Biotransformations week 4 Flashcards
True or false: Constant monitoring, recycling, modifying and distributing of all compounds
- absorbed from the digestive tract and delivered by the portal vein and
- received from the periphery delivered by the hepatic artery
Fenestration of and gaps between the endothelial cells and lack of a basement membrane between the endothelial cells and hepatocytes as well as slow blood flow allow for efficient exchange of compounds between the sinusoidal blood and the hepatocytes.
True.
What are the fxns of the liver?
xenobiotics
metabolic waste products
Most xenobiotics and metabolic waste products are:
a. hydrophilic
b. lipophilic
XENOBIOTICS: No value to the body and must be disposed of: food additives, pharmaceuticals, recreational drugs, alcohol, tobacco products, environmental toxins, etc.
Metabolic waste products –cellular components and biomolecules that cannot be degraded and eliminated by other cells (ammonia, bilirubin, etc)
Most are lipophilic so they must be modified for elimination.
What are phase I rxns? What are phase II rxns?
What types of molecules do these rxns process? What is the purpose?
What catalyzes phase I rxns?
Drugs and xenobiotics are metabolized primarily by two pathways. Phase I are oxidation reactions and Phase II are biosynthetic reactions. In Phase I a functional group (eg. Hydroxyl) is added by cytochrome P450. In Phase II a small, polar, endogenous molecule is added to the functional group (eg. glucuronic acid, sulfate, glutathione, amino acids or acetate). Net effect of both phases is to make a xenobiotic more polar and water soluble so it is readily excreted by kidneys or intestines via bile.
Phase I and/or II reactions:
- Process endogenous molecules to their active form
- Process xenobiotics and, as a result:
a. activate them
b. inactivate and eliminate them
c. turn them to toxins or carcinogens
What do cytochrome P450 (CYP) proteins do? What kind of proteins are they?
Where in the body do CYP proteins exist?
What are substrates for these enzymes?
What activities/rxns are CYP proteins involved in?
What may inhibition or induction of this system result in?
A family of heme proteins, called cytochrome P450, catalyzes the oxidation of a variety of diverse molecules in prokaryotes and all mammalian cells except mature red blood cells and skeletal muscle cells.
Substrates:
- endogenous steroids
- fatty acids (protaglandins and leukotrienes)
- cholesterol (bile acids)
- drugs food additives industrial by-products that enter the body
Role of the Cytochrome P450 system:
a) is involved in steroid hormone production
b) is involved in the metabolism of fatty acids, prostaglandins, leukotrienes, retinoids
c) activates or inactivates therapeutic agents
d) converts chemicals to highly reactive molecules which cause cell death, damage or mutations
Inhibition or induction of the system may result in drug- drug interactions and adverse effects. CYPs have specific rxns. if one not working, either cannot synthesize something or cannot detox something-accumulation of xenobiotic
What is the general rxn catalyzed by cytochrome P450?
What is this type of rxn called? Explain the general steps involved in this rxn.
The general reaction catalyzed by cytochrome P450 is NADPH + H+ + O2 + A-H –> NADP+ + H2O + A-OH
This is a monooxygenation reaction as one atom of molecular oxygen is incorporated into the substrate (A).
Anything that inhibits O2 delivery to cells or NADPH production (hypoglycemia for example) will inhibit these rxns.
In mammalian cells, what are the cellular locations of CYPs?
In mammalian cells cytochromes P450 are present in the smooth endoplasmic reticulum (microsomes) or in the inner mitochondrial membrane.
What specific rxns are CYPs involved in? (involving endogenous molecules and xenobiotics)
- Cytochrome P450 systems activate endogenous biomolecules
- Synthesis of steroid hormones
- Oxygenation of prostaglandins, eicosanoids
- Vitamin D activation
- Bile acid production
- Cytochrome P450 systems metabolize xenobiotics
- Process xenobiotics to activate them
- Process xenobiotics to inactivate and eliminate them
- Processing of chemicals to form toxins
What CYP is involved in steroid synthesis?
What is the precursor to steroid synthesis?
What molecule, when formed by this CYP, is the commitment to steroid synthesis?
What is required for these rxns?
What substrates are formed? What is the cellular localization of these rxns?
In what organs do these rxns occur?
Mitochondrial and endoplasmic reticulum cytochrome P450 systems are required to metabolize cholesterol stepwise into aldosterone and cortisol in the adrenal cortex, testosterone in testes and estradiol in ovaries.
