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2nd Shifting PHA6131 LEC > Toxic Responses of the Liver > Flashcards

Toxic Responses of the Liver Flashcards

1
Q

The ________ is the main organ where exogenous chemicals are metabolized and eventually excreted.

A

liver

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2
Q

T/F: The liver, with its multiple cell types and numerous functions, can respond in many different ways to acute and chronic insults.

A

True

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3
Q

The liver’s strategic location between ______________ and the rest of the body facilitates its maintenance of metabolic ______________ in the body.

A

intestinal tract; homeostasis

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4
Q

The liver extracts ingested nutrients, vitamins, metals, drugs, environmental toxicants, and waste products of bacteria from the blood for ____________, ___________, and/or excretion into ________.

A

catabolism; storage; bile

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5
Q

Formation of bile is essential for the uptake of ________ nutrients from the small intestine, protection of the small intestine from ___________ insults, and __________ of endogenous and xenobiotic compounds.

A

lipid; oxidative; excretion

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6
Q

_______________ is either a decrease in the volume of bile formed or an impaired secretion of specific solutes into bile

A

Cholestasis

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7
Q

Hepatocytes have a rich supply of _______________ and _______________ and thereby enhance their removal from the body.

A

phase I enzymes; phase II enzymes

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8
Q

T/F: phase II reactions determines whether a reactive metabolite will initiate liver cell injury or be safely detoxified.

A

False. The balance between phase I and phase II reactions determines whether a reactive metabolite will initiate liver cell injury or be safely detoxified.

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9
Q

These enzymes includes processes such as redox, and converting xenobiotics to electrophilic metabolites

A

phase I enzymes

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10
Q

These enzymes include conjugation, and glucuronidation that adds a polar group to a molecule, enhancing their removal from the body

A

phase II enzymes

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11
Q

It is a yellow pigment that also passes through the liver and excreted out from the body. Its high levels indicate liver or bile duct problems

A

Bilirubin

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12
Q

Cholestasis is a result of elevated serum levels of ____________ and ____________, which slows down the normal flow of the bile from the ______________. It causes itching, and jaundice

A

bile salts; bilirubin; gallbladder

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13
Q

T/F: The liver is the third organ, after the stomach, to encounter ingested nutrients, vitamins, metals, drugs, and environmental toxicants and waste products of bacteria that enter portal blood.

A

False. Liver is the first organ

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14
Q

T/F: The venous blood coming from the stomach and intestines also flows to the portal vein and to the liver, and eventually enter the systemic circulation

A

True

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15
Q

The loss of function of the liver also occurs if the toxicants kill a considerable amount of cells and when chronic insults lead to a replacement of cell mass by a non-functional ______________.

A

scar tissue

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16
Q

Bile contains bile acids, ______________, _____________, ______________, bilirubin, and other organic anions, proteins, ________, ions, and xenobiotics.

A

glutathione; phospholipids; cholesterol; metals

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17
Q

Hepatocytes begin the process by transporting bile acids, glutathione, and other solutes, including xenobiotics and their metabolites, into the ________________.

A

canalicular lumen

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18
Q

The canaliculi are separated from the ________________ between hepatocytes by ______________, which form a barrier permeable only to water, electrolytes, and to some degree to small ____________.

A

intercellular space; tight junctions; organic cations

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19
Q

This is the space formed by the specialized regions in the plasma membrane between the adjacent hepatocytes

A

canalicular lumen

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20
Q

This structure forms channels between the hepatocytes that connect to a series of larger channels or ducts within the liver

A

canaliculi

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21
Q

T/F: The major driving force of bile formation is the active transport of bile salts and other osmolytes into the major bile ducts.

A

False. The major driving force of bile formation is the active transport of bile salts and other osmolytes into the canalicular lumen.

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22
Q

Sodium-independent uptake of conjugated and unconjugated bile acids is performed by members of the ______________________________.

A

organic anion transporting polypeptides (OATPs)

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23
Q

T/F: Most conjugated bile acids like taurine and glycine conjugates are transported into hepatocytes by sodium-dependent transporters

A

True

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24
Q

T/F: OATPs also transport numerous drugs and hepatotoxicants.

A

True

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25
Q

Lipophilic cationic drugs, estrogens, and lipids are exported by the canalicular ____________________________, one of which is exclusive for _____________.

