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3rd Year > Toxicology Exam 2 > Flashcards

Toxicology Exam 2 Flashcards

1
Q

What are three factors that determine rate of disposition?

A

Blood flow
Affinity for target tissue
Transport from organ capillary beds into organ interstitial fluid

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2
Q

Major sites of sequestration

A

Plasma proteins
Body fat
Bone
Keratinized tissue/hair

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3
Q

Sequestration - Role of chemical nature of xenobiotics

A

lipophilic chemicals - albumin bind more

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4
Q

What is KD and why is it important?

A

Affinity constant for a given xenobiotic and its target (e.g., receptor)

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5
Q

Blood Brain Barrier

A

Helps maintain stable environment for brain
Separates neurons from some blood borne substances
The BBB is a serious limitation on efficacy drug therapies for treatment of CNS maladies
The continuous tight junctions that join the endothelial cells in the brain capillaries limit the diffusion of molecules across the BBB
No paracellular transport only ABC transporters through endothelium

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6
Q

Elimination - Primary sites

A

lungs, kidneys, liver

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7
Q

What is the first pass effect and enterohepatic circulation?

A

First-pass effect is a specialized example of presystemic elimination, enterohepatic is the movement of bile acid molecules from the liver to the small intestine and back to the liver.

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8
Q

Compare perfusion vs ventilation limited elimination in lungs

A

Once a gas is dissolved in the liquid phase of the lungs, it can move by diffusion down its concentration gradient. However, it must be soluble in the liquid phase first. This is why solubility is rate limiting.The more soluble the gas in the liquid the higher concentration of gas there is in the lungs are ventilation limited Less soluble needs high perfusion rate (blood flow) for the gas to continue to be absorbed

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9
Q

What do toxicokinetics measure in ADME?

A

Elimination

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10
Q

Classical models - what is it, advantages, and limitations

A

Based on xenobiotic concentration in blood plasma; Knowledge about anatomic structures/physiological process of tissues is not required; Simple but not cannot predict tissue concentration of xenobiotics

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11
Q

Physiological models - what is it, advantages, and limitations

A

Primary advantages over classical models, Allows interspecies extrapolation (i.e., lab animal to human), Allows kinetic analysis to any organ/tissue of the body

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12
Q

Classical models - One and Two compartment model

A

One compartment model: considers body as a one homogeneous central comprant and only one disproportionate phase - saturation (box becomes box) (under each box arrow pointing down)

Two compartment model: two disposition phases (box –> <– box)

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13
Q

Classical models - Compare 1st order and 0 order elimination and

A

First order is straight line - constant
Zero order is concave - elimination processes are saturated

Kel is 1st order elimination rate constant determined by slope
Kel and T1/2 are inversely related
T1/2 is time for plasma to decrease by 50% - the half life

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14
Q

volume of distribution

A

(Vd) relates the total amount of a xenobiotic in the body to its plasma concentration - from the models

  • Used to quantify distribution of a xenobiotic throughout the body
  • Reflects disruption out of plasma into extravascular tissue
  • It is a proportionality constant for a given xenobiotic (it is unique to each toxicant)
  • Vd is a constant only when elimination is NOT saturated
  • Xenobiotic concentration in plasma is inversely related to its Vd
  • It is the ratio of the total intravenous dose administered and initial plasma concentration
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15
Q

Describe what Total Body Burden, Clearance, Bioavailability are and the information that they provide

A

Cl is the rate of xenobiotic elimination from the body relative to its plasma concentration (plasma clearance rate)

Bioavailability (F): The fraction of dose absorbed into plasma
Bioavailability is critically important in determining toxicity

Total body burden is the amount of xenobiotic remaining in the body at any given time

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16
Q

Physiological model - What are four key parameters?

A

Anatomical: compartment/sub-compartment size (volume)

Physiological: cardiac output, blood flow, respiration rate

Xenobiotic: concentration into (Cin) and out of (Cout) compartments, elimination rate (influenced by KD, LogP, pKa, etc.)

Membrane transport mechanism

17
Q

Physiological model - describe the basic unit and flux factors

A

Basic unit: lumped compartment representing specific region of the body (e.g., organ system);

Each basic unit consists of three sub-compartments that the xenobiotic moves (fluxes) between

Three well-mixed sub-compartments if each organ: Vascular space, Interstitial space, Intracellular space

18
Q

Physiological model - What is the influence of lipophilicity on transport into cells: perfusion vs diffusion limited

A

Highly lipophilic xenobiotics don’t have flux factors because they can penetrate membranes by simple diffusion

Perfusion limited Physiologic- how fast can get into by blood flow rate
- Flux into intracellular space driven by simple diffusion
- Notice no flux factor in this case

Diffusion limited limited Physiologic - Rate of flux across cell membranes < rate of tissue perfusion
- Flux into intracellular space is driven by facilitated diffusion; needs SCL carriers

19
Q

Oxidation

A

remove electron from substrate goes to NADH, a charge with election NADPH (alcohol and aldehyde dehydrogenases) - have reduction reaction going along with it - NADH is in oxygenation form GOES TO A NAD+

