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Medical Biochemistry and Pathophysiology > Week 7C: Drug metabolism and detoxification, Glucuronyltransferases, Treatment Concepts Liver Disease > Flashcards

Week 7C: Drug metabolism and detoxification, Glucuronyltransferases, Treatment Concepts Liver Disease Flashcards

HC 43, 44, 45

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USMLE® Step 1 flashcards
1
Q

HC43: Why evolution of detoxification pathways

A

Clearance of toxic or beneficial plant metabolites
> plants have large variety of secondary metabolites which can be useful or toxic

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2
Q

Nagoya protocol for drug discovery from plants

A

Part of profit back to people who live near resources to maintain it

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3
Q

Cabbages contain metabolites like…

A

-Glucosinolates: can be converted to cyanates which are toxic
-Also: indoles, which activate AHR nuclear receptors, involved in inflammation gene programs

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4
Q

Toxic compounds of plants are poisonous dependent on the …

A

Dose

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5
Q

Detoxification deals with endogenous compounds as well, like…

A

Hormones

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6
Q

Detoxification molecule types

A

-Xenobiotics: in food or drugs etc
-Endogenous compunds like hormones and heme

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7
Q

Excretion mechanisms

A

-Feces via liver or stomach
-Urine via kidney

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8
Q

Detoxification phases

A

-Absorption and distribution
-Oxidation reactions by CYP enzymes and ADH for example (can be skipped) > introduction reactive groups
-Conjugation reaction by sulfotransferases or UDP-glucuronosyltransferase (can be skipped) > make more hydrophilic with sugar groups
-Excretion

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9
Q

Principal site drug biotransformation and other sites

A

Main: Liver
Other: gut, lungs, skin, kidneys

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10
Q

First passage contents from GI tract in blood

A

Liver via portal vein

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11
Q

Portal triad and flows in liver lobule

A

Portal triad: portal vein, bile duct, arteria hepatica
Blood flow: Portal vein / arteria hepatica > sinusoids > central vein
Bile flow: bile canaliculli > bile duct (reverse flow)

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12
Q

Phases drug metabolism

A

Phase I metabolism: oxidation (in intestine, kidney, liver)
(Phase 0 elimination: direct elimination)
Phase II metabolism: conjugation: add hydrophilic group
(Phase III) Elimination because increased water solubility (in intestine, kidney, liver)

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13
Q

Phase I metabolism: oxidation, by which enzymes

A

CYP isoforms

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14
Q

Why do similar doses have different effects in humans>

A

Polymorphisms in enzymes like CYP enzymes: higher or lower activity/expression

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15
Q

Acetaminophen (paracetamol) detoxification

A

Normally: acetaminophen (nontoxic) is conjugated to a sulfate group or glucuronide group. (nontoxic)
> when overdose, a part is oxidized by CYP2E1 to NAPQI (a reactive, toxic intermediate)
> Glutathione (reduced) used to neutralize NAPQI
> deprivation glutathione, ROS less neutralized > oxidative stress

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16
Q

NAPQI toxic effects

A

Protein adducts, oxidative stress

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17
Q

Acetaminophen toxicity is main cause liver failure. Which antidote can prevent the toxicity?

A

Addition N-acetyl cysteine to acetaminophen tablets
> N-acetyl cysteine as antidote

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18
Q

Glutathione ROS neutralization

A

2 GSH (reduced) + H2O2 > GSSG + 2 H2O (glutathione peroxidase)
> regeneration by NADPH
> glutathione depletion is toxic!

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19
Q

High concentration drug metabolites in bile (canaliculus) compared to plasma, what does this mean? Why can it vary between individuals?

A

Pumping molecules against concentration gradient > costs ATP
> ABC transporters
> a lot of ABC transporters have polymorphisms, different rates of detoxification.

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20
Q

When can diet give problems to ABC transporters in drug metabolism?

A

If they contain substrates for the transporter which occupy it.

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21
Q

Abcg2 -/- mice have burned ears, when?

