Liver metabolism Flashcards
(137 cards)
1
Q
What is xenobiotic biotransformation?
A
The process of converting lipophilic (fat-soluble) chemicals into hydrophilic (water-soluble) chemicals.
2
Q
Which reactions are involved in xenobiotic biotransformation?
A
- Hydrolysis
- Reduction
- Oxidation
- Conjugation
3
Q
What is the role of cytochrome P450 (CYP) in drug metabolism?
A
CYP enzymes metabolize over half of orally taken drugs and natural products/endobiotics.
4
Q
What are examples of conjugation reactions in xenobiotic metabolism?
A
- Glucuronidation
- Sulfonation
- Acetylation
- Methylation
- Conjugation with glutathione (GSH)
- Conjugation with amino acids (e.g., glycine, taurine, glutamine)
5
Q
What happens to the functional groups during hydrolysis, reduction, and oxidation?
A
They expose or introduce nucleophilic or electrophilic functional groups.
6
Q
What is first-pass elimination?
A
The process by which the small intestine and liver limit systemic exposure to orally ingested xenobiotics.
7
Q
What are xenosensors?
A
Ligand-activated receptors that upregulate the transcription of genes encoding xenobiotic-biotransforming enzymes.
8
Q
Fill in the blank: The major xenosensors include AhR, CAR, PXR, and ______.
A
PPARα
9
Q
What is the effect of induction on drug-metabolizing enzymes?
A
Induction increases the expression of drug-metabolizing enzymes.
10
Q
What is the significance of idiosyncratic drug reactions (IDRs)?
A
They are rare adverse events that do not involve an exaggerated pharmacological response.
11
Q
What role do environmental factors play in xenobiotic biotransformation?
A
They can introduce significant variation in drug metabolism, comparable to genetic factors.
12
Q
What is mutarotation in the context of xenobiotic biotransformation?
A
The conversion of one stereoisomer to another.
13
Q
What is the consequence of reactive oxygen species produced during biotransformation?
A
They can cause cell toxicity through oxidative stress and lipid peroxidation.
14
Q
What is the relationship between xenobiotic biotransformation and homeostasis?
A
Certain xenobiotics can alter homeostasis or cause toxicity by inducing biotransforming enzymes.
15
Q
List the organs that have high levels of xenobiotic-biotransforming enzymes.
A
- Small intestine
- Liver
- Brain
- Reproductive organs
16
Q
What is the impact of CYP enzymes on carcinogens?
A
They convert proximate carcinogens to ultimate carcinogens, leading to mutations and tumor initiation.
17
Q
What happens to the toxicity of electrophilic metabolites when conjugated with GSH?
A
Their toxicity and potential carcinogenicity are reduced or eliminated.
18
Q
What is the role of mass spectrometry in xenobiotic biotransformation?
A
It is used to characterize the structure of metabolites by detecting changes in mass.
19
Q
What is the function of carboxylesterases in hydrolysis?
A
They catalyze the hydrolysis of various xenobiotics and are predominantly found in the liver and intestine.
20
Q
What are paraoxonases?
A
Enzymes that catalyze the hydrolysis of a broad range of organophosphates and other compounds
21
Q
List the three paraoxonases expressed in humans.
A
- PON1
- PON2
- PON3
22
Q
Where is PON1 primarily found?
A
Liver microsomes and plasma
23
Q
What is the role of alkaline phosphatase in relation to prodrugs?
A
Hydrolyzes prodrugs to become active agents
24
Q
What do peptidases hydrolyze?
A
Amide bonds in peptides and proteins
25
What is the function of β-glucuronidase?
Hydrolyzes xenobiotic glucuronides
26
What do epoxide hydrolases detoxify?
Electrophilic epoxides
27
What type of reactions do alcohol dehydrogenases catalyze?
Oxidation of alcohols to aldehydes
28
What is the primary function of reductive dehalogenation?
Replacement of a halogen with hydrogen
29
List the three major mechanisms for dehalogenation.
