Detoxification Pathways in the Liver Flashcards
How are dietary toxins directed to the liver?
Via the portal vein
What size chemicals does the cytochrome P450 system oxidise?
Mr < 5000 - bigger than this will be dealt by the immune system
What is the nomenclature for cytochrome P450?
CYP family, subfamily, form e.g. CYP2A6
Where are cytochrome P450 located in vivo?
in endoplasmic reticulum and mitochondria
Where are cytochrome P450 located in vitro?
microsomes
Why is the cytochrome P450 called 450?
Because that is the maximum absorbance when bound with carbon monoxide
What is the role of all cytochromes?
To carry electrons involving Fe2+ > Fe3+
What is the role of cytochrome P450 in the liver?
to alter molecules to a soluble form so they can be excreted by the kidneys
What type of enzyme is cytochrome P450?
a monooxygenase - adds an OH group to the molecule
What reaction does cytochrome P450 catalyse?
formula – won’t paste from Evernote
What is the major reaction of cytochrome P450?
hydroxylation
What is epoxidation?
A reaction that can be done by P450 which results in a substrate that is highly reactive with DNA
Does the substrate just undergo one reaction?
No - can undergo multiple sequential reactions
How is the cytochrome P450 reaction initiated?
By the binding of a substrate to P450
What is the function of the reductase also present in the membrane?
To pass one electron at a time to cytochrome P450
How is a reactive oxygen species sometimes formed?
If the electrons which are passed as peroxide don’t hit the substrate
What is the active site in each P450 specific for?
a class of substrates that it will hydroxylate - all others will be be oxygenated
How does cytochrome P450 connect to the ER?
a hydrophobic foot
What part of the cytorchome P450 protein forms a ligand to the Fe in haem?
a cysteine anchor
How does the liver become tolerant to certain toxins?
higher levels of certain P450s are expressed when substrates are persistently present - either by activating the gene, stabilising the mRNA or by protecting it from turnover
How many genes for P450 are there in humans?
57
What is the outcome of inherited deficiencies in certain P450s?
poor metabolism of certain drugs
What is the result of a deficiency in CYP2D6?
failure to covert codeine to morphine
What is benzpyrene?
an inactive combustion product in smoke which can be converted to a carcinogen by P450
What is the Ames test?
A test to determine if a substrate is mutagenic with the action of P450
What is aflatoxin?
a substrate which can be made carcinogenic by P450 and contributes to the severity of kwashiorkor
What is dioxin?
a substrate in agent orange which activates the gene CYP1A1