A

Diet with chlorophyll (plants) > fermentation product made which is toxic

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22
Q

Why do people with dry ear wax have better body smell? ABCC11 pathway

A

ABCC11 transports SG-3MSH into cell in skin
> conjugated and excreted > cleaved by bacteria in skin > 3-MSH release which smells bad
> Dry ear wax: defect ABCC11

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23
Q

Regulation drug metabolism through nuclear receptors: Name four of these with their dimerization partner and ligand

A

All bind with RXR on DNA
-LXR binds oxysterols
-FXR binds bile salts
-PXR binds xenobiotics
-CAR binds xenobiotics

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24
Q

Activation PXR

A

PXR binds xenobiotic PXR ligand in cytosol
> to nucleus and dimerization with RXR
> Bind response element
> upregulate CYP3A isoforms

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25
Q

Role AHR in drug metabolism

A

Nuclear receptor
> regulates CYP1A1 and involved in programs for excretion drugs (of its ligand)
> present in immune cells and intestinal cells
-regulate barrier function (think defect in IBD or barrier for leakage bacterial contents in gut)
> activation by dietary and microbial compounds positively affects barrier function

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26
Q

Drug interactions: Why does St. Johns Wort with Ciclosporin lead to acute heart transplant rejection

A

-Transplant patients treated with immunosuppressive drug cyclosporine
> metabolized by CYP3A4 and transported by MDR1 Pgp (ABCB1) (Regulation via PXR)
> Hypericin, active compound in St Johns Wort activates PXR
> PXR controls expression of CYP3A4 and MDR1
> MDR1 rejects enterohepatic cycling by pumping from portal vein back into intestine and from liver to bile canaliculli
> lower cyclosporin in blood, metabolism increased by St. Johns Wort > rejection transplant

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27
Q

Grapefruit Juice drug interactions (GFJ)

A

GFJ inhibits CYP3A4 activity in enterocytes
> overdose of the drug when taking GFJ
> no metabolism of drug in enterocytes > too much of the drug, the hepatocytes cannot metabolize everything on their own

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28
Q

Amazonian psychedelic brew ayahuasca

A

Contains psychedelic compound DMT and an inhibitor of its metabolism: inhibitor of MAO (monoamine oxidase) (mixture two plants with each one)
> In serotonin neurons: serotonin receptor agonist (MAO degrades serotonin) > more release
> Hermaline inhibits MAO’s so that DMT is not metabolized
> higher levels DMT (agonist serotonin receptor)

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29
Q

HC44: Marker of liver damage

A

ALT: alanine aminotransferase
> normally not in blood

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30
Q

Tara flour, found in now banned vegan foods contained baikiain which is ..

A

a direct hepatotoxin

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31
Q

Causes unexpected drug toxicity

A

-Polymorphisms in drug metabolizing enzymes or drug-drug interactions

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32
Q

Functions of CYP2E1

A

Metabolism of ethanol and acetamoniphen
-Ethanol
> Ethanol to acetoaldehyde (then to acetate with two oxidation reactions creating NAD+, this first conversion can also be done by ADH)
-Acetaminophen
> to toxic NAPQI when high dose

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33
Q

Effect acute ethanol consumption after overdose acetaminophen

A

Beneficial
> compete for CYP2E1 activity, less toxic NAPQI made

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34
Q

Chronic alcohol consumption and acetaminophen cause problems. Why?

A

Chronic alcohol consumption upregulates the expression of CYP2E1 to deal with the ethanol.
> More conversion acetaminophen to toxic NAPQI

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35
Q

Alcohol flush response

A

Defect in the ALDH enzyme (aldehyde dehydrogenase) for conversion acetaldehyde (from ethanol metabolism) to acetate.
> accumulation acetaldehyde: toxic
> leads to crosslinking of DNA: possibly defects in birth.

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36
Q

Function UDP-glucuronyltransferases (UGTs)

A

Catalyze the conjugation of a wide variety of substrates with glucuronic acid
> UDP-glucuronic acid is the sugar donor
> glucuronidation of substrates renders them more water-soluble > facilitate excretion

37
Q

Effects glucuronidation

A

More water-soluble and less bio-active drugs
> in most drugs performed

38
Q

UGTs and odorant signal termination

A

Conjugate substances which interact with olfactory receptors
> also, the epithelial layer of the nose contains UGTs which conjugates the compounds to be excreted and removed

39
Q

UGTs conjugate drugs and odorants. But what elso?

A

-Inactivate steroid hormones
-Inactivate bilirubin

40
Q

UGT polymorphisms in testosterone doping

A

-Ratio testosterone to epitestosterone is measured (T/E ratio: if too high: doping)
> urine samples
> usually around 1:1
-Polymorphism in UGT2B17: deletion, T/E ratio does not increase after testosterone doping.