* Reductive dehalogenation
* Oxidative dehalogenation
* Double dehalogenation
30
What is the role of aldehyde oxidase?
Oxidizes aldehydes and can generate reactive oxygen species
31
What is the mechanism of oxidative deamination performed by amine oxidases?
Produces ammonia and an aldehyde from primary amines
32
What is cooxidation in the context of oxidative biotransformation?
The coupling of the reduction of hydrogen peroxide to the one-electron oxidation of other substrates.
33
How do peroxidases activate xenobiotics?
By transferring peroxide oxygen to the xenobiotic, leading to the formation of reactive metabolites.
34
What types of reactions do flavin monooxygenases (FMO) catalyze?
Oxidation of tertiary amines to N-oxides, secondary amines to hydroxylamines and nitrones, and primary amines to hydroxylamines and oximes.
35
What is the catalytic cycle of flavin monooxygenase (FMO)?
Involves reduction of FAD to FADH2, binding of oxygen, and transfer of oxygen to xenobiotics.
36
What are the general features of cytochrome P450 (CYP) enzymes?
They are heme-containing proteins involved in detoxifying xenobiotics and are present in various tissues.
37
What is the basic reaction catalyzed by CYP enzymes?
Monooxygenation, where one atom of oxygen is incorporated into a substrate and the other is reduced to water.
38
How does the CYP enzyme system receive electrons during catalysis?
Via a flavoprotein called NADPH–cytochrome P450 reductase (POR).
39
What are the steps involved in the catalytic cycle of CYP?
Involves eight steps: substrate binding, reduction of iron, oxygen binding, formation of superoxide, and substrate oxidation.
40
List the types of oxidation reactions catalyzed by cytochrome P450.
* Hydroxylation of aliphatic or aromatic carbon
* Epoxidation of a double bond
* Heteroatom oxygenation
* Heteroatom dealkylation
* Oxidative group transfer
* Cleavage of esters and carbamates
* Dehydrogenation
41
Which CYP gene families are primarily involved in xenobiotic biotransformation?
CYP1, CYP2, and CYP3 gene families.
42
What is the significance of the heme thiolate in the CYP catalytic cycle?
It provides a fifth ligand to the heme iron and facilitates electron transfer.
43
What is the role of cytochrome P450 (CYP) enzymes?
CYP enzymes catalyze the biotransformation of xenobiotics, including drugs and toxins.
44
Name two examples of reactions catalyzed by cytochrome P450.
* Cleavage of a thiophosphate (parathion)
* Dehydrogenation reactions
45
What factors can lead to decreased CYP enzymatic activity?
* Genetic mutations
* Environmental factors
* Exposure to xenobiotics
46
What are the consequences of decreased CYP enzyme activity?
It can lead to pharmacological or toxicological responses due to impaired drug biotransformation.
47
What is reaction phenotyping?
It is the identification of which CYP enzyme or enzymes are involved in eliminating a drug.
48
What are substrates in the context of CYP enzymes?
Substrates are compounds that are metabolized by specific CYP enzymes.
49
What environmental factors can influence CYP enzyme levels?
* Medications
* Foods
* Social habits (e.g., alcohol consumption)
* Disease status (e.g., diabetes, inflammation)
50
What is the significance of biomarkers in relation to CYP enzymes?
They can monitor CYP activity and assess the impact of drugs or xenobiotics on enzyme function.
51
What is the potential impact of CYP enzyme induction by one drug?
It can stimulate the metabolism of a second drug, decreasing its therapeutic effect.
52
Name two inhibitors of CYP enzymes.
* Selegiline
* Omeprazole
53
What is a consequence of drug-drug interactions involving CYP inhibition?
It can lead to altered drug metabolism and potential toxicity.
54
What are the two categories of inhibitory drug interactions?
Reversible and irreversible
## Footnote
These categories describe how the inhibition of enzymes affects drug metabolism.
