RNA: Metabolism Of Xenobiotics Flashcards
Is a compound that is foreign to the body. It may include drugs, chemical carcinogens, and various other compounds. May be excreted unchanged, or it may be metabolized by the body’s enzymes to other compounds.
Xenobiotics
Metabolism of Xenobiotics occur mostly in the
Liver
Xenobiotics may convert __________ into cytotoxic, muthagenic compounds.
Procarcinogenics
Metabolism of one xenobiotic may influence metabolism of another __________. Examples: drugs & other foreign non-essential compounds.
Xenobiotics
Xenobiotic metabolized before reaching general circulation
First-pass metabolism
Pathway of Xenobiotics Metabolism: Attachment of new functional groups, transformation of exist functional gro oxidation, reduction, hydroxylation, hydrolysis & etc.
Phase 1 Biotransformation/Hydroxylation
Pathway of Xenobiotics Metabolism: Masking of an existing functional group by acetylation, glycosylation, attachment of an AA, or other mechanism.
Phase 2 Conjugation
2 Phases of Xenobiotic Metabolism
Hydroxylation/Biotransformation and Conjugation
Catalyzed by cytochrome P450, a monooxygenase. May sometimes terminate the action of a drug. Other phase 1 reactions may include deamination, dehalogenation, desulfuration, epoxidation, peroxygenation and reduction. Reactions involving ________ also occur in phase 1.
Hydroxylation. Hydrolysis.
The reaction catalyzed by a _________ is as follows: RH + 02 + NADPH + R- OH + H2O + NADP. It is sometimes referred to as a Mixed Function Oxidase. Approximately 50% of the drugs humans ingest are metabolized by isoforms of __________.
Monooxygenase. Cytochrome P450.
Compounds produced in phase 1 are converted by specific enzymes to various polar metabolites by conjugation with glucuronic acid, sulfate, acetate, glutathione, or certain AA or by methylation.
Conjugation
The most frequent conjugation reaction
Glucuronidation
Is the glucuronyl donor
UDP-glucuronic acid
Are the catalyst in Glucuronication
Glucuronosyltransferases
Sulfate donor is ____________ called “active sulfate.”
Sulfation. Adenosine-3-phosphate-5-phosphosulfate PAPS.
Is a tripeptide consisting of glutamic acid, cysteine, and glycine.
Glutathione
Are conjugated to the nucleophilic GSH: R+GSH—>R-S-G. The enzymes catalyzing these reactions are called ____________ and are present in high amounts in liver _______.
Electrophilic xenobiotics(carcinogens). Glutathione S-transferases. Cytosol.
Catalyzed by acetyltransferases present in the cytosol of various tissues, particularly the _________. X+Acetyl-CoA-X+CoA.
Acetylation. Liver.
Used in the treatment of tuberculosis, is subject to acetylation.
Isoniazid
In Acetylation, Polymorphic types of __________ exist, resulting in individuals who are classified as slow or fast acetylators.
Acetyltransferases
Are more subject to certain toxic effects of isoniazid because the drug persists longer in these individuals.
Slow Acetylators
Has several soluble UDP-Gluc-transferases
Liver
Is found in many tissues including liver
NAT enzymes
Purpose of Xenobiotics: to increase the _________ of the xenobiotic and facilitate _______ from the body.
Water solubility. Excretion.
Purpose of Xenobiotics: If xenobiotic is not metabolized, it would remain in the ___________ and would be stored indefinitely in the _________.
Nonpolar state. Adipose tissue.
Fate of Xenobiotic Metabolism: It may be converted from an _______ to a biologically ______ compound (prodrug or ________)
Inactive. Active. Procarcinogen.
Fate of Xenobiotic Metabolism: Additional phase 1 reactions may convert the active compounds to _______ or _______ forms prior to conjugation.
Less active. Inactive.
Fate of Xenobiotic Metabolism: In other cases, it is the ________ reactions that convert the active products of phase 1 reactions to less active or inactive species, which are subsequently excreted in the urine or bile.
Conjugation
Fate of Xenobiotic Metabolism: In few cases, conjugation may increase the biologic activity of a
Xenobiotic
Properties of Human Cytochrome P450: All are _________. Exhibit ______ substrate specificity.
Hemoproteins. Broad.
Properties of Human Cytochrome P450: Found mostly in the ________ but is also present in other tissues.
Liver
A mitochondrial or ER enzyme. Activity may be induced or depressed by certain drugs, causing drug interactions.
Human Cytochrome P450
Used to prevent blood clotting, is metabolized by a cytochrome which is induced by __________. Thus when both drugs induce are given, dose of this drug must be increased to achieve therapeutic doses.
Warfarin. Phenobarbital.
Properties of Human Cytochrome P450: Exhibits genetic ________, so different individuals metabolize drugs differently.
Polymorphism
Properties of Human Cytochrome P450: Activity is affected also by tissue or organ _________.
Disease (cirrhosis)
Properties of Human Cytochrome P450: ________ is involved in the reaction mechanism.
NADPH
Properties of Human Cytochrome P450: The preferred lipid in its structure is
Phosphatidylcholine
Is a member of family 1 subfamily A and is the first individual member of the subfamily.
CYP1A1
Response to _______ may be affected by age, sex and genetic factors. May result in cell injury, allergies or carcinogenesis.
Xenobiotics
Genetic factors
Pharmacogenomics
Reaction to drugs
Pharmacogenetics