41
Q

UGT reaction

A

Substrate + UDPGA > Subtrate-glucuronide + UDP

42
Q

Some drugs can become active after conjugation, like …

A

Morphine

43
Q

Heme detoxification to bilirubin

A

Senescent erythrocytes taken up by macrophages
> release hemoglobin > to heme
> Heme + O2 + NADPH > Biliverdin (green) + ferric iron Fe3+ + CO (heme oxygenase)
> Biliverdin > bilirubin (yellow) (BVR, biliverdin reductase)

44
Q

In heme degradation, iron is salvaged and the rest is …

A

excreted
Heme: part hemoglobin and CYP enzymes

45
Q

Heme oxidation to biliverdin generates CO, this is toxic. But other function?

A

Regulator of many physiologic processes

46
Q

Bilirubin transport in plasma

A

Bund to albumin

47
Q

Which compound of heme metabolism may play a role in detoxification?

A

Bilirubin

48
Q

Glucuronidation of bilirubin

A

In liver by UGT1A1 (ER)
> BR > BMG and BDG (conjugated)
> first: BR from cytosol to ER.
> conjugated bilirubin

49
Q

Bilirubin accumulation causes…

A

Jaundice, yellowish skin

50
Q

Bilirubin metabolism in colon

A

Metabolism to urobilinogens > this makes feces brown

51
Q

What happens with feces of patients with severe bile flow obstruction (cholestasis)

A

White feces

52
Q

Crigler-Najjar disease

A

Partial or complete absence of bilirubin UGT > unconjugated hyperbilirubinemia, severe toxicity and jaundice

53
Q

Gilbert syndrome, and the danger of chemotherapy

A

Polymorphisms in bilirubin UGT promotor reduce expression > neonatal jaundice and possible high toxicity of chemotherapeutic irinothecan
> that is normally conjugated by the BR UGT
> irinotecan converted to SN-38 which is glucuronidated and detoxified
> deficient: SN-38 metabolized to neurotoxic compounds

54
Q

Polymorphism in Gilbert syndrome

A

The TATA box in bilirubin UGT promotor has 6 or 7 TAs. > 7 TA variant has lower activity

55
Q

Combination 7TA BR UGT with deficiency glucose 6 phosphate dehydrogenase (G6PD).

A

G6PD (PPP committed enzyme!, make NADPH, for glutathione and reducing oxidative stress) > high erythrocyte turnover
> more heme to metabolize
> life threatening high serum bilirubin at birth

56
Q

Which form of bilirubin is neurotoxic?

A

Unconjugated

57
Q

Crigler-Najjar problem onset

A

Deficient UGT1A1
> problems directly after birth
> phototherapy as only cure

58
Q

Gunn rat model

A

Defect UGT1A1 activity: Crigler-Najjar model > jaundice

59
Q

Gunn rats become infertile after diet with …

A

soy
> contains phytoestrogens, resemble and act like estrogen
> insufficient glucuronidation > infertility

60
Q

HC45: Liver disease symtoms

A

Fatigue, itch, jaundice, pain, fever, infection, anxiety, higher risk for cancer

61
Q

Types of liver diseases

A
  • Lifestyle related: alcohol, MASLD
  • Infection related: viral hepatitis
  • Drug related: acetaminophen, herbal supplements, mushrooms
  • Autoimmuity related: AIH (auto-immune hepatitis), PSC (primary sclerosing cholangitis, scar formation), PBC
  • Inherited/inborn: structural and functional defects
62
Q

Problems when liver disease

A
  • Acute liver failure
  • Cirrhosis
  • Cancer
63
Q

Types of medication for liver disease

A

-Drug concepts
-Symptomatic relief

64
Q

Types of treatment liver disease

A
  • Lifestyle modifications
  • Preventive measures: vaccination (HebA/HebB), screenings (liver function tests)
  • Medications
  • Surgery and procedures: transplantation, resection etc
  • Lifestyle support
65
Q

Drug categories

A
  • Chemicals
  • Derived from living organisms: biologics
  • Mixtures: Plant/animal mixtures
66
Q

Viral hepatitis

A

-Lifestyle related for western world
-HBV, HCV, HDV, HEV
> HEV in meat, problem when immunocompromised

67
Q

Acute liver failure

A

-Varices bleeding due to hypertension
-Ascites: belly with fluids due to hypertension
-Hepatic encephalopathy: process that brain does not work well anymore due to hyperammonia
-Kidney dysfunction: toxic substances accumulate since liver does not detoxify.