A

multiple drug resistance (MDR) P-glycoprotein; phospholipids

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26
Q

Conjugates of glutathione, glucuronide, and sulfate are exported by ________________________________.

A

multidrug resistance–associated protein 2 (MRP2)

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27
Q

Name every efflux transporter

A

BSEP, bile salt export pump; MDR, multidrug resistance protein; MRP, multidrug resistance-associated protein; ABCG5/8, heterodimeric ATP binding cassette transporter G5/G8; BCRP, breast cancer resistance protein; Ostα/Ostβ, heterodimeric organic solute transporter alpha, and beta.

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28
Q

Name every uptake transporter

A

ASBT, apical sodium dependent bile salt transporter; NTCP, sodium taurocholate transporting polypeptide; OATP, organic anion transporting polypeptide; OCT, organic cation transporter; OAT, organic anion transporter.

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29
Q

Biliary excretion is important in the homeostasis of metals, notably copper, _____________, ____________, _______________, gold, silver, and _______________.

A

manganese; cadmium; selenium; arsenic

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30
Q

Inability to export Cu into bile is a central problem in ___________________, a rare genetic disorder characterized by accumulation of Cu in the liver and then in other tissues.

A

Wilson’s disease

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31
Q

These are biliary epithelial cells that lines the bile duct tubules and serves to transport bile from the liver to the small intestines

A

cholangiocytes

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32
Q

T/F: Hepatocytes executes most metabolic functions including bile secretion

A

True

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33
Q

___________ modify bile by absorption and secretion of solutes

A

Bile ducts

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34
Q

T/F: Secretion into biliary ducts is always a prelude to toxicant clearance by excretion in feces or urine.

A

False. Secretion into biliary ducts is usually, but not always, a prelude to toxicant clearance by excretion in feces or urine.

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35
Q

Exceptions occur when compounds are repeatedly delivered into the intestinal lumen via bile, efficiently absorbed from the intestinal lumen, and then redirected to the liver via portal blood, a process known as __________________.

A

enterohepatic cycling

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36
Q

T/F: Toxicant-related impairments of bile formation are more likely to have detrimental consequences in populations with other conditions where biliary secretion is marginal.

A

True

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37
Q

This type of hepatobiliary injury is caused by representatives toxins like amiodarone, CCl4, ethanol, fialuridine, tamoxifen, and valproic acid

A

Fatty liver

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38
Q

This type of hepatobiliary injury is caused by representatives toxins like acetaminophen, allyl alcohol, Cu, dimethylformaldehyde, and ethanol

A

Hepatocyte death

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39
Q

This type of hepatobiliary injury is caused by representatives toxins like diclofenac, ethanol, halothane, and tienilic acid

A

Immune-mediated response

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40
Q

This type of hepatobiliary injury is caused by representatives toxins like chlorpromazine, cyclosporin A, 1,1-dichloroethane, estrogens, Mn, and phalloidin

A

Canalicular cholestasis

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41
Q

This type of hepatobiliary injury is caused by representatives toxins like alpha-naphthylisothiocyanate, amoxicillin, methylene dianiline, and sporidesmin

A

Bile duct damage

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42
Q

This type of hepatobiliary injury is caused by representatives toxins like anabolic steroids, cyclophosphamide, microcystin, and pyrrolizidine alkaloids

A

Sinusoidal disorders

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43
Q

This type of hepatobiliary injury is caused by representatives toxins like CCl4, ethanol, thioacetamide, vitamin A, and vinyl chloride

A

Fibrosis and cirrhosis

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44
Q

This type of hepatobiliary injury is caused by representatives toxins like aflatoxin, androgens, arsenic, thorium dioxide, and vinyl chloride

A

Tumors

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45
Q

What are the hepatobiliary injuries caused by ethanol?

A

Fatty liver, hepatocyte death, immune-mediated response, fibrosis and cirrhosis

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46
Q

What are the hepatobiliary injuries caused by CCl4?

A

Fatty liver, fibrosis and cirrhosis

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47
Q

What are the hepatobiliary injuries caused by vinyl chloride?

A

fibrosis and cirrhosis, and tumors

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48
Q

____________ is characterized by cell swelling, leakage, nuclear disintegration (karyolysis), and an influx of inflammatory cells.