ADH and ALDH transfer 1 electron from the substrate to NAD+

Cofactors: NAD+/NADH AND NADP+/NADPH

20
Q

Monooxygenation

A

1 atom molecular attaches to substrate and other atom goes to make water this is p450 it just splits

P450 needs electron step activation of oxygenation and other step of oxidation of the electron from a substrate that takes it from NADPH which gives off two NADH but only one electron donated from SIP.
P450 reductase pick up electrons required for SIP
This is indirectly because NADH does not interact with SIP
P450 splits oxygenation
Step 1 activation of oxygen
Step 2 oxidation of substrate
Accepts electron from NADPH then use that electron to active molecular oxygenation once oxygenation is activated then step 2 use it to split atom so one oxygen goes to water and other oxygen to substrate

21
Q

What are three possible effects of biometabolism of xenobiotics

A

Activation of a xenobiotic
Inactivation of a xenobiotic
Elimination of a xenobiotics

22
Q

Biometabolism - Role in elimination

A

Conversion of a xenobiotic to a form that favors elimination (e.g., lipophilic to hydrophilic)

23
Q

Biometabolism Phase 1

A

Oxidation, reduction, oxygenation or hydrolysis reactions , Exposes/introduces functional groups on xenobiotics (e.g., R-OH; R-C=O; R-COOH; R-NH2; R-SH),
May affect hydrophilicity of xenobiotics
May facilitate conjugation in phase II

24
Q

Biometabolism Phase 2

A

Phase 2: Conjugation reactions, Covalent addition of various types of chemical groups,
May also affect hydrophilicity of xenobiotics
May facilitate elimination of xenobiotics

25
Q

Phase 1 oxidation of xenobiotics -
CYP monooxygenation reaction

What are four requirements for the CYP reaction and their function in the reaction cycle?

A

Molecular oxygen (O2)
Heme Fe (Iron)
Cytochrome P450 reductase
Cytochrome b5

26
Q

Phase 1 oxidation of xenobiotics -
CYP monooxygenation reaction

What do step 1 and step 2 do in the reaction cycle?

A

Step 1 activation of oxygen
Step 2 oxidation of substrate

27
Q

Phase 1 oxidation of xenobiotics -
CYP monooxygenation reaction

What are the functions of electrons in step 1 and type 2?

A

Accepts electron from NADPH then use that electron to active molecular oxygenation once oxygenation is activated then step 2 use it to split atom so one oxygen goes to water and other oxygen to substrate

28
Q

Phase 1 oxidation of xenobiotics -
CYP monooxygenation reaction

What is the role of iron in step 1?

A

iron is important for electron utilization by the P450 CYP

29
Q

Phase 2 conjugation reactions
What Increase hydrophilicity and what decrease hydrophilicity?

A

Increase:
Glucuronidation highly charged polar
Sulfonation (sulfation) highly charged polar
Covalently bond to substrate for both

Decrease: No change or decrease hydrophilicity - can make xenobiotic liquify - no water soluble
N-Acetylation
Methylation

30
Q

Functional groups on substrate in the N acetylation

A

Amine functional groups: R-NH2 1N - NAT AND O NOT LIQUID

Hydrazine functional groups: R-NH-NH2 2N

Requires Acetyl-coenzyme A (acetyl-CoA) as a co-substrate

Required enzyme: there are two N-acetlytransferases (NATs) - NAT-1 and NAT-2

Hydrogen can be a potential substrate

31
Q

Functional groups on substrate in the methylation reactions

A

Catechol O-methyltransferase (COMT) - 2 HO - does not add hydrophilicity

Phenol O-methyltransferase (POMT) - 1 OH

Requires S-adenosylmethionine (SAM) as a co-substrate

Required enzyme: O- (OH), N- (NH2), S- (SH) methyltransferases

32
Q

What are the xenosensors and what do they do?

A

Xenosensors are xenobiotic receptor proteins that elicit changes in response to xenobiotic exposure

Xenosensors alter transcription of mRNA from genes

Target genes of xenosensors are involved in biotransformation and elimination processes

33
Q

Two partner proteins

A

Retention partners: Proteins that bind to xenosensors and block transcription by prevent them from binding to DNA

Activation partners: Proteins that bind to xenosensors and assists their transport and/or binding to DNA

Not all xenosensors require a retention partner, Some only require ligand binding to activate transport

34
Q

Distinguish between auto vs gratuitous induction

A

Auto induction pathway: biotransformation of a ligand xenobiotic

Gratuitous induction pathway: biotransformation of a second nonligand xenobiotic

35
Q

Polymorphisms - What are they?

A

Allelic differences in genes that can be passed between generations (e.g., from parents to offspring)

They are often changes in the DNA sequence of a gene

They can be single nucleotide switches (SNPs)

They can be additions or deletions of larger DNA sequences

They can change amino acid sequence of proteins

They can produce phenotypic variation between individuals in response to xenobiotics

They may affect drug safety by changing the potency or efficacy of a drug

36
Q

Polymorphisms - How were they thought to evolve?

A

Positive selection pressure on variant alleles of biotransformation enzymes within certain human populations; Adaptation to environmental variables; Different human populations may be exposed to different xenobiotics in their respective environments

3rd Year (18 decks)

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