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Y Biochem III > WK09L1 - Biotransformation I (Ben) > Flashcards

WK09L1 - Biotransformation I (Ben) Flashcards

1
Q

What are the 3 phases involved in biotransformation?

A
  1. Oxidation (actually oxygenation, via CYP450s)
  2. Conjugation (addition of some molecule, after which molecule can leave the cell)
  3. Transport - mediated by transporters
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2
Q

Generally, what is the activity of a xeno-/endobiotic molecule after phase I of biotransformation?

(compared to its activity prior to biotransformation)

A

The molecule is generally inactive or less active, however…

… it is often more reactive due to the addition of oxygen.

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3
Q

In what 2 ways can products of phase I of biotransformation be dangerous?

A

Oxygenated molecules can connect to proteins/nucleic acids forming so-called adducts which can be the basis for chemical carcinogenesis.

Also, when 2nd O of the O2 used in oxygenation is not fully reduced to water, it can lead to ROS formation.

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4
Q

In general what type of enzymes usually perform phase I of biotransformation?

And what kind of co-factors are involved?

A

Mixed function oxidases (usually CYP450s)

using O2 and NADPH

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5
Q

How is biotransformation regulated generally?

A

At the level of gene transcription

- Biotransformation enzymes are connected to various transcription factors and the compounds they produce may also have receptors which regulate their metabolism (or even have other biological effects).

(not even sure what this means honestly, but he said it…)

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6
Q

Although the products of biotransformation reactions are often inactive, what kind of activity can they sometimes have?

A

Products of all phases of biotransformation can have receptor effects.

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7
Q

What is the general function of phase I of biotransformation?

A

Formation of functional groups on the original molecule in order to increase its polarity, thereby increasing water solubility and excretability.

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8
Q

What 4 general types of reactions occur in phase I of biotransformation?

A
  1. Oxidation
  2. Reduction
  3. Hydrolysis
  4. Hydratation
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9
Q

What are the components of the CYP450 system?

Where is it found and generally what is it?

A

CYP450 systems are electron transport chains in the ER membrane.

(AKA microsomal respiration b/c resembles ETC on mitochondrial membrane)

  • Components:
    • Flavoprotein: NADPH-P450 Oxidoreductase
    • Lipids: Phosphatidylcholine
    • Hemoprotein: Cytochrome b5 / CYP450
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10
Q

What is the reductase-to-p450 ratio range?

A

1:10 - 1:100

(also no idea what this means but it’s on the slide)

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11
Q

What element is required for the binding of oxygen in CYP450 reactions?

What form of this element and how is it converted to this form?

A

Iron is needed (CYP450 is a hemoprotein)

  • needs to be in ferro form
  • ferri –> ferro conversion occurs via donation of an electron by NADPH
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12
Q

How can NADPH be oxidized in CYP450 systems?

A

By the flavoprotein NADPH-CYP450 oxidoreductase

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13
Q

How does flavoprotein electron donation take place in the case of CYP450 systems?

A

In two steps…

  1. Ferri-ferro conversion - 1st e- is donated to iron to convert it to ferro form (allowing it to now bind oxygen)
  2. Superoxide formation - 2nd e- forms superoxide anion

(didn’t totally get this either, his explanation was more complicated but this seemed to be the essence of it… also this slide is missing from the .PDF)

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14
Q

What is another possible oxygen donor in CYP450 rxns?

A

Peroxide in the lipid membrane.

(not sure if he meant other possible electron donor here… said O donor)

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15
Q

How many CYP families are important in drug metabolism?

And where are they expressed?

A

4 families: CYP1-4

  • expressed mainly in liver but also in areas in contact with environment (skin, GI, lungs, kidneys)
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16
Q

How do the flavoproteins and CYP450 enzymes vary in different CYP450 systems?

A

Flavoprotein is always the same.

CYP450 has many isozymes which perform different functions.

17
Q

Which CYP enzyme is present in the largest amounts in the human liver?

What are some of its substrates, inhibitors and inducers?

(don’t think we really need to know this… esp. the sub/inhib/ind part… it’s in a couple slides that he just clicked past during lecture)

A
  • *CYP3A4**
    approx. 30% of CYP enzyme load in liver
  • Substrates: cyclosporin, erythromycin, midazolam, nifedipine
  • Inhibitors: ketoconazole, gestodene
  • Inducers: barbiturates, rifampicin, dexamethason, carbamazepine
18
Q

What are some substrates of the CYP1 family of P450 enzymes?

A
  • Polycyclic Aromatic Hydrocarbons: benzpyrene, benzanthracene, etc.
    • (organic pollutants from petroleum products + burnt food)
  • Theophylline
  • Caffeine
  • Phenacetin (metab. into acetaminophen)
19
Q

What are some inducers of the CYP1 family of P450 enzymes?

