Metabolic Phases: Phase I Flashcards
What is Phase I ?
Alteration of the original compound that expose the xenobiotic to –OH, -NH2, -SH and -COOH functional groups.
Phase I involves
- Hydrolysis
- Reduction
- Oxidation
What is Hydrolysis?
This is the process by which cleavage occurs due to the addition of water.
What functional group can all be metabolized by hydrolysis.
Esters, amides, hydrazides, and carbamates
The enzymes that catalyse these hydrolytic reactions
Carboxylesterases and amidases,
Where are typically hydrolytic enzymes found ?
in the cytosol, but microsomal esterases and amidases have been described, and some are also found in plasma.
Carboxylesterases have
amidase activity
Amidases have
esterase activity.
Hydrolysis of esters is usually done by
esterases.
Where is esterases found?
They are usually found in the blood, but can be found in tissues such as the liver as well.
3 Classes of esterases.
- A-esterases include arylesterase and paraoxonase (lactonase).
- B-esterases include carboxylesterase and cholinesterase. They are inhibited by paraoxon.
- C-esterases acetylesterase as their substrate prefered is acetyl esters. They are not inhibited by paraoxon.
Esterase activity is important to the _____ and the ____ of _____.
Esterase activity is important in both the detoxication and toxicity of organophosphates.
Acetylcholinesterase is inhibited by organophosphates such as _____ and _____.
paraoxon and malaoxon.
What is malathon?
Malathion, a widely used insecticide, is primarily metabolised by carboxylesterase in mammals, which is a detoxication route.
Pesticide Metabolites Paraoxon and Malaoxon Cause
Cellular Death in Cultured Human Pulmonary Cells via Different Mechanisms
Organophosphorus (OP) pesticides are known to induce
pulmonary toxicity in both humans and experimental animals.
The effects of parathion and malathion, as well as their respective metabolites, paraoxon and malaoxon, on primary cultured human large and small airway cells were studied
to elucidate the mechanism of OP-induced cytotoxicity.
Following a 24-hour exposure to paraoxon and malaoxon, there
was a dose-dependent increase in cytotoxicity.
Treatment with parathion or malathion had
no effect at clinically relevant concentrations.
Caspase activation was induced by_____ exposure, but not by ______exposure.
Caspase activation was induced by paraoxon exposure, but not by malaoxon exposure.
Caspase inhibition with drugs protected against
paraoxon-induced cell death but not malaoxon-induced cell death.
Caspase inhibition with drugs protected against
paraoxon-induced cell death but not malaoxon-induced cell death.
The hydrolysis of amides are catalysed
by amidases in the liver, but can be done also by plasma esterases.
The ester functional group made from
an ether and Carboxylic acid
The amide functional group made from
an amine and Carboxylic acid
The hydrolysis of esters and amides occur
when a nucleophile electron rich specie such as water or hydroxyl ion
What is reduction?
This is the process by which a compound gains
1. Electron
2. Hydrogen
3. Loses oxygen
Aldehyde, ketones, disulfides, sulfoxides or basically nitrogen containing groups
undergo reduction.
Aldehyde, ketones, disulfides, sulfoxides or basically nitrogen containing groups broken down by
enzymatic agents and non-ezymatic agents.
What are enzymatic agents ?
Cytochrome P450
What are non enzymatic agents?
Nonezymatic agents – Gut microflora, FAD (Flavin Adenine Dinucelotide), NADP (Nicotineamide Adenine Dinucelotide Phosphate)
Reductions Reactions Focused on
- Azo- and Nitro- Reduction
- Carbonyl Reduction
- Disulfide Reduction
- Dehalogenation
What is oxidation?
This is the process by which a compound loses an electron, gains oxygen and hydrogen.
Many of the enzymes mentioned in reduction perform oxidation as well such as
Cytochrome P450, alcohol dehydrogenase and aldehyde dehydrogenase.
Oxidation Reactions Focused on
- Dealkylation
- Desulfation
- Oxidation of alcohol
What is Dealkylation?
The process of removing an alkyl group from nitrogen (N), sulfur (S) and oxygen (O) atoms. This is done by microsomal enzymes. A corresponding aldehyde is a result of the reaction.
What is Desulfuration?
The process of replacing sulfur with oxygen.
Parathion is
an insecticide (organophosphate)
What happens when parathion enters the body?
When in the body the reaction appears to be catalysed by either cytochromes P-450 or the FAD-containing monooxygenases and therefore requires NADPH and oxygen.
What is the more toxic compound of parathion and why is this bad for the bod?y
paraoxon which can inhibit cholinesterase
Oxidation in alcohol can occur by
By two ways:
1. Microsomal enzyme activity by Cytochrome P450
2. Non microsomal enzyme activity by alcohol dehydrogenase (ADH) and is the major pathway
Why would NAD be used to aid ADH than NADPH?
ADH uses the aid of NAD, but NADPH can be used as well but the reaction would be slower.
The NAD enzyme works on
both primary and secondary alcohols, with primary ones having a faster reaction.
Primary & Secondary Alcohols are converted in to their respective aldehydes
which are further converted
to respective acids by aldehyde dehydrogenase (ALDH).