55
What types of reversible inhibitors exist?
Competitive, noncompetitive, uncompetitive (or mixed)
## Footnote
Each type of inhibitor interacts differently with the enzyme.
56
What are metabolism-dependent inhibitors (MDIs)?
Irreversible inhibitors that can be completely irreversible or quasi-irreversible
## Footnote
These inhibitors impact the metabolism of drugs in significant ways.
57
What is the process of CYP induction?
Upregulation of xenobiotic-biotransforming enzymes and transporters
## Footnote
This process enhances the elimination of xenobiotics during high exposure.
58
What is the role of xenosensors in CYP induction?
They mediate the induction of enzymes and transporters in response to xenobiotic exposure
## Footnote
Xenosensors are crucial for the adaptive responses of the body to foreign substances.
59
What is the first step in CYP induction?
Binding of ligand (xenobiotic) to the receptor
## Footnote
This triggers conformational changes necessary for receptor activation.
60
What happens after ligand binding in the CYP induction process?
Dimerization of the ligand-bound receptor with a partner protein
## Footnote
This forms a DNA-binding heterodimer essential for gene transcription.
61
What is the final step in the CYP induction process?
Gene transcription leading to increased levels of CYP mRNA and protein
## Footnote
This results in enhanced enzyme activity necessary for drug metabolism.
62
What do xenosensors have that allows them to bind ligands?
A ligand-binding domain (LBD) and a DNA-binding domain (DBD)
## Footnote
These domains are crucial for their function in gene regulation.
63
What are the main types of conjugation reactions?
Glucuronidation, sulfonation, acetylation, methylation, conjugation with glutathione, conjugation with coenzyme A, conjugation with amino acids
## Footnote
Conjugation reactions modify xenobiotics to enhance their excretion.
64
Where are UDP-glucuronosyltransferases (UGTs) predominantly located?
In the endoplasmic reticulum of the liver, kidney, gastrointestinal tract, lungs, prostate, mammary glands, skin, brain, spleen, and nasal mucosa
## Footnote
UGTs play a significant role in glucuronidation.
65
What is the primary effect of methylation on xenobiotics?
Generally decreases aqueous solubility and masks functional groups
## Footnote
Methylation can affect the biotransformation and excretion of xenobiotics.
66
What is the cofactor for methylation?
S-adenosylmethionine (SAM)
## Footnote
SAM is essential for transferring methyl groups to substrates.
67
What is the major pathway for the biotransformation of aromatic amines?
N-acetylation
## Footnote
This process converts aromatic amines to less water-soluble aromatic amides.
68
What enzymes catalyze N-acetylation?
N-acetyltransferases (NATs)
## Footnote
NATs require acetyl coenzyme A (acetyl-CoA) as a cofactor.
69
What are the principal pathways for amino acid conjugation of xenobiotics?
* Conjugation of xenobiotics with carboxylic acid groups to amino acids * Conjugation of aromatic hydroxylamines with carboxylic acid groups of amino acids.
70
Which amino acids are involved in the first pathway of amino acid conjugation?
* Glycine * Glutamine * Taurine.
71
What is the main site of amino acid conjugate elimination?
Primarily in urine.
72
What is glutathione composed of?
Glycine, cysteine, and glutamic acid.
73
What is the primary function of the liver?
Processing foods and substances absorbed from the intestinal tract and delivering processed nutrients to other organs
## Footnote
The liver also contributes to immunity and metabolizes exogenous chemicals for excretion.
74
What initiates chemical-induced liver injury?
Formation of a toxic metabolite
## Footnote
This triggers intracellular responses that can lead to dysfunction or death of hepatic parenchymal cells.
75
What are the two main sources of blood supply to the liver?
Hepatic artery and hepatic portal vein
## Footnote
The hepatic portal vein supplies blood that contains food-borne xenobiotic agents.
76
What is the structural organization of the liver lobule?