A

Necrosis

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49
Q

T/F: Apoptosis is characterized by cell shrinkage, nuclear disintegration, formation of apoptotic bodies, and a lack of inflammation.

A

False. Apoptosis is characterized by cell shrinkage, nuclear FRAGMENTATION, formation of apoptotic bodies, and a lack of inflammation.

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50
Q

T/F: Apoptosis can be detected biochemically by assaying plasma (or serum) for liver cytosol-derived enzymes - AST or ALT or GGT

A

False. Necrosis can be detected biochemically by assaying plasma (or serum) for liver cytosol-derived enzymes - AST or ALT or GGT

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51
Q

T/F: Apoptosis is always a single-cell event, for the purpose of removing cells no longer needed during development or elimination of aging cells

A

True

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52
Q

It is the death of hepatocytes in certain functional regions.

A

Zonal necrosis

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53
Q

It is characterized by the randomly distributed death of single hepatocytes or small clusters of hepatocytes.

A

Focal cell death

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54
Q

It is a massive death of hepatocytes with only a few or no remaining survivors.

A

Panacinar necrosis

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55
Q

Mechanisms of toxicant-induced injury to liver cells include ________________, binding to cell _________________, _______________________, disruption of the cytoskeleton, and massive _______________.

A

lipid peroxidation; macromolecules; mitochondrial damage; calcium influx

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56
Q

The mechanisms of toxicant-induced injury leads to mitochondrial membrane permeability transition pore opens, causing __________ of the membrane potential, depletion of cellular ________, and necrotic cell death.

A

collapse; ATP

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57
Q

T/F: The loss of ATP inhibits the ion pumps in the plasma membrane results in the loss of cellular ion homeostasis and causes the characteristic swelling of necrosis, which would lead to cellular edema and destruction of the cell membrane

A

True

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58
Q

In canalicular cholestasis, when biliary excretion of the yellowish bilirubin pigment is impaired, this pigment accumulates in the skin and eyes, producing ____________, and spills into urine, which becomes ________________________.

A

jaundice; bright yellow or dark brown

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59
Q

T/F: Toxicant-induced cholestasis can be transient or chronic; when substantial, it is associated with cell swelling, cell death, and inflammation.

A

True

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60
Q

In canalicular cholestasis, ___________________ is vulnerable to toxicant effects on the functional integrity of sinusoidal transporters, canalicular exporters, cytoskeleton-dependent processes for transcytosis, and the contractile closure of the canalicular lumen.

A

bile formation

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61
Q

Changes that weaken the junctions that form the structural barrier between the blood and the canalicular lumen allow solutes to ____________ of the canalicular lumen.

A

leak out

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62
Q

One hepatotoxicant that causes tight junction leakage is ______________________.

A

α-naphthylisothiocyanate

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63
Q

What are the six potential mechanisms for cholestasis?

A

Impaired intake, diminished transcytosis, impaired secretion, diminished contractility of canaliculus, leaky paracellular junctions, and concentration of reactive species

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64
Q

What potential mechanism of cholestasis can result from inhibition of a transporter or retraction of a transporter away from the canalicular membrane

A

Impaired secretion

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65
Q

T/F: Compounds that produce cholestasis do not necessarily act by a single mechanism or at just one site.

A

True

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66
Q

________________ impairs bile acid uptake and canalicular contractility.

A

chlorpromazine

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67
Q

__________________ is a well-known cause of reversible canalicular cholestasis.

A

estrogens

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68
Q

__________________________ decrease bile salt uptake by effects at the sinusoidal membrane, including a decrease in the Na+,K+ATPase necessary for Na-dependent transport of bile salts across the plasma membrane and changes in the lipid component of this membrane.

A

Estrogens and progestins

69
Q

T/F: Most chemicals that cause canalicular cholestasis are excreted in bile where proteins and lipids in the canalicular region encounter a high concentration of these chemicals.

A

True

70
Q

Observations consistent with the concentration mechanism in the bile have been reported for ________, reactive thioether glutathione conjugates of _______________, and ____________.

A

Mn; 1,1-dichloroethylene; sporidesmin

71
Q

T/F: OATPs can contribute to the liver injury potential of toxicants.

