Biotransformation Flashcards
Enzmes that hydrolyze xenobiotics
Carboxyesterases- CES1(liver, lung), CES2(intestine, liver), AADAC(liver), humans lack any in plasma
Cholinesterases- AChE (muscle, brain, selective), BChE (plasma, other tissues)
Paraoxonases (lactonases)- PON1(liver ER, plasma), PON2(mitochodria), PON3(liver, kidney ER, plasma)
Epoxide hydrolases
What does AADAC do to biotransform which xenobiotics?
Deacetylates (hydrolyzes) phenacetin, 2-acetylaminofluoride
Also hydrolyzes flutamide
What is physostigmine and what is it used for?
AKA eserine
Parasympathomimetic that reversibly inhibits AChE and BChE
Naturally found in calabar bean
Used to treat atropine toxicity, Datura, Atropa belladona poisining, glaucoma, delayed gastric emptying
Drugs that selectively inhibit AChE and BChE in the brain are used for what and give examples
Treat Alzheimers disease
Eg: rivastigmine, tacrine, gelantamine, donepezil
Organophospates MOA, examples, and antidotes
Bind the active site of cholinesterase or carboxyesterase-> inactive cholinesterase -> excess ACh leads to parasympathetic effects
can also undergo dealkylation (“aging”) which impedes release
Eg: nerve agents- soman, sarin
Pesticides- parathion, malathion, diazonon, chlorpyrifos
Naturally occurring- anatoxin a(S) from bluegreen algae, physostigmine from Calabar bean, huperzine A from club moss, solandine from green potatoes, cocaine from Erythroxylum coca plant
Carbamate pesticide have similar MOA- aldicarb, carbaryl, carbofuran
Antidotes- pralidoxime (2-PAM), obidoxime
Paraoxonases
Hydrolyze OPs, organphosphonites, aromatic carboxylic acid esters, cyclic carbonates, lactones, oxidized phospholipids
Calcium dependent, contain -SH group
Inhibited by EDTA, metal ions, and mercurials
Only PON1 has arylesterase activity and can hydrolyze oxon metabolites of OPs
All can hydrolyze different lactones
How does alkaline phosphatase affect prodrugs?
ALK is present on the luminal surface of enterocytes and can hydrolyze prodrugs into their active form to be absorbed
How does B-glucuronidase contribute to enterohepatic circulation?
When a drug is glucuronidated and excreted in bile, B-glucuronidase can hydrolyze it and release the parent drug and be reabsorbed
Epoxide hydrolases
Catalyze the trans addition of water to alkene epoxides and arene oxides
Carboxyesterases
Hydrolyze esters and amides
Azo and nitro reduction are generally catalyzed by:
Intestinal microflora
Azos and nitros get reduced to amines
List the enzymes that catalyze reduction of aldehydes and ketones to alcohols
AKRs- aldo keto reductases; cytosolic, can also oxidize
SDRs- short chain dehydrogenases/reductases, cytosol and ER
MDRs- medium chain “”
ALDHs- aldehyde dehydrogenases
NQO- NAD(P)H- quinone oxido reductase
mARC
mitochondrial amidoxime reducing component
molybdenum containing enzyme that catalyzes dehydroxylation of amidoximes and N-hydroxy compounds
requires NADH, cytochrome b5, NADH-cytochrome b5 reductase
Converts -N-OH to -N-H
What are the two most important molybdoenzymes and what os their location in the cell?
XOR xanthine oxidoreductase- 2 forms: xanthine oxidase and xanthine dehydrogenase
AO aldehyde oxidase
Cytosol
Can oxidize, but can also reduce (even AO, but requires anaerobic conditions and reducing substrate)
What 2 organs have the most AO?
Liver and adrenal
Compare the types of carbon atoms that CYP likes to oxidize versus those that XOR and AO like to oxidize.
CYP- oxidize carbon atoms with high electron density
XOR, AO- oxidize carbon atoms with low electron density (eg: carbon atoms adjacent to nitrogen)
But there is some overlap
What are the 3 main substrate groups for AO?
Aldehydes, especially aromatic ones
Nitrogen heterocycles
Imminium ions
What group has SNPs in the AOX1 gene?
Italians
How does AO activity compare amongst the species?
Human and monkey>rodents(male>female)>dogs (absent)
Large differences in roles due to different number and function of AO genes
What is cotinine and how is it formed?
Metabolite of nicotine excreted in urine
Formation of a C=N double bond in pyrrole ring-> nicotine imminium ion -> oxidixed by AO
Name 3 inhibitors of AO
Raloxifene (selective estrogen receptor modulator)- estrogenic effects on bone, anti-estroden on breast and uterus
Perphenazine (antipsychotic)
Menadione (nutritional supplement with Vit K activity)
Hydralazine
Proadifen (methadone analog) - widely used as CYP inhibitor, also inhibits AO
What are the two types of amine oxidases?
- FAD containing mitochondrial MAOs, PAO and spermine oxidase (SMOX)
- Copper containing amine oxidases CuAOs that contain CuII and a quinone residue
What are the CuAOs and where are they located?
- Lysyl oxidase LOX- intracellular
- Diamine oxidase DAO aka AOC1
- Semicarbazide sensitive SSAOs - plasma and plasma membranes
Class I amine oxidases
MAOA, MAOB, PAO, SMOX
Oxidative deamination of primary, secondary and tertiary amines-> produces ammonia or primary amine and an aldehyde which is usually further oxidized to carboxylic acid or reduced to alcohol
MAO
Located in the MOM of many tissues incl brain, but now erythrocytes
MAOA - placenta, locus coerulus
MAOB- platelets, lymphocytes, chromaffin cells, raphe nuclei
MAOs don’t work on pyrrolidine or piperidine ring nitrogens
Don’t work as well when there is substitution at the alpha carbon
What are triptan drugs?
tryptamine-based drugs used in the treatment of migraines, agonists for serotonin 5-HT1B and 5-HT1D receptors at blood vessels and nerve endings in the brain
What is the preferential inhibitor of each MAO?
MAOA- clorgyline
MAOB- selegiline (L-deprenyl)
Biotransformation of MPTP
Crosses BBB and oxidized by MAOB in astrocytes, then auto oxidizes to MPP+ (ultimate toxicant) which is transported by the dopamine transporter into neurons -> impairs mito respiration (complex I)-> kills dopaminergic neurons causing Parkinson’s like disease
Classes of compounds that undergo one electron oxidation rxns by peroxidases
Aromatic amines
Phenols
Hydroquinones
Polycyclic hydrocarbons
(Electrophlic quinones are often produced)