Hexagonal lobules oriented around a central vein with portal triads at the corners
## Footnote
Portal triads contain a portal venule, hepatic arteriole, and bile ducts.
77
What are the three regions of the liver lobule?
Periportal, centrilobular, midzonal
## Footnote
These regions correspond to the blood flow and exposure to oxygen.
78
Define the acinus concept in liver anatomy.
Reflects blood flow into sinusoids with three zones: zone 1, zone 2, zone 3
## Footnote
Zone 1 is closest to the portal triad, while zone 3 is nearest to the central vein.
79
What is the primary type of cell in the liver and its percentage composition?
Hepatic parenchymal cells (HPCs), about 60% of liver cells
## Footnote
HPCs perform most metabolic functions of the liver.
80
What is the role of sinusoidal endothelial cells (SECs)?
Facilitate exchange of fluids and molecules between the sinusoid and HPCs
## Footnote
SECs have fenestrae that allow small molecules to cross into the space of Disse.
81
What are Kupffer cells and their function?
Resident macrophages of the liver that ingest and degrade particulate matter
## Footnote
They also produce cytokines and can act as antigen-presenting cells.
82
What do hepatic stellate cells (HSCs) primarily store?
Vitamin A
## Footnote
HSCs can also control blood flow in the sinusoids and initiate liver fibrosis when activated.
83
How do HPCs begin the process of bile formation?
By active transport into the canalicular lumen of bile acids, GSH, and other osmotically active compounds
## Footnote
This transport drives the passive movement of water and electrolytes into bile.
84
What are the two major types of immune cells found in the liver?
Natural Killer (NK) cells and Natural Killer T (NKT) cells
## Footnote
Both cell types are involved in immune responses and can modify activities of other liver cells.
85
What happens to oxygen concentration as blood flows from zone 1 to zone 3 in the liver?
Oxygen concentration decreases
## Footnote
HPCs in zone 3 are exposed to lower oxygen levels due to high metabolic demands.
86
What are ATP-dependent efflux pumps in hepatocytes responsible for?
Transporting various anions across the basolateral membrane of HPCs
## Footnote
These pumps are part of the multidrug resistance-associated proteins (MRPs; ABCC) family.
87
What are the main types of transporters involved in bile secretion?
Exporters:
* BSEP
* MDR
* MRP
* ABCG5/8
* BCRP
* Ostα/Ostβ
Uptake Transporters:
* ASBT
* NTCP
* OATP
* OCT
* OAT
## Footnote
Exporters move solutes into the lumen of the canaliculus, while uptake transporters extract solutes from the blood.
88
What is fatty liver (steatosis)?
Increased lipid (mainly triglyceride) content of hepatocytes (HPCs)
## Footnote
It can occur due to insulin resistance or exposure to hepatotoxicants.
89
What are the characteristics of oncotic necrosis?
Cell swelling, leakage of cellular contents, nuclear disintegration, and influx of inflammatory cells
## Footnote
Associated with the release of intracellular enzymes such as ALT and AST.
90
What initiates the extrinsic pathway of apoptosis?
Binding of ligands (e.g., Fas ligand, TNF-α) to their respective death receptors
## Footnote
This triggers the formation of the death-inducing signaling complex (DISC).
91
What is the intrinsic pathway of apoptosis triggered by?
Cytotoxic stress or DNA damage
## Footnote
It activates the tumor suppressor p53, leading to the formation of proapoptotic Bcl-2 family members.
92
What is cholestasis characterized by?
Elevated serum concentrations of bile salts and bilirubin
## Footnote
Defined as a decrease in bile formation or impaired secretion of specific solutes into bile.
93
What are the molecular mechanisms contributing to cholestasis?
Increased hepatic uptake, decreased biliary excretion, increased biliary reabsorption (cholehepatic shunting)
## Footnote
For example, inhibition of BSEP can lead to bile acid accumulation.
94
What is the consequence of sinusoidal endothelial cell (SEC) damage?