A

True

72
Q

T/F: The hepatotoxicity of phalloidin, microcystin, and amanitin is facilitated by the efflux through OATPs.

A

False. The hepatotoxicity of phalloidin, microcystin, and amanitin is facilitated by the UPTAKE through OATPs.

73
Q

____________, ___________, and _____________, which are known to directly inhibit the bile salt export pump (BSEP).

A

Rifampicin; bosentan; troglitazone;

74
Q

_____________________ inhibit BSEP from the canalicular side after excretion by MRP2.

A

Estrogens and progestins

75
Q

A substantial inhibition of _________________ can lead to the accumulation of these compounds in hepatocytes and may directly cause cell injury.

A

bile salt excretion

76
Q

Bile acids are substrates for the __________________________________, downregulate NTCP and limit bile acid uptake.

A

nuclear farnesoid X receptor (FXR)

77
Q

_____________ causes increased expression of transporters on the canalicular and basolateral membranes, which all work to limit the amount of bile acid accumulation.

A

FXR Activation

78
Q

Damage to the intrahepatic bile ducts (which carry bile from the liver to the GI tract) is called ________________________________.

A

cholangiodestructive cholestasis

79
Q

A useful biochemical index of bile duct damage is a sharp elevation in ___________________________ activity.

A

serum alkaline phosphatase

80
Q

Bile duct injury may cause sloughing of the epithelial cells into the lumen, cell edema, and inflammation which may contribute to _____________

A

obstruction

81
Q

Initial lesions following a single dose of cholangiodestructive agents include
1. swollen _________________,
2. debris of damaged cells within _____________ of the biliary tract, and;
3. inflammatory cell infiltration of _____________

A

biliary epithelium
lumens
portal tracts

82
Q

A rare response is the loss of bile ducts, a condition known as ______________________.

A

vanishing bile duct syndrome

83
Q

Vanishing bile duct syndrome has been reported in patients receiving _____________, anabolic steroids, contraceptive steroids, or __________________.

A

antibiotics; carbamazepine

84
Q

It is a specialized capillary with numerous fenestrae for high permeability.

A

sinusoid

85
Q

Functional integrity of the sinusoid can be compromised by dilation or blockade of its lumen or by progressive destruction of its _____________________.

A

endothelial cell wall

86
Q

______________ will occur when red blood cells become caught in the sinusoids.

A

Blockade

87
Q

A consequence of extensive sinusoidal blockade is that the liver becomes engorged with blood cells, and the rest of the body goes into ____________.

A

shock

88
Q

It is a rare liver vascular injury disease characterized by damage to small, hepatic vessels affecting small sinusoidal epithelium that would result in complications such as intrahepatic congestion, liver damage, and portal hypertension

A

Sinusoidal Obstruction Syndrome (SOS)

89
Q

Disruptions of the sinusoid are considered the early structural features of the vascular disorder known as ____________________.

A

venoocclusive disease

90
Q

Venoocclusive disease occurs after exposure to ____________________

A

pyrrolizidine alkaloids

91
Q

This is a condition where some veins in the liver are blocked, and causes a decrease of blood flow inside the liver and may lead to liver damage.

A

Venoocclusive disease

92
Q

Venoocclusive disease is a clinical syndrome characterized by _____________, ____________, _____________, and jaundice due to sinusoidal congestion.

A

hepatomegaly; ascites; weight gain

93
Q

The most frequent cause of venoocclusive disease is _____________________________, and it is also seen after solid organ transplantation

A

hematopoietic stem cell transplantation

94
Q

_____________, and _____________ disrupt the integrity of the hepatocyte cytoskeleton by affecting proteins that are vital to its dynamic nature, preventing the disassembly of actin filaments.

A

Phalloidin and microcystin

95
Q

_____________ uptake into hepatocytes leads to an accentuated actin web of cytoskeleton, and the canalicular lumen dilates.

A

Phalloidin

96
Q

T/F: Phalloidin came from fungal sources, while microcystin is from blue-green algae

A

True

97
Q

_______________ uptake into hepatocytes leads to hyperphosphorylation of cytoskeletal proteins.

A

Microcystin

98
Q

_____________________ of cytoskeletal structural and motor proteins are critical to the dynamic integrity of the cytoskeleton.