In adrenal mitochondria CYP11A1 (desmolase) catalyzes side chain cleavage to convert cholesterol to pregnenolone and the commitment to steroid synthesis. Pregnenolone is the first steroid hormone precursor produced.
In three steps, each of which requires an NADPH and O2, cholesterol is converted to pregnenolone using the single CYP11A1.
Pregnenolone is transported to the cytosol and oxidized to progesterone.
What are congenital adrenal hyperplasias (CAHs)?
What is the most common CAH? What enzyme is involved?
What are the sx of this disease?
The adrenal cortex is the major site for steroid hormone production and is more active in fetal than adult life. Congenital adrenal hyperplasias (CAHs) are diseases associated with insufficient cortisol production. The most common CAH is a deficiency in CYP21A2, the cytochrome P450 needed to convert 17D-hydroxyprogesterone to 11 deoxycortisol and then to cortisol. Mineralocorticoids and glucocorticoids are virtually absent (classic form) or deficient (non-classic form). This leads to an increase in the pituitary hormone ACTH which regulates cortisol production, increased adrenal hyperplasia and increased androgenic hormones, DHEA and androstenedione. Increased androgenic steroids causes virilization in females, precocious sex organ development in males and diseases related to salt imbalance due to decreased aldosterone.
What CYP is involved in metabolism of vit D3? What does this family of CYPs do to D3?
What CYP catalyzes the rate limiting step in bile acid synthesis? What bile acid is formed? How is this CYP regulated? What is the cellular localization of this rxn?
What CYP processes leukotriene B4? What is the result of its action?
Cytochrome CYP27 family members metabolize vitamin D3 to produce 1,25-dihydroxy vitamin D3, the active form of this hormone.
Liver uses this system in bile acid synthesis. The rate-limiting step in the synthetic pathway is the cholesterol-7 hydroxylase, an ER-associated enzyme in the liver (CYP450). It catalyzes the formation of cholic acid from cholesterol. This enzyme is inhibited by its product, cholic acid.
Cytochrome CYP4 family members process leukotriene B4 to 20-hydroxy-leukotriene B4 a less chemotactic agent, and produce derivatives of arachidonic acid which may have important regulatory functions.
What does oxidation of xenobiotics by cytochrome P450 do to these molecules?
Where are most of these enzymes located? Where else in the body are they found?
The xenobiotics oxidized by cytochrome P450 make the lipophilic substances more soluble in the aqueous environment, usually less active or toxic and more readily excreted in urine or bile.
Most of these enzymes are in the liver and some in the intestines.
What CYP metabolizes 50% of drugs?
What is the cellular localization of CYPs that metabolize drugs?
What are common features of CYPs that metabolize drugs?
CYP3A4 metabolizes about 50% of drugs
CYP2D6 metabolizes about 20% of drugs
CYP2C9 and 19 metabolizes about 15% of drugs
CYP1A2, 2A6 and 2B6 metabolizes about 15% of drugs
Common features of these CYPS:
Found in smooth ER (microsomal enzymes)
Can turn over several substrates (competition)
Inducible by their best substrates
CYPs can modify xenobiotics to
a. Activate them
b. Inactivate them
c. Form toxins
Explain the role of CYP3A4 in the activation of drugs.
How does CYP3A4 activate drugs? How can taking multiple drugs be harmful as it pertains to CYP3A4?
What CYP metabolizes acetominophen? How does it modify acetominophen?
What molecule is acetominophen processed into?
What effect does alcohol have on the metabolism of acetominophen?
What potential harmful effects can acetominophen and alcohol (taken together) have on the body?
Acetaminophen (Tylenol) is eliminated through:
• modification by sulfation and glucuronidation
• CYP2E1 can modify Tylenol to NAPQI (N-acetyl-p- benzoquinoneimine), which needs to be conjugated with glutathione to be eliminated
NAPQI may bind to cellular proteins, cause cell death and severe liver damage.
Problem: CYP2E1 is induced by alcohol
-turns more acetaminophen to NAPQI
-can lead to greater liver damage depending on the quantities and timing of alcohol and acetaminophen consumed.
If glutathione is low and the amount of acetaminophen is high, the effects of NAPQI become significant.
Acetaminophen poisoning is the most common call to poison centers and causes 35% of liver failures.
