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33 Cards in this Set

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What are two non-synthetic (phase 1) reactions that are not cytochrome P450 mediated (non-microsomal oxidations)?
Alcohol dehydrogense - converts alcohol or ethanol to acetylaldehyde
Aldehyde dehydrogenase - converts acetaldehyde to acetic acid
What does Disulfiram/antabuse do?
It inhibits aldehyde dehydrogenase which blocks the conversion of acetaladehyde to acetic acid causing flushing, sweating, headache, nausea,...
what are some reduction reactions that we learned about?
How the hell should I know.. I don't pay attention in class... J/K
Nitroreductions
Ketoreductions
Azoreductions
Most of these reactions occur in an anaerobic environment.
What are three major types of Hydrolysis reactions?
Esterase - liver, plasma, and kidney
Amidase - breads down amides in the liver
Epoxide Hydrolase - found in the liver and virtually all tissues.
What does esterase do or prevent?
Hydrolizes procaine (anesthetic). Therefore, this needs to be site injected to prevent breakdown.
What does a polymorphism of esterase do?
Causes what is known as Succinylcholine apnea.
Succinylcholine is used during surgery as a muscle relaxant typically metabolized within 5-10 minutes. Test with a low dose first.
How many forms of Epoxide hydrolases are there?
two:
Microsomal endoplasmic reticulum
Soluble
What type of phase I reactions are there and what type of phase II?
Phase I:
Oxidation, reduction, and hydrolysis
Phase II:
Conjugation
Phase III:
Drug transporters involved in drug excretion (this is an occassional reference)
What are the various types of Phase II reactions?
Glucuronidation
Sulfate Conjugation
Acetylation
Glutathione Conjugation
Methylation
Amino Acid Conjugation
What does increasing water solubility do to the excretion rate of a compound?
It increases and allows it to be more readily gotten rid of
What is a benefit of glucuronyl transferases?
It prevents enterohepatic recycling by making the compuonds more water soluble and excretable into the urinary system.
Whatis a pitfall of glucuronidation in the intestines?
Bacteria can break down the glucuronidation making the compound less water soluble and easily reabsorbed back into the body.
What is the induction process of glucuronyl transferases?
They are developmentally induced meaning that they are very low at or absent in neonates.
What is the utility of glucuronyl transferases?
Prevention of neonatal jaundice by metabolism and clearance of bilirubin and various drugs
What is the cause of Neonatal Jaundice?
level of unconjugated bilirubin in the blood becomes high enough t transfer across the blood-brain barrier into the CNS, resulting in kernicterus. Irrversible damage and ultimately death
What is Gray Baby syndrome?
Also caused by lack of glucuronyl transferase enzymes. Inability to conjugate chloramphenicol causing severe CNS damage and death. Identified by gray pallor to the baby's skin
What is Crigler-Najjar syndrome?
Kernicterus, irreversible CNS damage, patients die at young age. These are due to genetic deficiency of glucuronyl transferase.
Describe the sulfate conjugation reaction.
Phosphoadenosyl phosphosulfate is the activated form of sulfate that allows the sulfate to be transferred by sulfyl transferases to the metabolite with the use of ATP. Rapid Saturation of pathway!!
What does N-Acetyl transferases do and where are they found?
It acetylates stuff and it is found in the cytoplasm
What happens when there is a polmorphism in the N-acteyl transferases (acetylation polymorphism)?
There is a difference in gene structure not amount of enzyme.
Causes one to be rapid or slow acetylators
What drug is used to test for N-acetyl transferase polymorphisms?
isoniazid
What are the two major forms of N-acetyl transferases (stupid question)?
NAT1 and
NAT2 - expressed in the liver and intestines
What are the ethnic groups associated with rapid vs. slow acetylators?
Rapid - Eskimos, Chinese, and Japanese
Slow - Egyptians, Israelis, Scandinavians, and Finnish
What are the consequences of being a slow acetylator?
Isoniazid-induced neurotoxicity
Drug-induced lupus erythematosus
Arylamine-induced bladder cancer
What are the consequences of being a rapid acetylator?
Isoniazid-induced hepatitis
Colorectal cancer
Where do the glutathione conjugation enzymes typically reside?
Cytosol and Mitochondria of numerous tissues
What are most glutathione conjugates excreted as and what is the process??
Following glutahione conjugation cleavage reactions remvoe glycine and glutamate. Cystine will then be acetylated to form mercapturic acid which is the typical form that is excreted.
How many variations of Glutahione Sula-transferase enzymes are there and what do the polymorphisms cause?
GSTM 1: Polymorphism causes a truncation of the enzyme, preventing the full length molecule from bing formed. 50% prevalence
GSTM 2, GSTM 3, and GSTM 4 are the others, but unidentified polymorphism characteristics
What did the mice experiment with glutathione and acetaminophen tell us?
As long as glutathione was available to conjugate to the acetaminophen the liver was okay, but after levels fell the drug became toxic to hepatocytes. This has ramifications similar to CYP2E1 which is the alcohol metabolizer. If alcohol induces the P450 system taking tylenol will cause conversion to the toxic metabolite causing liver damage. Glutathione is protective, but at decreased levels it is insufficient.
What does methyl transferases do and where are they found?
It methylates and is found in the cytoplasm and endoplasmic reticulum. Activated form is S-adenosyl methionine
What is the primary amino acid in amino acid conjugation and where are the enzymes found?
Glycine
Found in mitochondria and the cytoplasm
What are factors affecting drug metabolism?
Genetic differences
Age differences
Species differences
Black swallowtail butterflies are able to feast on which plant because of what?
A plant of the parsely family that contains xanthotoxin which is a natural pesticide. The butterfuly has a CYP6B1. Humans have a P450 that allows us to eat parsely as well.