Loss of barrier function and extensive blood accumulation in the liver parenchyma
## Footnote
This can lead to hemorrhage and is a feature of sinusoidal obstruction syndrome.
95
What activates the innate immune system during liver injury?
Injury-induced inflammatory response
## Footnote
Involves circulating blood cells and resident Kupffer cells.
96
What drugs are known to inhibit beta-oxidation and are associated with steatosis?
Examples include:
* Amiodarone
* Tamoxifen
* Doxycycline
* Tetracycline
* Pirprofen
## Footnote
These drugs can lead to increased lipid accumulation in the liver.
97
What are the main types of circulating blood cells involved in hepatotoxic responses?
Platelets, neutrophils, lymphocytes, monocytes
## Footnote
These cells contribute to the inflammatory response and hepatotoxicity.
98
What are DAMPs and their role in liver injury?
Damage-associated molecular patterns such as HMGB1
## Footnote
DAMPs stimulate toll-like receptors on inflammatory cells, triggering inflammation.
99
What critical role do neutrophils play in liver injury?
Removal of pathogens and cell debris
## Footnote
They also can cause additional tissue injury if directed against viable liver cells.
100
What triggers the proliferation of liver cells after hepatectomy?
Loss of hepatocyte progenitor cells (HPCs)
## Footnote
This leads to restoration of liver mass.
101
What characterizes hepatic fibrosis?
Accumulation of excessive fibrous tissue and collagen types I and III
## Footnote
It occurs in response to chronic liver injury.
102
What is the main cause of hepatic fibrosis in humans worldwide?
Viral hepatitis
## Footnote
Other causes include biliary obstruction and alcoholic/nonalcoholic steatohepatitis.
103
What happens to the liver architecture during fibrosis?
Formation of interconnecting fibrous scars and nodules
## Footnote
This alters the hepatic cytoarchitecture and limits liver function.
104
What are the three main ways to classify liver injury?
Morphology (histopathology), serum or plasma biomarkers (clinical chemistry), nature of the toxic response (intrinsic vs. idiosyncratic)
## Footnote
Each classification provides a different conceptual framework for understanding liver injury.
105
What type of liver necrosis is commonly caused by toxicants that are metabolized to more toxic metabolites?
Centrilobular necrosis
## Footnote
This occurs because enzymes that bioactivate many chemicals to toxic metabolites are concentrated in centrilobular regions.
106
What does increased serum alkaline phosphatase (ALP) activity indicate?
Hepatobiliary injury
## Footnote
ALP is not specific to liver injury, as it occurs in other organs.
107
Define 'Intrinsic' toxic responses.
Responses with a well-defined dose response relationship, producing injury in all individuals
## Footnote
These are also known as Type A responses or 'toxic hepatitis'.
108
What are 'Idiosyncratic' drug reactions?
Adverse responses occurring in a minority of patients at therapeutic doses, often with unclear dose relationships
## Footnote
These are also referred to as Type B reactions.
109
What initiates the pathogenesis of chemical-induced liver injury?
Molecular initiating events that trigger other events within and outside of HPCs
## Footnote
This leads to progression to HPC death and liver dysfunction.
110
What is the first step in liver injury caused by a chemical?
Entry of the chemical into HPCs
## Footnote
Lipophilic compounds can readily diffuse into HPCs.
111
What happens when the rate of toxic metabolite production exceeds detoxification capacity?
HPC injury can ensue
## Footnote
This occurs when the liver cannot handle the overload of toxic metabolites.
112
What is the primary pathway of ethanol metabolism in the liver?
Alcohol dehydrogenase (ADH) oxidizes ethanol to acetaldehyde
## Footnote
This pathway leads to the production of NADH.
113
What condition is characterized by hepatic lipid accumulation due to ethanol abuse?
Steatosis
## Footnote
This can progress to steatohepatitis with increasing inflammation.
114
What can long-term ethanol abuse lead to in the liver?
