Enzymes
Enzymes are adding something or modifying target compound
The presence of versions of these can be different between species as well as the genetic sequence can be different between individuals and populations.
How does biotransformation change?
of toxicants changes with age - can also decline in seniors
Lower expression of detox enzymes in babies
- Early an late life stages have lower expression of detox enzymes
Genome and life stage is important
What does biotransformation do to hydrophobic compounds?
biotransformation converts the compound to a hydrophilic form to facilitate transport out of the cell and the body.
– Also makes it unable to diffuse across the membranes uncontrolled
Phospholipid bilayer is semi permeable so if its hydrophilic and leaves the cell it cant easily enter back without some sort of membrane protein which provides control
List the 3 stages of biotransformation
- Compound is modified
- Compound is conjugated
- compound is exported out of the cell
Describe Phase 1 of Biotransformation
Caused by enzymes that are either constitutively expressed (i.e., all the time) or induced by exposure to a class of toxicant – At least 22 different types of Phase I enzymes – Can take place in different parts of the cell (endoplasmic reticulum, mitochondria, cytoplasm, nuclei) • A modification of the compound often by exposing or introducing a - OH (hydroxy), -NH2 (amine), -SH (thiol), or -COOH (carboxyl) through: – Oxidation – Reduction – Hydrolysis
What are the most common enzymes used in Phase 1?
cytochrome P450 enzymes
– Often called CYPs.
– Involved in oxidation of compounds.
Cytochrome P450s
A heme containing enzyme that adds 1 oxygen molecule to a substrate (i.e., the toxicant).
– Highest Concentration The endoplasmic reticulum of the liver, but found in almost all tissues.
What are the roles of CYP genes?
The tolerance of an organism to exposure to different types of toxicants is related to the number of CYP genes which allows them to produces lots of cytochrome and make us successful species
*THE SPECIES THAT DO WELL ARE ABLE TO BREAK DOWN A LARGE VARIETY OF TOXICANTS
CYP2D6
demethylates (thus activates) codeine (which on it’s own isn’t very active) to morphine (which is!).
• 1 to 7% of Caucasians have a hyperactive variant = super fast
• About 1% of Asians and Africans have a hypoactive variant = slow
How does drinking grapefruit juice affect drug intake?
drinking grapefruit juice can alter pharmaceutical uptake and metabolism!
These compounds inhibit some human CYP450s, especially CYP3A4, which metabolizes many of the drugs we use.
– Toxicants that are metabolized by this P450 are processed slower if you’ve had a few glasses of grapefruit juice!
– Known drug interactions include erythromycin, warfarin and amphetamines.
• Grapefruit can also interfere with transporters in the small intestine
and affect absorbance of some drugs [e.g., Allegra (fexofenadine)]!
Describe Phase 2
Reactions where Phase I metabolites are conjugated with or coupled to endogenous compounds to create more hydrophilic metabolites for excretion.
With the exception of glucuronosyltransferases, most Phase II enzymes are located in the cytosol.
Phase 1: converting from
Phase 1: converting from harmful form into less harmful form but not always the case