And what is unique about the inducibility of CYP1 as compared to that of other CYP families?

A
  • Methylcholanthrene (highly carcinogenic PAH)
  • Dioxins + Dioxin derivatives
    • industrial byproducts / pollutants
  • Cigarette smoke
  • CYP1 is inducible up to 100x … most are only induced to 3-4x their normal levels.
20
Q

What pathology is commonly seen in people with high inducibility of CYP1 family enzymes?

And what does this observation likely mean?

A

There is a high co-incidence of bronchial carcinoma in people with highly inducible CYP1 enzymes.

This means inducibility is likely genetic.

21
Q

What molecule is important in regulating the induction of CYP1 family enzymes?

What enzyme genes are found on the “gene battery” of this molecule?

And what does this mean about inducibility and the phases of biotransformation?

(He used this term without explaining it. Basically seems to mean the total collection of genes affected by a certain regulatory mechanism.)

A

Aryl Hydrocarbon Receptor (AHR)

  • an intracellular receptor/transcription factor for which the enodogenous ligand is unknown
  • its “gene battery” contains 2 CYP450 enzymes and 2 conjugation enzymes (UDP-glucuronyl transferase + glutathione transferase)
  • this shows the controlled sequencing of biotransformation phases via the coordinated induction of all enzymes needed
22
Q

What does the acronym TEXB mean?

What potentially pathological mechanism does TEXB play a role in?

A

Total Effective Xenogenic Burden

  • amount of accumulated xenobiotic molecules in the body
  • can have endocrine disrupting effects because some xenobiotics can activate hormone receptors
23
Q

What important CYP1 inducer was found in high levels in patients during the Vietnam war?

(prob not important but was a specific example of an inducer he mentioned)

A

TCDD

  • 2,3,7,8-Tetrachlorodibenzodioxin
  • was a contaminant in agent orange
24
Q

What are the inducers of CYP2 family enzymes?

2 are also substrates, which?

(not entirely sure about those 2… he seemed to be saying they were substrates, but was unclear)

A
  • Phenobarbital
  • Ethanol (substrate!)
  • Acetone (substrate!)
  • Diazepam derivatives
25
Q

What is the molecule responsible for regulation/induction of CYP2 family enzymes?

A

CAR (constitutive androstane receptor)

  • another intracellular receptor
26
Q

What are some CYP2A substrates?

(2)

A

Steroids

Tesosterone

27
Q

What are some CYP2B substrates?

(3)

A

Progesterone

Vitamin D3

Anti-epileptics

28
Q

What are some CYP2C substrates?

(2)

A

Mephenytoin

Anti-epileptics

29
Q

What are some CYP2D substrates?

(3)

A

Anti-depressants

Beta blockers

Antihypertensives (Debrisoquine)

30
Q

The importance of what CYP450-related phenomenon was discovered via issues with drug metabolism using CYP2 family enzymes?

A

Poor Metabolizers + Extensive Metabolizers

  • drugs must reach certain levels in the plasma in order to be effective
  • some people have significantly higher or lower rates of metabolism of drugs via P450 enzymes
  • this can make dosing difficult in the so called “poor” and “extensive” metabolizer patients
31
Q

Inducibility of CYP2 family enzymes is connected with what pathologies?

Why might this be?

A

GI and bronchial carcinomas

  • oxygenated (post-phase I) biotransformation intermediates can often be carcinogenic
  • if these enzymes are highly induced in someone, they may create large amounts of these carcinogenic intermediates
32
Q

What are some substrates of CYP2E?

A

Ethanol

Acetone

33
Q

What are some substrates of CYP3 family enzymes?

(3)

A

Antibiotics

nifedipin

cyclosporin

34
Q

What are some inducers of CYP3 family enzymes?

A

Steroids:

Oral contraceptives

Pregnenolone Carbonitirl (PCN)

35
Q

What is an inducer of CYP4 family enzymes?

A

Clofibrate

  • an antihyperlipidemic
36
Q

What are some substrates of CYP4 family enzymes?

A

Fatty acids

eicosanoids

37
Q

What is the receptor important in induction of CYP4 family enzymes?

A

PPAR

  • peroxisome proliferator-activated enzyme
38
Q

Describe the activation and intracellular action of the receptor responsible for CYP1A1 induction.

A
  • PAHs or HPAHs (H=halogenated) bind to the AHR (aryl hydrocarbon receptor)
  • HSP90 (heat-shock protein) acts as chaperone protein of AHR, stabilizes it
  • ARNT (AHR nuclear transport protein) forms heterodimer complex with AHR + this complex binds to DREs (digoxin response elements) on DNA

Y Biochem III (34 decks)

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