A

Reversible phosphorylations

99
Q

_______________________________ produced by large amounts of microcystin leads to marked deformation of hepatocytes

A

Extensive hyperphosphorylation

100
Q

Lower doses of microcystin interfere with vesicle transport by hyperphosphorylating the transport protein, _____________.

A

dynein

101
Q

_____________, or steatosis, is defined as an appreciable increase in the hepatic lipid content, which is <5 wt% in the normal human liver.

A

Fatty liver

102
Q

__________________ due to central obesity and sedentary lifestyle.

A

Insulin resistance

103
Q

T/F: Insulin resistance is the most common cause of hepatic steatosis

A

True

104
Q

Acute exposure to hepatotoxicants like ___________________ and some drugs can induce steatosis.

A

carbon tetrachloride

105
Q

____________ is by far the most relevant drug or chemical leading to steatosis in humans and in experimental animals.

A

Ethanol

106
Q

T/F: Drug-induced steatosis is reversible and does not lead to the death of hepatocytes.

A

True

107
Q

The metabolic inhibitors _________,__________, and ___________ cause fat accumulation without causing cell death.

A

ethionine, puromycin, and cycloheximide

108
Q

Although steatosis alone may be benign, it can develop into __________________, which can be alcoholic or non-alcoholic, which is associated with significant liver injury.

A

steatohepatitis

109
Q

Livers with steatosis can be more susceptible to additional insults such as hepatotoxicants or _________________

A

hepatic ischemia

110
Q

The previously preferred hypothesis of nonalcoholic steatohepatitis (NASH) considered ______________________ in hepatocytes as the initial pathological event causing steatosis, with any additional stress (e.g., oxidant stress or lipid peroxidation) causing progression to steatohepatitis.

A

triglyceride accumulation

111
Q

T/F: Triglyceride accumulation with any additional stress has recently been overturned and a new hypothesis postulates that nonalcoholic fatty liver disease (NAFLD) is mainly caused by lipotoxicity of nontriglyceride fatty metabolites.

A

True

112
Q

________________ is the accumulation of extensive amounts of collagen fibers in response to direct injury or to inflammation.

A

hepatic fibrosis

113
Q

Hepatic fibrosis, with repeated chemical insults, destroyed hepatic cells are replaced by ______________.

A

fibrotic scars

114
Q

The primary cause of hepatic fibrosis/cirrhosis in humans worldwide is ______________.

A

viral hepatitis

115
Q

Fibrosis can be induced by chronic exposure to drugs and chemicals, especially ____________ and ___________

A

ethanol and heavy metals.

116
Q

T/F: Cirrhosis is reversible, but it has a poor prognosis for survival, and is usually the result of repeated exposure to chemical toxicants.

A

False. Not reversible

117
Q

The rare, highly malignant angiosarcomas are derived from _____________________.

A

sinusoidal lining cells

118
Q

Hepatocellular cancer has been linked to abuse of ____________, _____________, and a high prevalence of ____________-contaminated diets.

A

androgens; alcohol; aflatoxin

119
Q

_______________, or thorium dioxide, accumulates in Kupffer cells and emits radioactivity throughout its very extended half-life, thus increasing the risk of developing __________________ about 14-fold and over 100-fold for liver cancers.

A

Thorotrast; gallbladder cancer

120
Q

These are phagocytic cells that forms the lining of the sinusoids of the liver and is involved in the breakdown of red blood cells

A

Kupffer cells

121
Q

T/F: The membrane-rich liver concentrates hydrophilic compounds.

A

False. The membrane-rich liver concentrates lipophilic compounds.

122
Q

T/F: Other toxicants are rapidly extracted from blood because they are substrates for sinusoidal transporters.

A

True

123
Q

______________________ initially affects the sinusoidal stellate cells, which actively extract and store this vitamin.

A

Vitamin A hepatotoxicity

124
Q

______________________ becomes manifest when cells exceed their capacity to complex cadmium with the metal binding protein __________________

A

Cadmium hepatotoxicity; metallothionein

125
Q

T/F: Alcoholics are vulnerable to the hepatotoxic effects of acetaminophen at dosages within the high therapeutic range.