Replacement of functional liver mass with scar tissue
## Footnote
This results in impaired hepatic functions.
115
What is the primary pathway of ethanol metabolism in the liver?
Alcohol dehydrogenase (ADH) oxidizes ethanol to acetaldehyde, transferring electrons to NAD+ to produce NADH.
## Footnote
More than 90% of a dose of ethanol is metabolized in the liver.
116
What does acetaldehyde get oxidized to in ethanol metabolism?
Acetate in a NAD+-dependent reaction by acetaldehyde dehydrogenase (ALDH).
117
What role does CYP2E1 play in ethanol metabolism?
It is an alcohol-inducible enzyme involved in a second pathway of ethanol metabolism, dependent on NAD+ availability.
118
What is the consequence of ethanol metabolism by CYP2E1?
It produces intracellular oxidant stress that can induce mitochondrial dysfunction and cell death of hepatocytes.
119
What is hepatocellular steatosis?
A common feature of chronic alcohol consumption characterized by excessive fatty acid synthesis.
120
How does ethanol exposure affect triglyceride metabolism?
It inhibits the transfer of triglycerides from liver to adipose tissue and reduces VLDL release from hepatocytes.
121
What is the effect of acetaldehyde on VLDL?
It inhibits the incorporation of triglycerides into VLDL and reduces VLDL release from hepatocytes.
122
What is one of the key mediators in alcoholic liver disease?
TNF-α can promote cell death and is produced by activated Kupffer cells.
123
What are DAMPs and PAMPS in the context of liver injury?
DAMPs are damage-associated molecular patterns released from hepatocytes; PAMPS are pathogen-associated molecular patterns like LPS translocated from the intestine.
124
What is the role of acetaldehyde in liver injury?
It forms protein adducts and contributes to lipid peroxidation, promoting inflammatory liver injury.
125
What routes can lead to exposure to metals that cause liver injury?
Diet and inhalation of metal-containing particulates.
126
What is the role of biliary excretion in metal homeostasis?
It is crucial for maintaining levels of metals like copper, manganese, cadmium, and arsenic.
127
What are the three processes involved in the excretion of metals into bile?
1. Uptake across sinusoidal membranes of HPCs by membrane transporters or receptor-mediated endocytosis
2. Storage in binding proteins or lysosomes
3. Canalicular secretion via lysosomes, a GSH-coupled event, or by specific canalicular membrane transport via MRP2
128
Which metals are notably important in biliary excretion?
* Copper
* Manganese
* Cadmium
* Selenium
* Gold
* Silver
* Arsenic
129
What is a common outcome of acute iron toxicity in children?
Iron ingestion leading to hepatotoxicity
130
What is the Fenton reaction associated with?
The cytotoxicity of free iron and generation of highly reactive hydroxyl radicals
131
What are the determinants of individual susceptibility to hepatotoxicants?
* Xenobiotic metabolism
* Hepatobiliary transporters
* Protective enzymes
* Development and aging
* Sex
* Tissue reserve and regeneration
* Inflammatory stress
* Nutritional status
132
How does age affect susceptibility to hepatotoxicity?
Newborns have poorly expressed drug metabolizing enzymes; elderly individuals typically have reduced liver blood flow and differences in inflammatory responses
133
What is the role of sex in hepatotoxic responses?
Female sex is a risk factor for liver injury for several drugs and dietary supplements
134
What can cause chronic liver injury and fibrosis related to hepatobiliary transporters?
Genetic deficiency of certain hepatobiliary transporters
135
What type of liver injury is most commonly associated with antibiotics in Western countries?
Idiosyncratic drug-induced liver injury (IDILI)
136
What role do cytokines play in IDILI according to the inflammatory stress hypothesis?
They can activate cell death pathways and contribute to liver injury
137
What is the adaptive immunity hypothesis in relation to IDILI?
IDILI reactions are initiated when drugs are metabolized to reactive metabolites that bind covalently to proteins, leading to an immune response
