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Tox 300 > Metabolism > Flashcards

Metabolism Flashcards

1
Q

What is biotransformation

A

The enzyme-catalyzed conversion of one xenobiotic into another

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2
Q

What is detoxification

A

biotransformation results in a LESS toxic metabolite

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3
Q

What is bioactivation

A

biotransformation results in a MORE toxic metabolite

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4
Q

Why is it essential for biotransformation (or metabolism) of xenobiotic to more water-soluable metabolites

A

To terminate their biological activity and eliminate them from the body

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5
Q

What do biotranformation enzymes convert lipophilic xenobiotic into

A

highly water-soluble metabolites that are easily excreted from the body (mainly in urine and to a lesser extent bile/feces)

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6
Q

Biotransformation reactions phase 1

A

biotransformation enzymes modify the xenobiotic molecule mainly by oxidation (eg. addition of an -OH [hydroxyl] group to the xenobiotic)
[Oxidation, Reduction, Hydrolysis, Hydration, Dehalogenation]

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7
Q

Phase 2

A

synthetic reactions that conjugate the xenobiotic with highly polar endogenous compound in the cell (eg. a carbohydrate, sulphate, or acetate)
[Sulphation, Glucuronidation (add glucose), Glutathione conjugation, acetylation, amino acid conjugation, methylation]

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8
Q

Which organ is the most important site of xenobiotic biotransformation?

A

The liver is the most important, Tissue localization of xenobiotic-metabolizing enzymes
Relative amount - Tissue
high - Liver
medium - Lung, kidney, intestine
Low - Skin, testes, placenta, adrenals
Very low - Nervous system

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9
Q

Cytochrome P450-dependent monooxygenases

A

CYPs; aka mixed-function oxidases - are the major Phase 1 oxidative enzymes

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10
Q

Reactions in phase 1 usually involve adding what

A

adding or exposing a polar functional group (eg. -OH, -COOH, -NH2) to lipophilic xenobiotic molecule

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11
Q

CYP enzymes that biotransform xenobiotics are located on what

A

smooth endoplasmic reticulum

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12
Q

what does monooxygenase indicate

A

that they catalyze the insertion of an oxygen atom into the xenobiotic molecule, ie the simple hydroxylation reaction:
xenobiotic (R-H) + O2 + NADPH -> Metabolite (R-OH) + H2O + NADP+

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13
Q

CYP’s are also involved in which two reactions

A

a wide variety of catabolic (degradation) and anabolic (synthesis) reactions - involving endogenous compounds ie steroid hormone

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14
Q

> 100 different CYP enzymes have been identified (designated in families such as…)

A

CYP1, CYP2, CYP3, subfamilies CYP1A, CYP2E, CYP3A and specific enzymes CYP1A2, CYP1E2, CYP3A4 based on the DNA sequence similarity of genes coding for enzymes

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15
Q

CYPs are very versatile and unique enzymes due to…

A

broad and overlapping substrate specificities:

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16
Q

Broad:
Overlapping:

A

Broad: one enzyme can biotransform many xenobiotic
Overlapping: One xenobiotic can be biotransformed by several enzymes

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17
Q

CYPs usually ______ (_____) a xenobiotic but in certain cases can ________ a xenobiotic to a more pharmacologically or toxicologically active metabolite

A

CYPs usually inactivate (detoxify) a xenobiotic but in certain cases can a xenobiotic to a more pharmacologically or toxicologically active metabolite

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18
Q

CYP Basic Hydroxylation Reaction

A

R-H + O2 + NADPH -> R- OH + NADPH + H2O

R-OH = Hydroxylated metabolite
H2O = Byproduct

Gets oxidized by single hydroxyl group

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19
Q

Add a hydroxyl group to:
RCH2CH3

A

OH
|
RCHCH3

19
Q

Many enzymes involved in steroidogenesis are CYPS

A

-Produces steroids/hormones
- regulate physiological things
-regulates water balance
- all have these genes, transcription, & expressions of these genes determine these physiological functions

20
Q

What is the hepatic portal venous system

A

delivers all substances absorbed from the GI tract to the liver before they reach the systemic circulation and be delivered to the rest of the body (to exert effects)

21
Q

What is the first pass effect

A

vertebrate animals evolved to detoxify to survive against ingesting lethal substances through plants
Can result in nearly complete inactivation (>90%) of certain drugs (and xenobiotics) after oral ingestion

22
Q

First pass effect; liver cycle

A

Drugs that are absorbed from the gut may be biotransformed by enzymes in the gut wall and liver before reaching the systemic circulation. This process lowers their degree of bioavailability, cycle of reabsorption

23
Q

Oral bioavailability

A

The fraction of an orally administered xenobiotic that reaches the systemic circulation in an unchanged form

bioavailability = AUC oral/ AUC IV

AUC = area under the curve

24
Q

The major increase in water solubility (and thus excretability) of xenobiotic occurs after which phase

A

after phase 2 reactions, which add (conjugate) a large water-soluble group to an existing polar functional group on the molecule

25
Q

Glucuronidation, what enzyme does it require
where is it located

A

The major phase 2 biotransformation pathway in mammals, requires enzyme UDP-glucuronosyl transferase (UGT) and co-factor UDP-glucuronic acid
located on smooth ER membrane

26
Q

Where is majority of phase 2 enzymes located

A

located in the cytoplasm, the glucuronidation is located in smooth ER membrane

27
Q

Sulfation

A

Enzyme sulfotransferase (ST) and cofactor PAPS

28
Q

Acetylation

A

Enzyme N-acetyltransferase (NAT) and cofactor actyl coenzyme A

29
Q

Phase 1 > ______>Phase 2

A

phase 1> hydroxylated group > phase 2

30
Q

GST

A

Glurathione S-Transferase = enzyme
abundant enzyme - approx 5% of cytosolic protein in liver cells

31
Q

GSH

A

Glutathione - cofactor
- detoxifies
- most potant antidonte

32
Q

review
Phase 1 - bioactivating or detoxification

A

oxidation, reduction, hydrolysis, hydroxylation

33
Q

Review phase 2 - bioactivation or detoxification

A

conjuation

34
Q

Biotransformation: which of the following 6 pathways are good or bad

A
35
Q

Foreign compound - Stable metabolite - Excretion

A

constant GOOD effects

36
Q

Foreign compound - Toxic/reactive metabolite - metabolism/reaction with protective agents - stable metabolite - excretion

A

bad to toxic reaction
good to stable metabolite

37
Q

Foreign compound - Toxic/reactive metabolite - Reaction with critical targets - Toxic effect (A)

A

constant bad effects

38
Q

Foreign compound - stable metabolite - toxic effect (A)

A

Good effect to stable metabolite
Bad effect to toxic effect

39
Q

Foreign compound - stable metabolite - Excretion

A

Constant good

40
Q

Foreign compound - toxic effect

A

constant bad

41
Q

Genetic and environmental factors influencing biotranformation

A

enzyme induction and inhibition
- CYP enzymes and phase 2 enzymes can all be induced and inhibited

42
Q

What is induced
what in inhibited

A

induced - increased activity
inhibition - decreased activity

43
Q

Infraspecific differences

A

genetic differences - different forms in the expression of enzymes
can result in a subset of the population being “poor metabolizers” or “rapid metabolizers”

44
Q

ADH in humans

A

Alcohol dehydrogenase (ADH)

45
Q

influences of biotransformation

A
  1. enzyme induction and inhibition
  2. intraspecific differences
  3. interspecific differences
  4. sex and age
  5. Diet (nutritional factors)
  6. Disease (underlying pathology)
46
Q
A

Tox 300 (15 decks)

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