A

True

126
Q

The hepatotoxic effects of acetaminophen has widely been attributed to accelerated bioactivation of acetaminophen to the electrophilic ___________________________________ intermediate by ethanol induction of CYP2E1

A

N-acetyl-p-benzoquinone imine (NAPQI)

127
Q

T/F: Inhibitors of CYP3A, including many drugs and dietary chemicals, potentially influence acetaminophen toxicity.

A

False. Inducers of CYP3A

128
Q

T/F: In acetaminophen metabolism, large doses are enhanced by fasting and other conditions that deplete glutathione

A

True

129
Q

Antidote for acetaminophen toxicity

A

N-acetylcysteine (NAC)

130
Q

T/F: Morbidity and mortality associated with the consumption of alcohol is mainly caused by the toxic effects of ethanol on the liver.

A

True

131
Q

T/F: The targeted toxicity is due to the fact that <60% of a dose of ethanol is metabolized in the liver.

A

False. >90%

132
Q

T/F: The bioactivation of ethanol by alcohol dehydrogenase to acetaldehyde is the primary pathway of ethanol metabolism

A

True

133
Q

Both enzymes exhibit genetic polymorphisms that result in higher concentrations of acetaldehyde—a “________(fast/slow)” activity isozyme of alcohol dehydrogenase [ALD22] and a physiologically very “_________(fast/slow)” mitochondrial isozyme of aldehyde dehydrogenase [ALDH22].

A

Both enzymes exhibit genetic polymorphisms that result in higher concentrations of acetaldehyde—a “FAST” activity isozyme of alcohol dehydrogenase [ALD22] and a physiologically very “SLOW” mitochondrial isozyme of aldehyde dehydrogenase [ALDH22].

134
Q

T/F: Approximately 50% of the Asian population have slow aldehyde dehydrogenase, which explains why their alcohol consumption with this slow polymorphism leads to uncomfortable symptoms of flushing, and nausea due to high levels of acetaldehyde in the system

A

True

135
Q

The second major pathway involves the ____________________________, which __________ethanol to acetaldehyde.

A

alcohol-inducible enzyme CYP2E1; oxidizes

136
Q

The third pathway involves __________________. In this reaction, ethanol functions as an electron donor for the reduction of hydrogen peroxide to _________.

A

catalase in peroxisomes; water

137
Q

T/F: The capacity of alcohol-inducible enzyme CYP2E1 pathway is limited due to the low levels of hydrogen peroxide, where it is estimated that only less than 2% of the ethanol dose is metabolized through this pathway.

A

False. The catalase in peroxisomes pathway has the limited capacity.

138
Q

What ethanol metabolism pathway is located predominantly to hepatocytes of the centrilobular regions and requires oxygen and NADPH?

A

alcohol-inducible enzyme CYP2E1

139
Q

T/F: Due to the nature of alcohol inducible enzyme CYP2E1, its reaction is the most relevant for high doses of ethanol and chronic alcoholism

A

True

140
Q

_________________ is used as a model hepatotoxicant due to its preferential periportal (zone 1) hepatotoxicity.

A

Allyl alcohol

141
Q

Allyl alcohol is metabolized by alcohol dehydrogenase to _________, a highly reactive aldehyde, which is then further oxidized by aldehyde dehydrogenase to ________________.

A

acrolein; acrylic acid

142
Q

T/F: Acrolein formation is a critical event in liver injury.

A

True

143
Q

T/F: Age and gender differences in allyl alcohol hepatotoxicity can be explained by variations in the balance between alcohol dehydrogenase and aldehyde dehydrogenase expression.

A

True

144
Q

The preferential occurrence of allyl alcohol injury in zone 1 hepatocytes is caused by the predominant uptake of allyl alcohol in the _________________ and the __________ dependence of the toxicity.

A

periportal region; oxygen

145
Q

______________________ is caused by reductive stress where the excessive NADH formation leads to the mobilization of redox-active iron from storage proteins.

A

Lipid peroxidation

146
Q

T/F: Lipid peroxidation cannot become a relevant mechanism of cell injury because a compromised antioxidant status is not a contributing factor in its mechanism.

A

False. Lipid peroxidation can become a relevant mechanism of cell injury under conditions of compromised antioxidant status.

147
Q

_______________–dependent conversion of CCl4 to CCl3 and then to CCl3OO is the classic example of xenobiotic bioactivation to a free radical that initiates lipid peroxidation.

