liver detoxification Flashcards
define xenobiotics
foreign chemical substance not normally found or produced in the body which cannot be used for energy requirements
eg drugs
can be absorbed across lungs or skin OR ingested
how are xenobiotics excreted
bile , urine , sweat and breath
properties of pharmacologically active compounds
- lipophilic
- non-ionised at pH 7.4
- bound to plasma proteins to be transported in blood
lipophilic definition
able to dissolve in lipids/fats
to be able to pass through plasma membranes to reach metabolising
enzymes
what are the 2 types of enzymes involved in metabolic reactions
- microsomal enzymes
- non-microsomal enzymes
define microsomes
fragments of endoplasmic reticulum with attached ribosomes
where are microsomal enzymes found
in microsomes on smooth endoplasmic reticulum
mostly found in liver hepatocytes but can be found in the kidneys & lungs too
where are non-microsomal enzymes found
anywhere but microsomes
located in the cytoplasm & mitochondria of hepatocytes in the liver but also in other tissue too
which type of reactions do microsomal enzymes carry out
mainly Phase I reactions, but can do phase 2
what affects the activity of microsomal enzymes
drugs, food, age, bacteria & alcohol
which type of reactions do non-microsomal enzymes carry out
mainly Phase II reactions, but can do phase I
are non microsomal enzymes inducible
no
which reactions are non-microsomal enzymes involved in
all conjugation reactions except GLUCURONIDATION
which reactions are microsomal enzymes involved in
oxidative,reductive & hydrolytic reactions
how are drugs usually excreted
most are excreted by the kidneys
but lipophilic drugs are not effectively
removed
as they are passively absorbed
because they can diffuse through cell membranes easily
aim of drug metabolism
to make the drugs more polar so they cannot get across membranes and thus are easily excreted
where does drug metabolism mainly occur
liver
what are the 2 pathways for drug metabolism
phase 1 reaction
phase 2 reaction
what is phase 1 liver detoxification
the first line of defense against toxins. It consists of a group of enzymes known as the cytochrome P450 family
what is phase 2 liver detoxification pathway
neutralizes the byproducts of Phase I liver detoxification and other remaining toxins.
by making the toxins water-soluble.
so they can be excreted from the body - conjugation
what is the aim of phase 1 for lipophilic drugs
to make the drug more hydrophilic so that it can be excreted by the kidneys
- it does this by adding a hydroxyl group to the drug
Introduces reactive group to drug - attack point for conjugation
why do hydrophilic molecules not reach the metabolising enzymes
because they are excreted easily
what are the 4 methods of oxidation
- Hydroxylation (add -OH)
- Dealkylation (remove -CH side chains)
- Deamination (remove -NH)
- Hydrogen removal
what happens in reduction
hydrogen is added
so unsaturated bonds become saturated
what is functionalisation
- Introduces reactive group to drug
- Includes adding or exposing; -OH,-SH,-NH2,-COOH
- The product of the reaction is usually more reactive
- There is a small increase in HYDROPHILICITY
how do cytochrome P450 enzymes work
Uses heme group (Fe2+) to oxidise substances
the products are more water soluble
how to name cytochrome P450 enzymes
1st number = the family the enzyme belongs to
Letter= indicates subfamily
2nd number= individual genes involved
what is cytochrome P450 reductase
the enzyme required to transfer electrons from NADPH to CY P450
Contains flavoprotein which in turn consists of; Flavin adenine dinucleotide (FAD) & flavin mononucelotide (FMN)
what does FAD do
accepts electrons from NADPH
what does FMN do
electron donor to CYP’s
what can phase I reactions do
- Inactivate drugs
- Further activate drug
- Activate drug from pro-drug (inactive form of drug)
- Make a drug into a reactive intermediate (could be carcinogenic or toxic)
what happens in phase II reactions
“conjugation reaction”:
- Attachment of substituent groups (endogenous (from the body) molecules)
usually forms inactive products
what are phase II reactions catalysed by
transferases
where do phase II reactions occur
mainly in liver, but can occur in other tissues like the lungs & kidneys
what is a glucuronidation reaction
- Adding a glucuronic acid group
- Increases hydrophilicity
- substances produced from this are glucoronides
- process forms covalent bonds
enzyme for glucoronidation reaction
glucuronosyltransferase/ UGT - microsomal
what is Uridine diphospho-glucuronic acid (UDPGA)
a co-enzyme/donor
compound required to conjugate glucuronic acid,
functions of cytochrome p450 enzymes
- detoxification of xenobiotics
- cellular metabolism
- homeostasis