68
Q

Drugs that cure

A

Cause total elimination of the disease
> on infection area
> antibiotics
> chemotherapy
> antiviral HCV drugs which eliminate virus entirely
> organ/cell transplantation (does require immunosuppressive drugs as well)
> boosting own immune system

69
Q

HCV treatment

A

Harvoni: combination tablet ledipasvir and sofosbuvir.
> inhibit the nucleotide polymerase
» for certain genotypes of HBC

70
Q

HBV treatment

A

No treatment
> HBV docks to transporter
> research working on inhibiting docking receptor > mix different targets

71
Q

Types of monoclonal antibodies (biologicals)

A

-Omab: mouse antibody
-Zumab: only the hypervariable region is non-human
-Umab: fully human
> mAbs become cheaper once off patent

72
Q

Biosimilars

A

Similar function as the original drug (like mAb) but made by competitor company , same function, but cheaper

73
Q

aCD20 mAb

A

Eliminate B-cells in autoimmunity

74
Q

mAbs in liver disease

A

Efficient against liver tumors, not for liver damage

75
Q

Gene therapy for liver disease: two types for two problems

A

-Defect in each hepatocyte > gene therapy for all cells
-Secreted protein lacks: transduce smaller amounts of hepatocytes until enough secretion to be functional > or enzymatic conversions for bilirubin detoxification for example

76
Q

AAV mediated gene therapy pros and cons

A

Advantages
> Low immunogenecity
> High transduction efficiency
> Tropism: certain favourite cell type: hepatocyte
> Non-integrating
Disadvantages
> Tropism
> Non-integrating: you can lose it
> Packaging size: cannot fit very large genes
> Neutralizing antibodies

77
Q

Why can gene therapy only be done once?

A

Second dose: recognized and neutralized by own immune response

78
Q

Gene editing types

A

DNA or RNA editing

79
Q

DNA editing

A

CRISPR-Cas9
> to prevent disease
> for example bile salt transporter NTCP where HBV docks > edit NTCP

80
Q

CCR5 gene editing

A

Prevent HIV infection because mutation in CCR5 gene prevents it

81
Q

Risk CCR5 variants (homozygous CCR5 delta 32)

A

Higher risk dying when infected with West Nile Virus

82
Q

Non heritable gene editing types

A

RNA editing
> mRNA
> Antisense RNA
> RNAi
> Aptamers
> Adenosine deaminases acting on RNA (ADARs)

83
Q

RNA vaccine

A

Package RNA to get it into cells
> mRNA in LNPs in liver disease (nanoparticles)
> dampen fibrosis in repeated damage models or stimulate regeneration after acetaminophen intoxication for example

84
Q

LNP components

A

Coat to target the right cell (monolayer phospholipids)
> hepatcyte, stellate cell, Kupffer cell, sinuoidal endothelial cell
> seperate receptors

85
Q

ADAR

A

RNA deaminases to target the mRNA
> change the A (adenosine) to I
> I is recognized as G (guanine) by ribosomes
> G>A mutation account for most single nucleotide variants (SNVs, 28%)
> make protein inactive like CCR5 or NTCP

86
Q

Liver surgery

A

-Resection and ablation
-Cystectomy
-Bypassing
-Transjugular intrahepatic portosystemic shunt (TIPS)
> bypass a plot
> branch of portal vein and hepatic vein connected
> hypertension resolved, no ascites (swelled belly)
-Transplantation

87
Q

Transplantation liver: integrated perfusion machine

A

-Keeps transplant liver in healthy state
> surgery can be done next day
> better preparation of recipient and surgeons
> liver uses lots of oxygen: highly oxygenated
> shock with temperature and oxygen while on the pump
> livers not suitable for transplantation may seem suitable afterwards
> liver is outside body: factors to stimulate regeneration in body of the liver to make full liver out of liver transplants is researched

88
Q

Symptom relieve for liver disease

A

Itch, anxiety, fever

89
Q

Drug: plant/food mixtures

A

Can contain metabolites which include toxins which need to be detoxified
> batch-to-batch variation: hard to study efficacy
> possible toxicity
> easy administration

Medical Biochemistry and Pathophysiology (16 decks)

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