A

Cytochrome P450

148
Q

T/F: CCl3 involves CYP2E1.

A

True

149
Q

_________-induced lipid peroxidation increases the permeability of the plasma membrane to Ca2+, leading to severe disturbances of calcium homeostasis and _____________.

A

CCl4; necrotic cell death

150
Q

Recent research indicates that CCl4 also induces significant ________________________, which is dependent on lipid peroxidation events and on ____________ activity.

A

mitochondrial damage; CYP2E1

151
Q

The liver has a high capacity to restore lost tissue and function by ________________.

A

regeneration

152
Q

T/F: Loss of hepatocytes due to hepatectomy or cell injury triggers the proliferation of all immature liver cells.

A

False. Mature liver cells

153
Q

Tissue repair is _________________ up to a threshold, after which the injury is too severe and cell proliferation is inhibited.

A

dose–responsive

154
Q

The main reason for an inflammatory response is to remove ________ and __________ cells.

A

dead; damaged

155
Q

T/F: In an inflammatory response, under certain circumstances, these inflammatory cells can aggravate the existing injury by the release of directly cytotoxic mediators or by the formation of pro and anti-inflammatory mediators.

A

True

156
Q

What are the chemicals that induce immune-mediated injury mechanisms in the liver

A

halothane, tienilic acid, and dihydralazine

157
Q

A delay in the onset of the injury or the requirement for repeated exposure to the drug and the formation of antibodies against drug-modified hepatic proteins are characteristic features of _______________, but the mechanisms are not well understood.

A

immune reactions

158
Q

T/F: Two proposed mechanisms of canalicular cholestatic liver injury are the hapten hypothesis and the danger hypothesis

A

False. Two proposed mechanisms of immune-mediated liver injury are the hapten hypothesis and the danger hypothesis

159
Q

________________ promotes helper T-cell activation leading to T-cell responses to the antigen.

A

Hapten formation

160
Q

The danger hypothesis postulates that damaged cells release _____________, which induce the upregulation of a peripheral protein B7 on activated _____________________, which, when paired with ________ on T cells, generates a costimulatory signal.

A

danger signals; antigen-presenting cells (APCs); CD28

161
Q

T/F: In immune-mediated idiosyncratic hepatotoxicity, the absence of this costimulatory signal, the antigens derived from drug-modified proteins inhibits immune tolerance.

A

False. In the absence of this costimulatory signal, the antigens derived from drug-modified proteins INDUCE immune tolerance.

162
Q

__________________ drugs for the therapy of hepatitis B and AIDS infections cause mitochondrial DNA damage directly, when incorporation of the analog base leads to ___________ or early termination of polypeptides.

A

Nucleoside analog; miscoding

163
Q

The severe hepatic mitochondrial injury produced by the nucleoside analog ____________ is attributed to its higher affinity for the polymerase responsible for mitochondrial DNA synthesis than for the polymerases responsible for nuclear DNA synthesis.

A

fialuridine

164
Q

T/F: Mitochondrial DNA is also more vulnerable to miscoding (mutation) due to its limited capacity for repair.

A

True

165
Q

T/F: Alcohol abuse causes mitochondrial injury by miscoding or mutation

A

False. Alcohol abuse causes mitochondrial injury by shifting the bioactivation/detoxification balance for ethanol

166
Q

T/F: Idiosyncratic drug hepatotoxicity is a rare but potentially serious adverse event, which is dose-dependent.

A

False. Idiosyncratic drug hepatotoxicity is a rare but potentially serious adverse event, which is not clearly dose-dependent.

167
Q

T/F: Idiosyncratic toxicity is a leading cause of the failure of drugs in clinical testing, and it is the most frequent reason for posting warnings, restricting use, or even withdrawing the drug from the market.

A

True

168
Q

T/F: It is likely that gene defects is the only requirement to be present in an individual to trigger the severe liver injury.

A

False. It is likely that a combination of gene defects and adverse events need to be present simultaneously in an individual to trigger the severe liver injury.

169
Q

A detailed _________________ of patients with idiosyncratic responses to drug exposure may give additional insight.

A

genomic analysis

2nd Shifting PHA6131 LEC (6 decks)

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